# Interleukin 23 receptor: Expression and regulation in immune cells

Ikram Mezghiche, Hanane Yahia-Cherbal, Lars Rogge, Elisabetta Bianchi

► To cite this version:

Ikram Mezghiche, Hanane Yahia-Cherbal, Lars Rogge, Elisabetta Bianchi. Interleukin 23 receptor: Expression and regulation in immune cells. European Journal of Immunology, 2023, 54 (1), pp.e2250348. 10.1002/eji.202250348. hal-04551629

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# Interleukin 23 receptor: Expression and regulation in immune cells

Ikram Mezghiche, Hanane Yahia-Cherbal, Lars Rogge, Elisabetta Bianchi

► To cite this version:

Ikram Mezghiche, Hanane Yahia-Cherbal, Lars Rogge, Elisabetta Bianchi. Interleukin 23 receptor: Expression and regulation in immune cells. European Journal of Immunology, 2023, 54 (1), pp.e2250348. 10.1002/eji.202250348. hal-04551629

HAL Id: hal-04551629

https://hal.science/hal-04551629v1

Submitted on 18 Apr 2024

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
REVIEW

# Interleukin 23 receptor: Expression and regulation in immune cells

Ikram Mezghiche ID, Hanane Yahia-Cherbal, Lars Rogge and Elisabetta Bianchi

Institut Pasteur, Université Paris Cité, Paris, France

The importance of IL-23 and its specific receptor, IL-23R, in the pathogenesis of several chronic inflammatory diseases has been established, but the underlying pathological mechanisms are not fully understood. This review focuses on IL-23R expression and regulation in immune cells.

**Keywords:** Chronic inflammatory diseases • Gene regulation • Interleukin-23 (IL-23) • Interleukin-23 receptor (IL-23R) • Transcription factors

## Introduction

IL-23 was identified in 2000 based on the homology of its IL-23p19 subunit to IL-12p35 [1]. Early data indicated that IL-23 enhanced IFN-γ production by memory CD4+ T cells; however, it was later shown that IL-23 also induced IL-17 production by these cells [2]. The observation that IL-23p19 knock-out mice but not IL-12p40 knock-out mice were protected from brain autoimmune inflammation, in the EAE model [3], provided the first evidence that IL-23 was a key player in inflammatory diseases. Genome-wide association studies subsequently demonstrated an important role of the IL-23 signaling pathway in the pathogenesis of several chronic inflammatory diseases, including Crohn's disease [4], axial spondyloarthritis [5], and psoriasis (Pso) [6]. IL-23 therefore appeared to be an excellent pharmacological target for inflammatory diseases, a notion that has been validated in the clinics by the successful treatment of Pso, psoriatic arthritis, and Crohn's disease with IL-23 blockers [7, 8]. IL-23 signals via a heterodimeric receptor (in this review: IL-23R) composed of a specific subunit, IL23R, and the IL12Rβ1 subunit, which is shared with the IL-12 receptor [9]. IL-23 signaling has been studied in particular in the context of Th17 cell differentiation and function, but more recent data have demonstrated high frequencies of IL-23R-positive “innate-like” T-cell populations, in particular, mucosal-associated invariant T cells and γδ T cells [10]. Very recent data have demon-

strated the important role of IL-23 signaling in infectious conditions. Patients with autosomal recessive IL-23R deficiency display Mendelian susceptibility to mycobacterial disease due to impaired IFN-γ production and, less frequently, to chronic mucocutaneous candidiasis due to impaired IL-17A/F production [11]. Here, we focus on two questions: what are the immune cells that express the IL23R and how is IL23R expression acquired.

## The IL-23R: Structure and signaling

IL-23 is a heterodimeric cytokine formed by two disulfide-bound subunits: p19 (encoded by *IL23A*) and p40 (encoded by *IL12B*) [1]. The latter subunit is shared with another inflammatory cytokine, IL-12 [12, 13]. IL-23 and IL-12 receptors also share a common chain: IL-12Rβ1 pairs with the IL23R chain to form the IL-23 receptor complex (IL-23R) that confers responsiveness to IL-23, or with IL-12Rβ2 to form the IL-12 receptor complex [14]. Only human IL-23 exhibits affinity for the human IL-23R [9] and the interaction of both p40 with IL-12Rβ1 and p19 is required for competent signaling of IL-23R [15, 16]. Recently, the crystal structure of the human IL-23R has been solved. Bloch et al proposed a sequential assembly mechanism of the receptor complex in which the IL23R chain first binds to IL-23p19 subunit exclusively via its N-terminal domain. This induces a conformational change of the IL-23 heterodimer that enables the p40 subunit to bind to IL-12Rβ1 with high affinity and to recruit the complex [17]. IL-12Rβ1 and IL23R lack intrinsic kinase activity

<footnote>Correspondence: Dr. Ikram Mezghiche
e-mail: ikram.mezghiche@pasteur.fr</footnote>
REVIEW

# Interleukin 23 receptor: Expression and regulation in immune cells

Ikram Mezghiche ID, Hanane Yahia-Cherbal, Lars Rogge and Elisabetta Bianchi

Institut Pasteur, Université Paris Cité, Paris, France

The importance of IL-23 and its specific receptor, IL-23R, in the pathogenesis of several chronic inflammatory diseases has been established, but the underlying pathological mechanisms are not fully understood. This review focuses on IL-23R expression and regulation in immune cells.

**Keywords:** Chronic inflammatory diseases • Gene regulation • Interleukin-23 (IL-23) • Interleukin-23 receptor (IL-23R) • Transcription factors

## Introduction

IL-23 was identified in 2000 based on the homology of its IL-23p19 subunit to IL-12p35 [1]. Early data indicated that IL-23 enhanced IFN-γ production by memory CD4+ T cells; however, it was later shown that IL-23 also induced IL-17 production by these cells [2]. The observation that IL-23p19 knock-out mice but not IL-12p40 knock-out mice were protected from brain autoimmune inflammation, in the EAE model [3], provided the first evidence that IL-23 was a key player in inflammatory diseases. Genome-wide association studies subsequently demonstrated an important role of the IL-23 signaling pathway in the pathogenesis of several chronic inflammatory diseases, including Crohn's disease [4], axial spondyloarthritis [5], and psoriasis (Pso) [6]. IL-23 therefore appeared to be an excellent pharmacological target for inflammatory diseases, a notion that has been validated in the clinics by the successful treatment of Pso, psoriatic arthritis, and Crohn's disease with IL-23 blockers [7, 8]. IL-23 signals via a heterodimeric receptor (in this review: IL-23R) composed of a specific subunit, IL23R, and the IL12Rβ1 subunit, which is shared with the IL-12 receptor [9]. IL-23 signaling has been studied in particular in the context of Th17 cell differentiation and function, but more recent data have demonstrated high frequencies of IL-23R-positive “innate-like” T-cell populations, in particular, mucosal-associated invariant T cells and γδ T cells [10]. Very recent data have demon-

strated the important role of IL-23 signaling in infectious conditions. Patients with autosomal recessive IL-23R deficiency display Mendelian susceptibility to mycobacterial disease due to impaired IFN-γ production and, less frequently, to chronic mucocutaneous candidiasis due to impaired IL-17A/F production [11]. Here, we focus on two questions: what are the immune cells that express the IL23R and how is IL23R expression acquired.

## The IL-23R: Structure and signaling

IL-23 is a heterodimeric cytokine formed by two disulfide-bound subunits: p19 (encoded by *IL23A*) and p40 (encoded by *IL12B*) [1]. The latter subunit is shared with another inflammatory cytokine, IL-12 [12, 13]. IL-23 and IL-12 receptors also share a common chain: IL-12Rβ1 pairs with the IL23R chain to form the IL-23 receptor complex (IL-23R) that confers responsiveness to IL-23, or with IL-12Rβ2 to form the IL-12 receptor complex [14]. Only human IL-23 exhibits affinity for the human IL-23R [9] and the interaction of both p40 with IL-12Rβ1 and p19 is required for competent signaling of IL-23R [15, 16]. Recently, the crystal structure of the human IL-23R has been solved. Bloch et al proposed a sequential assembly mechanism of the receptor complex in which the IL23R chain first binds to IL-23p19 subunit exclusively via its N-terminal domain. This induces a conformational change of the IL-23 heterodimer that enables the p40 subunit to bind to IL-12Rβ1 with high affinity and to recruit the complex [17]. IL-12Rβ1 and IL23R lack intrinsic kinase activity

<footnote>Correspondence: Dr. Ikram Mezghiche
e-mail: ikram.mezghiche@pasteur.fr</footnote>
1.a

<figure><img src="image_2.png" /></figure>

1.b

<figure><img src="image_3.png" /><figcaption>**Figure 1.** IL-23R structure and expression on immune cell subsets. (a) Schematic representation of the IL-23 receptor complex and the IL-12 receptor complex. Abbreviations: Ig-like domain, immunoglobulin-like domain; CHR, cytokine-binding homology region; FnIII, Fibronectin III. (b) Expression of IL-23R in the main immune cell populations. Most studies have focused on T-cell populations. Created with BioRender.com</figcaption></figure>

and signal through the recruitment of JAK tyrosine kinases. IL-12Rβ1 recruits TYK2, whereas IL23R interacts with JAK2 and the latter association is indispensable for IL-23 signaling [18, 19] (Fig. 1). The activation of Tyk2 and Jak2 by IL-23R promotes mainly STAT3, but also STAT1, STAT4 and STAT5 phosphorylation [9]. In contrast, IL-12Rβ2-mediated signaling promotes predominantly STAT4 phosphorylation [20], but can also induce STAT1 and STAT5 phosphorylation [21]. IL-23 receptor complex signaling has been extensively reviewed in [16].

## The IL23R locus

In humans, the *IL23R* gene is located on chromosome 1 and is directly adjacent to the *IL12RB2* gene. IL-12 stimulation was shown to induce *IL23R* expression [22], raising interesting questions about the coordinated versus exclusive regulation of these two genes in differentiating T-helper cells. Several *IL23R* isoforms may be produced by alternative splicing, resulting in premature termination and frameshifts that can generate receptors lacking the signaling components, or isolated ectodomains with the potential to act as decoy receptors [23–25]. The functional significance of these isoforms is unclear, although several have been detected in human NK and T cells, and some are preferentially expressed in lung carcinoma cells [23].

## Functional effect of coding genetic variants

A large number of genetic variants have been described at the *IL23R* locus (see [26] for an extensive review). The single nucleotide polymorphism rs11209026 is the best characterized functionally. This single nucleotide polymorphism has been associated with protection against the development of several CIDs, including CD, axSpA, Pso, and psoriatic arthritis [4, 27–32]. The

minor allele G to A variant introduces an amino acid change (Arg381Gln) in the intracellular domain of the IL-23R, in the proximity of the JAK2 kinase binding site. Human T cells carrying the minor allele show reduced IL-23-dependent STAT3 phosphorylation and IL-17 production, and subjects carrying this variant have decreased frequencies of circulating Th17 or IL-23R⁺ T cells [33–35]. Coffre et al. found that CD4⁺ T cells from SpA patients carrying the minor allele express lower levels of genes associated with both Th1 and Th17 differentiation and function, including *IL17*, *RORC*, *IFNG*, *IL12RB2*, and *IL23R* itself, supporting the protective role of this genetic variant [36].

Reduced STAT3 activation was also observed with two other protective coding variants (G149R, V362I) when expressed in Hela cells. In this case, reduced functionality of the variants could also be linked to reduced IL23R protein maturation and stability [37].

## Immune cell subsets expressing the IL-23R

To fully understand the role of IL-23 in protective immunity and in disease, it is important to identify the cells that are responsive to this cytokine. Many of these studies have been performed in mouse models. IL-23R was identified in 2002 [9] and has been mostly studied in the context of Th17 cells [2]. However, the important role of IL-23 in complex CID may suggest a broader role of this cytokine and more recently the attention has shifted to other immune cells, including innate-like T lymphocytes.

### IL-23R in conventional T cells

Parham et al. [9] in 2002 described the presence of *IL23R* transcripts in T helper 1 cell clones. IL-23 became a focus of attention when it was shown to promote a distinct subset of murine
<figure><img src="image_2.png" /><figcaption>**Figure 1.** IL-23R structure and expression on immune cell subsets. (a) Schematic representation of the IL-23 receptor complex and the IL-12 receptor complex. Abbreviations: Ig-like domain, immunoglobulin-like domain; CHR, cytokine-binding homology region; FnIII, Fibronectin III. (b) Expression of IL-23R in the main immune cell populations. Most studies have focused on T-cell populations. Created with BioRender.com</figcaption></figure>

and signal through the recruitment of JAK tyrosine kinases. IL-12Rβ1 recruits TYK2, whereas IL23R interacts with JAK2 and the latter association is indispensable for IL-23 signaling [18, 19] (Fig. 1). The activation of Tyk2 and Jak2 by IL-23R promotes mainly STAT3, but also STAT1, STAT4 and STAT5 phosphorylation [9]. In contrast, IL-12Rβ2-mediated signaling promotes predominantly STAT4 phosphorylation [20], but can also induce STAT1 and STAT5 phosphorylation [21]. IL-23 receptor complex signaling has been extensively reviewed in [16].

## The IL23R locus

In humans, the *IL23R* gene is located on chromosome 1 and is directly adjacent to the *IL12RB2* gene. IL-12 stimulation was shown to induce *IL23R* expression [22], raising interesting questions about the coordinated versus exclusive regulation of these two genes in differentiating T-helper cells. Several *IL23R* isoforms may be produced by alternative splicing, resulting in premature termination and frameshifts that can generate receptors lacking the signaling components, or isolated ectodomains with the potential to act as decoy receptors [23–25]. The functional significance of these isoforms is unclear, although several have been detected in human NK and T cells, and some are preferentially expressed in lung carcinoma cells [23].

## Functional effect of coding genetic variants

A large number of genetic variants have been described at the *IL23R* locus (see [26] for an extensive review). The single nucleotide polymorphism rs11209026 is the best characterized functionally. This single nucleotide polymorphism has been associated with protection against the development of several CIDs, including CD, axSpA, Pso, and psoriatic arthritis [4, 27–32]. The

minor allele G to A variant introduces an amino acid change (Arg381Gln) in the intracellular domain of the IL-23R, in the proximity of the JAK2 kinase binding site. Human T cells carrying the minor allele show reduced IL-23-dependent STAT3 phosphorylation and IL-17 production, and subjects carrying this variant have decreased frequencies of circulating Th17 or IL-23R⁺ T cells [33–35]. Coffre et al. found that CD4⁺ T cells from SpA patients carrying the minor allele express lower levels of genes associated with both Th1 and Th17 differentiation and function, including *IL17*, *RORC*, *IFNG*, *IL12RB2*, and *IL23R* itself, supporting the protective role of this genetic variant [36].

Reduced STAT3 activation was also observed with two other protective coding variants (G149R, V362I) when expressed in Hela cells. In this case, reduced functionality of the variants could also be linked to reduced IL23R protein maturation and stability [37].

## Immune cell subsets expressing the IL-23R

To fully understand the role of IL-23 in protective immunity and in disease, it is important to identify the cells that are responsive to this cytokine. Many of these studies have been performed in mouse models. IL-23R was identified in 2002 [9] and has been mostly studied in the context of Th17 cells [2]. However, the important role of IL-23 in complex CID may suggest a broader role of this cytokine and more recently the attention has shifted to other immune cells, including innate-like T lymphocytes.

### IL-23R in conventional T cells

Parham et al. [9] in 2002 described the presence of *IL23R* transcripts in T helper 1 cell clones. IL-23 became a focus of attention when it was shown to promote a distinct subset of murine
T-helper cells producing IL-17 [2]. IL-23 supports the expansion and survival of established murine Th17 cells [38] and Th17 clones express higher levels of IL-23R transcripts and IL-12Rβ1 than Th1 cells [39]. IL-23 can upregulate its own receptor in TCR-stimulated human CD4⁺ T cells and increase IL-22 secretion but is not required for IL-17A production from stimulated memory CD4⁺ T cells [40].

Although murine double-positive thymocytes express constitutively *Il23r*, conventional T cells in the periphery show IL-23R expression only upon activation [41, 42].

IL-6 plays a major role in *Il23r* induction in mouse CD4⁺ T cells [43]. In particular, IL-6 and TGF-β3 induce development of highly pathogenic Th17 cells, with increased expression of *Il23r* and *Il22* [44]. IL-23 signaling in murine CD4⁺ T cells induces Blimp-1, which enhances transcription of pathogenic factors [45]. IL-23R expression is important for disease development in several mouse models, including autoimmune encephalitis [46] and adjuvant-induced arthritis [47].

In vitro, differentiation of naïve CD4⁺ T cells with IL-12 and IL-21 also induces high levels of IL-23R, which confers pathogenicity to Th1-like cells during intestinal inflammation [48]. IL-23 also expanded IL-17-producing tissue-resident memory CD4⁺ T cells (TRM17) in the skin of mice infected with *C. albicans*. IL-23 blockade in mice and in psoriasis patients leads to depletion of skin TRM17 cells [49].

T-follicular helper cells (Tfh) isolated from an EAE mouse model also expressed IL-23R and IL-17 after restimulation in vitro [38]. IL-23 signaling induced a Tfh-IL-17 phenotype and promoted AID-mediated class-switch recombination [50].

A subset of regulatory T cells that expresses the transcription factor RORγt may also be responsive to IL-23 [51], although IL-23 signaling in this population may have different outcomes in different experimental settings, suggesting the need for further investigation. Murine intestinal Treg express higher levels of *Il23r* than Treg in other tissues [52], and expression of RORγt and IL-23R depends on the microbiota strain [53, 54]. In a colitis model, IL-23R signaling decreases Treg frequency in the gut and impairs their suppressive functions [52, 55], possibly because of reduced expression of Foxp3 [56]. However, Yang et al. [51] described the enhanced suppressive activity of the Foxp3⁺RORγt⁺ T-cell population in a colitis model, a difference that may depend on the different donor strains used for the transfer. IL-23 signaling also had a positive effect on Treg expansion in skin disease models, where IL-23 induced accumulation of Treg cells that express RORγt and IL-17, and treatment with anti-IL-23p19 reduced the number of skin Th17-like-Tregs [57].

CD4⁺ FOXP3⁺ T cells expressing *IL23R* along with *RORC* and *IL17F* were also detected in a Th17-like T-regulatory cell cluster in humans by single-cell RNA profiling [58].

IL-23 may also affect the function of type 1 regulatory T cells in inflammatory bowel disease patients, decreasing their IL-10 production [59].

Similar to CD4⁺ T cells, IL-23R expression can be induced in murine naïve CD8⁺ T cells by IL-6 and TGF-β [60]. In mice, CD8⁺ T cells constitute about 10% of eGFP-IL23R⁺ cells in the spleen

[61], and IL-23 supports the production of IFNγ/IL-17 in CD8⁺ T cells [60].

Human memory CD161⁺ CD8⁺ T cells also respond to IL-23 [62]. *IL23R⁺* IL-17A⁺ CD8⁺ αβ T cells are enriched in synovial fluid from psoriatic arthritis patients, suggesting that these cells may support chronic inflammation [63]. Similarly to what was observed for Th1 cells, enrichment of T-bet⁺*IL-23R⁺* CD8⁺ T cells was observed in the intestine and blood of Graft-versus-Host Disease patients [64].

## IL-23R in innate-like T cells

Mucosal-associated invariant T cells (MAIT) constitutively express the IL-23R in both mice and humans, where it can be already detected in cord blood MAIT cells [65]. Up to 85% of lung MAIT cells expressed IL-23R in naïve reporter mice [66]. *Il23r* expression is further increased by TCR stimulation and addition of cytokines, such as IL-12, IL-18, and IL-15 [67]. In mouse models, the expression of either T-bet or RORγt distinguishes MAIT1 from MAIT17 cells, the latter preferentially expressing *Il23r* [68]. IL-23 signaling can also expand a MAIT-17/1 phenotype [66]. These distinct subsets cannot be identified in humans, where *IL23R* constitutes a “core” gene for all MAIT cells [69–71]. The expression of *IL23R* is higher in human tissue-resident (mucosal, lung, skin, liver and entheses) MAIT cells [10, 66], [72–74]. The enrichment of IL-23R expressing MAIT cells in synovial fluid from psoriatic arthritis and rheumatoid arthritis patients [75] and in peripheral blood of spondyloarthritis patients [10] suggests a role for IL-23R⁺ MAIT cells in the pathogenesis of CID.

It has been shown that both murine and human γδ T cells constitutively express IL-23R [76, 77]. The expression of *Il23r* in murine γδ T cells has been extensively studied. γδ T cells constitute the major IL-23R-expressing subset in lymphoid organs of naïve mice [61, 78] and produce IL-17 in response to IL-23 stimulation [76, 79, 80]. Spleen γδ T cells from naïve mice show low expression of *Il23r* mRNA and protein, but express IL-23R after antigen stimulation in vivo and have immunosuppressive activity on Th17 cells [81]. Murine IL-23R⁺/IL-1R⁺γδ T cells were found to display a focused TCR repertoire, supporting a role for antigen recognition in the expansion of this subset [53]. In the mouse, IL-23 responsive γδ T cells belong mainly to the Vγ4⁺ and Vγ6⁺ subsets [82] and may play a role in protection against infections [79, 83].

In humans, IL-23R may be preferentially expressed on Vγ9Vδ2 cells that also express high levels of IFNγ and cytotoxic molecules [77]. Human IL23R⁺ γδ T cells may also play a role in inflammatory disease. Entheseal IL23R⁺ γδ T cells express high levels of *IL23R* transcripts [84], and IL-23R⁺ cells are enriched in the joints of spondylarthritis patients [85]. IL-23R⁺ γδ T cells were also increased in children with primary nephrotic syndrome [86]. Like their murine counterpart, human γδ T cells were shown to produce IL-17 and IL-22 in response to IL-23 stimulation [85].
T-helper cells producing IL-17 [2]. IL-23 supports the expansion and survival of established murine Th17 cells [38] and Th17 clones express higher levels of IL-23R transcripts and IL-12Rβ1 than Th1 cells [39]. IL-23 can upregulate its own receptor in TCR-stimulated human CD4+ T cells and increase IL-22 secretion but is not required for IL-17A production from stimulated memory CD4+ T cells [40].

Although murine double-positive thymocytes express constitutively *Il23r*, conventional T cells in the periphery show IL-23R expression only upon activation [41, 42].

IL-6 plays a major role in *Il23r* induction in mouse CD4+ T cells [43]. In particular, IL-6 and TGF-β3 induce development of highly pathogenic Th17 cells, with increased expression of *Il23r* and *Il22* [44]. IL-23 signaling in murine CD4+ T cells induces Blimp-1, which enhances transcription of pathogenic factors [45]. IL-23R expression is important for disease development in several mouse models, including autoimmune encephalitis [46] and adjuvant-induced arthritis [47].

In vitro, differentiation of naïve CD4+ T cells with IL-12 and IL-21 also induces high levels of IL-23R, which confers pathogenicity to Th1-like cells during intestinal inflammation [48]. IL-23 also expanded IL-17-producing tissue-resident memory CD4+ T cells (TRM17) in the skin of mice infected with *C. albicans*. IL-23 blockade in mice and in psoriasis patients leads to depletion of skin TRM17 cells [49].

T-follicular helper cells (Tfh) isolated from an EAE mouse model also expressed IL-23R and IL-17 after restimulation in vitro [38]. IL-23 signaling induced a Tfh-IL-17 phenotype and promoted AID-mediated class-switch recombination [50].

A subset of regulatory T cells that expresses the transcription factor RORγt may also be responsive to IL-23 [51], although IL-23 signaling in this population may have different outcomes in different experimental settings, suggesting the need for further investigation. Murine intestinal Treg express higher levels of *Il23r* than Treg in other tissues [52], and expression of RORγt and IL-23R depends on the microbiota strain [53, 54]. In a colitis model, IL-23R signaling decreases Treg frequency in the gut and impairs their suppressive functions [52, 55], possibly because of reduced expression of Foxp3 [56]. However, Yang et al. [51] described the enhanced suppressive activity of the Foxp3+RORγt+ T-cell population in a colitis model, a difference that may depend on the different donor strains used for the transfer. IL-23 signaling also had a positive effect on Treg expansion in skin disease models, where IL-23 induced accumulation of Treg cells that express RORγt and IL-17, and treatment with anti-IL-23p19 reduced the number of skin Th17-like-Tregs [57].

CD4+ FOXP3+ T cells expressing *IL23R* along with *RORC* and *IL17F* were also detected in a Th17-like T-regulatory cell cluster in humans by single-cell RNA profiling [58].

IL-23 may also affect the function of type 1 regulatory T cells in inflammatory bowel disease patients, decreasing their IL-10 production [59].

Similar to CD4+ T cells, IL-23R expression can be induced in murine naïve CD8+ T cells by IL-6 and TGF-β [60]. In mice, CD8+ T cells constitute about 10% of eGFP-IL23R+ cells in the spleen

[61], and IL-23 supports the production of IFNγ/IL-17 in CD8+ T cells [60].

Human memory CD161+ CD8+ T cells also respond to IL-23 [62]. *IL23R+*, IL-17A+ CD8+ αβ T cells are enriched in synovial fluid from psoriatic arthritis patients, suggesting that these cells may support chronic inflammation [63]. Similarly to what was observed for Th1 cells, enrichment of T-bet+IL-23R+ CD8+ T cells was observed in the intestine and blood of Graft-versus-Host Disease patients [64].

## IL-23R in innate-like T cells

Mucosal-associated invariant T cells (MAIT) constitutively express the IL-23R in both mice and humans, where it can be already detected in cord blood MAIT cells [65]. Up to 85% of lung MAIT cells expressed IL-23R in naïve reporter mice [66]. *Il23r* expression is further increased by TCR stimulation and addition of cytokines, such as IL-12, IL-18, and IL-15 [67]. In mouse models, the expression of either T-bet or RORγt distinguishes MAIT1 from MAIT17 cells, the latter preferentially expressing *Il23r* [68]. IL-23 signaling can also expand a MAIT-17/1 phenotype [66]. These distinct subsets cannot be identified in humans, where *IL23R* constitutes a “core” gene for all MAIT cells [69–71]. The expression of *IL23R* is higher in human tissue-resident (mucosal, lung, skin, liver and entheses) MAIT cells [10, 66], [72–74]. The enrichment of IL-23R expressing MAIT cells in synovial fluid from psoriatic arthritis and rheumatoid arthritis patients [75] and in peripheral blood of spondyloarthritis patients [10] suggests a role for IL-23R+ MAIT cells in the pathogenesis of CID.

It has been shown that both murine and human γδ T cells constitutively express IL-23R [76, 77]. The expression of *Il23r* in murine γδ T cells has been extensively studied. γδ T cells constitute the major IL-23R-expressing subset in lymphoid organs of naïve mice [61, 78] and produce IL-17 in response to IL-23 stimulation [76, 79, 80]. Spleen γδ T cells from naïve mice show low expression of *Il23r* mRNA and protein, but express IL-23R after antigen stimulation in vivo and have immunosuppressive activity on Th17 cells [81]. Murine IL-23R+/IL-1R+γδ T cells were found to display a focused TCR repertoire, supporting a role for antigen recognition in the expansion of this subset [53]. In the mouse, IL-23 responsive γδ T cells belong mainly to the Vγ4+ and Vγ6+ subsets [82] and may play a role in protection against infections [79, 83].

In humans, IL-23R may be preferentially expressed on Vγ9Vδ2 cells that also express high levels of IFNγ and cytotoxic molecules [77]. Human IL23R+ γδ T cells may also play a role in inflammatory disease. Entheseal IL23R+ γδ T cells express high levels of *IL23R* transcripts [84], and IL-23R+ cells are enriched in the joints of spondylarthritis patients [85]. IL-23R+ γδ T cells were also increased in children with primary nephrotic syndrome [86]. Like their murine counterpart, human γδ T cells were shown to produce IL-17 and IL-22 in response to IL-23 stimulation [85].
More recently, a T-cell population co-expressing γδ and αβ receptors were described in mice and humans. These cells expressed high levels of IL-23R and displayed a hyperinflammatory phenotype in response to IL-23 [87].

Murine and human NKT are other populations that express the IL-23R and can produce IL-17 (and IL-21) in response to IL-23 stimulation [62, 85, 88]. In humans, a small fraction of NKT cells express IL-23R in peripheral blood. However, IL-23R⁺ NKT cells are enriched in the synovial fluid of patients with spondylarthritis [85]. IL-23 synergizes with IL-18 to promote IFNγ production in human NKT cells and to stimulate the proliferation of NKT and NK cells [89].

### IL-23R in other innate lymphoid cells

Innate lymphoid cells (ILC) are mostly tissue-resident lymphoid cells that lack an antigen-specific receptor. ILCs were also found to express *Rorc* and *Il23r* and to be involved in the development of innate colitis [69, 90–92]. ILCs can be assigned to different subsets (ILC1, ILC2, and ILC3) that mirror the Th1, Th2, and Th17 subsets of conventional T cells. The IL-23R is mainly expressed in the ILC3 subset, both in mice [69, 70] and in humans [93, 94], although IL-23 enhanced the differentiation and growth of both human ILC1 and ILC3 [95].

ILC3 cells in synovial tissue of spondylarthritis patients express *RORC* and *IL23R* and respond to IL-23 by expressing *IL22* and *CSF2*, but not *IL17A* [93].

### IL-23R in NK cells

*IL23R* transcripts were first detected in human NK clones and cell lines by Parham et al. [9]. IL-23 treatment was shown to induce human NK activation and secretion of IFNγ [96].

### IL-23R in B cells

B cells constitute about 10% of eGFP-IL-23R⁺ cells in mouse spleen [61], but the role of IL-23 in this population has been poorly studied.

Primary B cells from healthy humans do not express IL-23R, which is upregulated in acute lymphoblastic leukemia B cells [97]. IL-23 signaling in acute lymphoblastic leukemia B-cells induced apoptosis and inhibited proliferation, exerting antileukemic activity [97]. Expression of the IL23R chain, in the absence of IL-12Rβ1, was also reported in chronic lymphocytic leukemia B cells, and correlated with tumor progression [98]. The role of IL-23 signaling in normal B-cell function is poorly investigated. Cell surface staining for IL-23R was also detected on plasma cells from healthy donors, which responded to IL-23 by increasing IgM secretion [99].

### IL-23R in myeloid cells

Very little is known about IL-23R expression and function in myeloid cells. Parham et al. [9] found that human monocytes and dendritic cells (DC) express negligible levels of *IL23R*, however murine bone-marrow-derived (but not peritoneal) macrophages stimulated with LPS and IL-10 expressed *Il23r* in the absence of detectable *Il12rb1*, which could be induced by IFNγ stimulation. Inflammatory macrophages isolated from brains of mice with EAE, but not from healthy mice, expressed *Il23r* [3], and in a house dust mite model of airway inflammation, IL-23R positive cells in the lung were mainly macrophages and CD11⁺ dendritic cells [100]. These data suggest that IL-23R in myeloid cells may be expressed only in particular conditions, consistent with the lack of expression by unstimulated human myeloid cells reported in databases [101, 102]. Surface expression of IL-23R was described for human monocyte-derived macrophages, which responded to IL-23 treatment with increased secretion of proinflammatory cytokines [103, 104]. Mycobacterial infection also increased the expression of IL-23R and IL-23 in human and murine macrophages [105].

Low levels of *IL23R* mRNA have been reported in human dendritic cells [9] and IL-23R levels were elevated in monocyte-derived DC from patients with HBV-related liver failure [106]. IL-23 was described to have adjuvant effects on DC priming ability [107]; however, IL-23 signaling in DCs has not been further investigated.

Similarly, activated granulocytes have been reported to express IL-23R in inflammatory murine models of colitis or aspergillosis [108, 109], but confirmation of the role of IL-23 in these cells is lacking.

A challenge for the characterization of IL-23R expression is the scarcity of reliable anti-IL23R antibodies and the fact that IL-23R is expressed only at low frequencies in most resting cells.

### Transcriptional regulation of IL-23R

The transcriptional mechanisms regulating IL-23R expression have been mainly addressed in the context of murine Th17 cell differentiation (Table 1, Fig. 2).

Transcription factors of the AP1 family play an important role in Th17 determination and in *Il23r* transcription. In particular, JunB binds cooperatively with BATF and IRF4 to an AP1-IRF composite motif [110, 111], which is also observed at the *Il23r* locus [112]. BATF binding may be determinant to start *IL23r* expression, as it was shown to occur also at sites of closed chromatin, and was proposed to act as a pioneer factor in inducing chromatin remodeling by recruiting the boundary transcription factor CTCF [113]. Further mechanistic studies will be required to precisely define the role of this pathway in inducing IL-23R expression.

Several of the Th17-inducing transcription factors may also affect *IL23r* transcription indirectly, for example by acting on the expression of *Roryt*, which also binds to the *Il23r* locus and regulates its activation [114, 115]. Other factors, such as T-bet,
More recently, a T-cell population co-expressing γδ and αβ receptors were described in mice and humans. These cells expressed high levels of IL-23R and displayed a hyperinflammatory phenotype in response to IL-23 [87].

Murine and human NKT are other populations that express the IL-23R and can produce IL-17 (and IL-21) in response to IL-23 stimulation [62, 85, 88]. In humans, a small fraction of NKT cells express IL-23R in peripheral blood. However, IL-23R⁺ NKT cells are enriched in the synovial fluid of patients with spondylarthritis [85]. IL-23 synergizes with IL-18 to promote IFNγ production in human NKT cells and to stimulate the proliferation of NKT and NK cells [89].

### IL-23R in other innate lymphoid cells

Innate lymphoid cells (ILC) are mostly tissue-resident lymphoid cells that lack an antigen-specific receptor. ILCs were also found to express *Rorc* and *Il23r* and to be involved in the development of innate colitis [69, 90–92]. ILCs can be assigned to different subsets (ILC1, ILC2, and ILC3) that mirror the Th1, Th2, and Th17 subsets of conventional T cells. The IL-23R is mainly expressed in the ILC3 subset, both in mice [69, 70] and in humans [93, 94], although IL-23 enhanced the differentiation and growth of both human ILC1 and ILC3 [95].

ILC3 cells in synovial tissue of spondylarthritis patients express *RORC* and *IL23R* and respond to IL-23 by expressing *IL22* and *CSF2*, but not *IL17A* [93].

### IL-23R in NK cells

*IL23R* transcripts were first detected in human NK clones and cell lines by Parham et al. [9]. IL-23 treatment was shown to induce human NK activation and secretion of IFNγ [96].

### IL-23R in B cells

B cells constitute about 10% of eGFP-IL-23R⁺ cells in mouse spleen [61], but the role of IL-23 in this population has been poorly studied.

Primary B cells from healthy humans do not express IL-23R, which is upregulated in acute lymphoblastic leukemia B cells [97]. IL-23 signaling in acute lymphoblastic leukemia B-cells induced apoptosis and inhibited proliferation, exerting antileukemic activity [97]. Expression of the IL23R chain, in the absence of IL-12Rβ1, was also reported in chronic lymphocytic leukemia B cells, and correlated with tumor progression [98]. The role of IL-23 signaling in normal B-cell function is poorly investigated. Cell surface staining for IL-23R was also detected on plasma cells from healthy donors, which responded to IL-23 by increasing IgM secretion [99].

### IL-23R in myeloid cells

Very little is known about IL-23R expression and function in myeloid cells. Parham et al. [9] found that human monocytes and dendritic cells (DC) express negligible levels of *IL23R*, however murine bone-marrow-derived (but not peritoneal) macrophages stimulated with LPS and IL-10 expressed *Il23r* in the absence of detectable *Il12rb1*, which could be induced by IFNγ stimulation. Inflammatory macrophages isolated from brains of mice with EAE, but not from healthy mice, expressed *Il23r* [3], and in a house dust mite model of airway inflammation, IL-23R positive cells in the lung were mainly macrophages and CD11⁺ dendritic cells [100]. These data suggest that IL-23R in myeloid cells may be expressed only in particular conditions, consistent with the lack of expression by unstimulated human myeloid cells reported in databases [101, 102]. Surface expression of IL-23R was described for human monocyte-derived macrophages, which responded to IL-23 treatment with increased secretion of proinflammatory cytokines [103, 104]. Mycobacterial infection also increased the expression of IL-23R and IL-23 in human and murine macrophages [105].

Low levels of *IL23R* mRNA have been reported in human dendritic cells [9] and IL-23R levels were elevated in monocyte-derived DC from patients with HBV-related liver failure [106]. IL-23 was described to have adjuvant effects on DC priming ability [107]; however, IL-23 signaling in DCs has not been further investigated.

Similarly, activated granulocytes have been reported to express IL-23R in inflammatory murine models of colitis or aspergillosis [108, 109], but confirmation of the role of IL-23 in these cells is lacking.

A challenge for the characterization of IL-23R expression is the scarcity of reliable anti-IL23R antibodies and the fact that IL-23R is expressed only at low frequencies in most resting cells.

### Transcriptional regulation of IL-23R

The transcriptional mechanisms regulating IL-23R expression have been mainly addressed in the context of murine Th17 cell differentiation (Table 1, Fig. 2).

Transcription factors of the AP1 family play an important role in Th17 determination and in *Il23r* transcription. In particular, JunB binds cooperatively with BATF and IRF4 to an AP1-IRF composite motif [110, 111], which is also observed at the *Il23r* locus [112]. BATF binding may be determinant to start *IL23r* expression, as it was shown to occur also at sites of closed chromatin, and was proposed to act as a pioneer factor in inducing chromatin remodeling by recruiting the boundary transcription factor CTCF [113]. Further mechanistic studies will be required to precisely define the role of this pathway in inducing IL-23R expression.

Several of the Th17-inducing transcription factors may also affect *IL23r* transcription indirectly, for example by acting on the expression of *Roryt*, which also binds to the *Il23r* locus and regulates its activation [114, 115]. Other factors, such as T-bet,
<table><caption>**Table 1.** Transcription factors that bind to the murine and human loci encoding IL-23R.</caption><thead><tr><th>Factor</th><th>Description</th><th>Technique</th><th>Reference</th></tr></thead><tbody><tr><td colspan="4" style="text-align:center; font-weight:bold;">Murine</td></tr><tr><td>Irf4</td><td>ChIP seq analysis on murine naïve CD4<sup>+</sup> cells differentiated under Th17 polarizing condition demonstrates binding of Irf4, Batf, and JunB to the AICEs motifs present in the promoter and intron 3 of the Il23r locus.</td><td>ChIP-seq<br>Knock-out<br>EMSA</td><td>[110]</td></tr><tr><td>Irf4<br>Batf<br>JunB</td><td>Binding of Batf, Irf4, and Junb at Il23r promoter, intron 3, 6, and 7 was detected by ChIP seq in Th17 differentiating cells.</td><td>ChIP-seq</td><td>[127]</td></tr><tr><td>Roryt</td><td>Roryt binds to the Il23r promoter and to introns 3 and 6 in Th17 cells. Foxp3 binding was observed in iTregs at intron 6 of Il23r.</td><td>ChIP-seq</td><td>[115]</td></tr><tr><td>Foxp3<br>p300<br>JunB</td><td>Binding of JunB and p300 to the promoter and the introns 3, 6, and 7 of the Il23r locus.</td><td>ChIP-seq</td><td>[128]</td></tr><tr><td>Blimp1<br>Stat3<br>p300<br>Roryt</td><td>ChIP seq was performed in IL-17.EGFP<sup>+</sup> cells differentiated in the presence of TGFb, IL-6, and IL-23. Blimp1 binds Il23r intron 3, together with Stat3, p300 and Rorgt. Stat3 binds at several regions in the Il23r locus.</td><td>ChIP-seq</td><td>[45]</td></tr><tr><td>Hif1α<br>Roryt<br>p300</td><td>HiF1alpha binds the Il23r promoter together with Rorgt and p300 in CD4<sup>+</sup> cells activated under the Th17 skewing condition.</td><td>ChIP-PCR</td><td>[129]</td></tr><tr><td>Rbpj</td><td>Naïve CD4<sup>+</sup> T cells were sorted from CD4<sup>+</sup>RBPJ<sup>flox/flox</sup> mice and differentiated under the Th17 polarizing condition. In Th17 cells, Rbpj binds the Il23r promoter, to a site (1100 bp upstream of the TSS) distinct from those bound by other factors indicated in this table.</td><td>ChIP-PCR</td><td>[130]</td></tr><tr><td>Batf<br>Ctcf<br>Ets1<br>Med12</td><td>Batf was shown to bind the Il23r locus (promoter and introns 2,3 and 6 in Th17 cells) and to pioneer the opening of the chromatin. Batf-induced binding of Ctcf, Ets1, and Med12 to the Il23r locus.</td><td>ChIP-seq<br>Knock-out</td><td>[113]</td></tr><tr><td>Rora<br>Roryt</td><td>ChIP-seq experiments revealed Rorgt binding at the Il23r promoter, intron 3 and 6, and Rora binding to the Il23r promoter and intron 3 in Th17 cells.</td><td>ChIP-seq<br>Knock-out</td><td>[114]</td></tr><tr><td>Tbet</td><td>Direct binding of T-bet to the Il23r promoter was shown in splenocytes from Va2.3/Vb8.2 TCR-transgenic mice activated with myelin basic protein peptide. The binding induces decrease in Il23r expression.</td><td>ChIP-PCR<br>Knock-down</td><td>[116]</td></tr><tr><td>Tbet</td><td>T-bet binding was also observed at Il23r third intron in a transfer model of colitis and negatively regulates its expression.</td><td></td><td>[117]</td></tr><tr><td>Tbet</td><td>T-bet binds to Il23r locus (introns 3 and 6) in murine Th1 cells.</td><td></td><td>[118]</td></tr><tr><td>Stat3</td><td>Stat3 binds to Il23r (intron 3) in CD4<sup>+</sup> T cells activated in the presence of IL-23 and IL-6.</td><td>ChIP-seq</td><td>[121]</td></tr><tr><td>Clock</td><td>Binding of Clock at the Il23r promoter in splenic γ/δ<sup>+</sup> T cells isolated from wild-type mice.</td><td>ChIP-PCR</td><td>[131]</td></tr><tr><td colspan="4" style="text-align:center; font-weight:bold;">Human</td></tr><tr><td>FOSL1/<br>FOSL2<br>BATF</td><td>Colocalization of FOSL1/FOSL2 and BATF binding at the IL23R promoter in Th17 cells induced from Naïve isolated Cord blood CD4 cells.</td><td>ChIP-seq</td><td>[120]</td></tr><tr><td>BRD4</td><td>BRD4 binds to the IL23R locus in CD4<sup>+</sup> T cells activated through the TCR. A selective BET inhibitor reduced Il-23r expression in vitro and in a graft-versus-host disease model.</td><td>ChIP-seq<br>Inhibitor<br>treatment</td><td>[132]</td></tr></tbody></table>

may display context-dependent effects on IL-23R expression: T-bet was shown to increase *Il23r* levels in an EAE model by direct binding to the *Il23r* promoter but to repress *Il23r* in Th17 cells in a colitis model [116, 117]. T-bet was reported to bind the

*Il23r* gene also in Th1 cells, without affecting IL23R expression [118].

FOSL proteins play a complex role in the regulation of Th17 differentiation and IL-23R expression. In the mouse, FOSL2
<table><caption>**Table 1.** Transcription factors that bind to the murine and human loci encoding IL-23R.</caption><thead><tr><th>Factor</th><th>Description</th><th>Technique</th><th>Reference</th></tr></thead><tbody><tr><td colspan="4" style="text-align: center; font-weight: bold;">Murine</td></tr><tr><td>Irf4</td><td>ChIP seq analysis on murine naïve CD4<sup>+</sup> cells differentiated under Th17 polarizing condition demonstrates binding of Irf4, Batf, and JunB to the AICEs motifs present in the promoter and intron 3 of the Il23r locus.</td><td>ChIP-seq<br>Knock-out<br>EMSA</td><td>[110]</td></tr><tr><td>Irf4<br>Batf<br>JunB</td><td>Binding of Batf, Irf4, and Junb at Il23r promoter, intron 3, 6, and 7 was detected by ChIP seq in Th17 differentiating cells.</td><td>ChIP-seq</td><td>[127]</td></tr><tr><td>Roryt</td><td>Roryt binds to the Il23r promoter and to introns 3 and 6 in Th17 cells. Foxp3 binding was observed in iTregs at intron 6 of Il23r.</td><td>ChIP-seq</td><td>[115]</td></tr><tr><td>Foxp3<br>p300<br>JunB</td><td>Binding of JunB and p300 to the promoter and the introns 3, 6, and 7 of the Il23r locus.</td><td>ChIP-seq</td><td>[128]</td></tr><tr><td>Blimp1<br>Stat3<br>p300<br>Roryt</td><td>ChIP seq was performed in IL-17.EGFP<sup>+</sup> cells differentiated in the presence of TGFb, IL-6, and IL-23. Blimp1 binds Il23r intron 3, together with Stat3, p300 and Rorgt. Stat3 binds at several regions in the Il23r locus.</td><td>ChIP-seq</td><td>[45]</td></tr><tr><td>Hif1α<br>Roryt<br>p300</td><td>HiF1alpha binds the Il23r promoter together with Rorgt and p300 in CD4<sup>+</sup> cells activated under the Th17 skewing condition.</td><td>ChIP-PCR</td><td>[129]</td></tr><tr><td>Rbpj</td><td>Naïve CD4<sup>+</sup> T cells were sorted from CD4<sup>+</sup>RBPJ<sup>flox/flox</sup> mice and differentiated under the Th17 polarizing condition. In Th17 cells, Rbpj binds the Il23r promoter, to a site (1100 bp upstream of the TSS) distinct from those bound by other factors indicated in this table.</td><td>ChIP-PCR</td><td>[130]</td></tr><tr><td>Batf</td><td>Batf was shown to bind the Il23r locus (promoter and introns 2,3 and 6 in Th17 cells) and to pioneer the opening of the chromatin. Batf-induced binding of Ctcf, Ets1, and Med12 to the Il23r locus.</td><td>ChIP-seq<br>Knock-out</td><td>[113]</td></tr><tr><td>Rora<br>Roryt</td><td>ChIP-seq experiments revealed Rorgt binding at the Il23r promoter, intron 3 and 6, and Rora binding to the Il23r promoter and intron 3 in Th17 cells.</td><td>ChIP-seq<br>Knock-out</td><td>[114]</td></tr><tr><td>Tbet</td><td>Direct binding of T-bet to the Il23r promoter was shown in splenocytes from Va2.3/Vb8.2 TCR-transgenic mice activated with myelin basic protein peptide. The binding induces decrease in Il23r expression.</td><td>ChIP-PCR<br>Knock-down</td><td>[116]</td></tr><tr><td>Tbet</td><td>T-bet binding was also observed at Il23r third intron in a transfer model of colitis and negatively regulates its expression.</td><td></td><td>[117]</td></tr><tr><td>Tbet</td><td>T-bet binds to Il23r locus (introns 3 and 6) in murine Th1 cells.</td><td></td><td>[118]</td></tr><tr><td>Stat3</td><td>Stat3 binds to Il23r (intron 3) in CD4<sup>+</sup> T cells activated in the presence of IL-23 and IL-6.</td><td>ChIP-seq</td><td>[121]</td></tr><tr><td>Clock</td><td>Binding of Clock at the Il23r promoter in splenic γ/δ<sup>+</sup> T cells isolated from wild-type mice.</td><td>ChIP-PCR</td><td>[131]</td></tr><tr><td colspan="4" style="text-align: center; font-weight: bold;">Human</td></tr><tr><td>FOSL1/<br>FOSL2<br>BATF</td><td>Colocalization of FOSL1/FOSL2 and BATF binding at the IL23R promoter in Th17 cells induced from Naïve isolated Cord blood CD4 cells.</td><td>ChIP-seq</td><td>[120]</td></tr><tr><td>BRD4</td><td>BRD4 binds to the IL23R locus in CD4<sup>+</sup> T cells activated through the TCR. A selective BET inhibitor reduced Il-23r expression in vitro and in a graft-versus-host disease model.</td><td>ChIP-seq<br>Inhibitor<br>treatment</td><td>[132]</td></tr></tbody></table>

may display context-dependent effects on IL-23R expression: T-bet was shown to increase *Il23r* levels in an EAE model by direct binding to the *Il23r* promoter but to repress *Il23r* in Th17 cells in a colitis model [116, 117]. T-bet was reported to bind the

*Il23r* gene also in Th1 cells, without affecting IL23R expression [118].

FOSL proteins play a complex role in the regulation of Th17 differentiation and IL-23R expression. In the mouse, FOSL2
<figure><img src="image_4.png" /><figcaption>**Figure 2.** Transcription factors binding to the Il23r locus. (a) Alignment of the human and murine IL23R loci, obtained with the VISTA browser. Regions with >70% identity are marked in color: Conserved noncoding sequences (CNS) in salmon, 5' and 3'-UTR in light blue, and exons in purple. (b) Epigenetic marks tracks were obtained from the GEO database with the following GSM ID: ATACseq, GSM4731624; H3K4me1, GSM4291301; H3K27ac, GSM4291309; and H3K4me3, GSM4291303. (c) Indication of transcription factors bound to the murine and to the human IL23R locus obtained from published ChIP data.</figcaption></figure>

controlled the inflammatory response by reducing the expression of proinflammatory cytokines such as IL17A and IL17F; however, FOSL2 was also important for Th17 maintenance and survival since it increased *Il23r*, *Il21*, and *Il12rb1* expression [112]. Over-expression of FOSL1 and JUNB together promotes murine Th17 differentiation, increasing the expression of *Il17*, *Rorc*, and *Il21*. Consistently, inhibiting *Fosl1* and *Junb* expression in vivo attenuated disease in an arthritis model [119]. Overexpression of FOSL1 in CD4⁺ T cells from healthy donors led to an increase in IL-17-producing cells and IL-17A secretion [119]. A recent study in humans showed that FOSL1, FOSL2, and BATF bind at the same site in the *IL23R* locus and at other Th17-associated genes. However, the study described a positive regulatory role of BATF but a negative role of FOSL proteins, since FOSL1 and/or FOSL2 over-expression decreased *IL23R* transcription. The authors suggested that BATF and FOSL proteins compete for binding to transcriptional partners and target genes [120].

Stat3 was also shown to directly regulate *Il23r* expression [45, 121]. Jain et al. [45] demonstrated that *Il23r* was downregulated in naive CD4⁺ T cells from STAT3 conditional KO mice, cultured under Th17 polarizing condition. *Il23r* expression was not affected in STAT1 KO mice.

## Posttranscriptional regulation of IL23R expression

IL23R expression can be controlled posttranscriptionally by several miRs, adding another layer of complexity to IL-23R regulation.

Let-7f targets IL23R 3'UTR and its overexpression decreases IL23R levels in human CD4⁺ T and K562 cells. Let-7f levels can be regulated by estrogen signaling in humans and in mice. Th17

cells from female asthma patients had lower let-7f expression and higher IL-23R expression than Th17 from male patients, and let-7f inhibition further increased IL-23R levels. Administration of estrogen and progesterone to ovariectomized mice decreased let-7f levels and increased IL-23R and IL-17 expression [122]. Consistently, Th17 cells from *Esr1*⁻/⁻ mice showed increased levels of let-7f and reduced IL-17 and IL-23R expression [123]. Over-expression of let-7g in activated CD4⁺ T cells protected from severe disease in a mouse model of multiple sclerosis, reducing the secretion of proinflammatory cytokines and *Il23r* expression in Th17 cells [124].

*Il23r* 3'UTR is also targeted by miR-34a and miR-34a⁻/⁻ mice show increased levels of IL-23R and IL-17 in the colon following infection with *Citrobacter rodentium* [125].

The inhibitory effect of miR146b-5p on IL-23R cell surface expression in chronic lymphocytic leukemia cells is mediated by the downregulation of the IL-12Rb1 chain of the receptor [126].

## Conclusion and perspectives

In the past decade, our understanding of the role of the IL-23/IL-23R pathway in health and disease has greatly advanced, resulting in the implementation of novel therapeutics of great efficacy for immune-mediated inflammatory diseases, such as psoriasis and psoriatic arthritis. However, much remains to be learned about IL-23 biological activity in health and disease.

The majority of the studies characterizing the IL-23/IL-23R pathway have focused on T lymphocytes, and primarily, on conventional CD4⁺ T cells. The biological functions of this pathway in other immune cells, such as innate lymphocytes, B cells, and myeloid subsets need to be further explored. The data available
<figure><img src="image_3.png" /><figcaption>**Figure 2.** Transcription factors binding to the Il23r locus. (a) Alignment of the human and murine IL23R loci, obtained with the VISTA browser. Regions with >70% identity are marked in color: Conserved noncoding sequences (CNS) in salmon, 5' and 3'-UTR in light blue, and exons in purple. (b) Epigenetic marks tracks were obtained from the GEO database with the following GSM ID: ATACseq, GSM4731624; H3K4me1, GSM4291301; H3K27ac, GSM4291309; and H3K4me3, GSM4291303. (c) Indication of transcription factors bound to the murine and to the human IL23R locus obtained from published ChIP data.</figcaption></figure>

controlled the inflammatory response by reducing the expression of proinflammatory cytokines such as IL17A and IL17F; however, FOSL2 was also important for Th17 maintenance and survival since it increased *Il23r*, *Il21*, and *Il12rb1* expression [112]. Over-expression of FOSL1 and JUNB together promotes murine Th17 differentiation, increasing the expression of *Il17*, *Rorc*, and *Il21*. Consistently, inhibiting *Fosl1* and *Junb* expression in vivo attenuated disease in an arthritis model [119]. Overexpression of FOSL1 in CD4⁺ T cells from healthy donors led to an increase in IL-17-producing cells and IL-17A secretion [119]. A recent study in humans showed that FOSL1, FOSL2, and BATF bind at the same site in the *IL23R* locus and at other Th17-associated genes. However, the study described a positive regulatory role of BATF but a negative role of FOSL proteins, since FOSL1 and/or FOSL2 over-expression decreased *IL23R* transcription. The authors suggested that BATF and FOSL proteins compete for binding to transcriptional partners and target genes [120].

Stat3 was also shown to directly regulate *Il23r* expression [45, 121]. Jain et al. [45] demonstrated that *Il23r* was downregulated in naive CD4⁺ T cells from STAT3 conditional KO mice, cultured under Th17 polarizing condition. *Il23r* expression was not affected in STAT1 KO mice.

## Posttranscriptional regulation of IL23R expression

*IL23R* expression can be controlled posttranscriptionally by several miRs, adding another layer of complexity to IL-23R regulation.

Let-7f targets *IL23R* 3'UTR and its overexpression decreases *IL23R* levels in human CD4⁺ T and K562 cells. Let-7f levels can be regulated by estrogen signaling in humans and in mice. Th17

cells from female asthma patients had lower let-7f expression and higher IL-23R expression than Th17 from male patients, and let-7f inhibition further increased IL-23R levels. Administration of estrogen and progesterone to ovariectomized mice decreased let-7f levels and increased IL-23R and IL-17 expression [122]. Consistently, Th17 cells from *Esr1*⁻/⁻ mice showed increased levels of let-7f and reduced IL-17 and IL-23R expression [123]. Over-expression of let-7g in activated CD4⁺ T cells protected from severe disease in a mouse model of multiple sclerosis, reducing the secretion of proinflammatory cytokines and *Il23r* expression in Th17 cells [124].

*Il23r* 3'UTR is also targeted by miR-34a and miR-34a⁻/⁻ mice show increased levels of IL-23R and IL-17 in the colon following infection with *Citrobacter rodentium* [125].

The inhibitory effect of miR-146b-5p on IL-23R cell surface expression in chronic lymphocytic leukemia cells is mediated by the downregulation of the IL-12Rb1 chain of the receptor [126].

## Conclusion and perspectives

In the past decade, our understanding of the role of the IL-23/IL-23R pathway in health and disease has greatly advanced, resulting in the implementation of novel therapeutics of great efficacy for immune-mediated inflammatory diseases, such as psoriasis and psoriatic arthritis. However, much remains to be learned about IL-23 biological activity in health and disease.

The majority of the studies characterizing the IL-23/IL-23R pathway have focused on T lymphocytes, and primarily, on conventional CD4⁺ T cells. The biological functions of this pathway in other immune cells, such as innate lymphocytes, B cells, and myeloid subsets need to be further explored. The data available
today indicate that most immune cells need to be activated in order to acquire responsiveness to IL-23. The stimuli and the transcriptional pathways that induce the IL-23R in the different cell types are variable, depend on the cell type and the environmental context, and are still poorly characterized. Additionally, future efforts should also focus on understanding the downstream effects of IL-23 signaling in the different cell types, and their role in disease settings.

**Acknowledgements:** IM was supported by a stipend from the Pasteur-Paris University (PPU) International PhD Program. HYC is supported by Janssen Research and Development and LR and EB are supported by Institut Pasteur.

**Conflict of interest:** The authors declare no conflict of interest.

**Data availability statement:** Data sharing is not applicable to this article as no datasets were generated or analysed during the current study

**Peer review:** The peer review history for this article is available at https://publons.com/publon/10.1002/eji.202250348

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3 Cua, D. J., Sherlock, J., Chen, Y., Murphy, C. A., Joyce, B., Seymour, B., Lucian, L. et al., Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. *Nature*. 2003. 421: 744-748.

4 Duerr, R. H., Taylor, K. D., Brant, S. R., Rioux, J. D., Silverberg, M. S., Daly, M. J., Steinhart, A. H. et al., A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. *Science*. 2006. 314: 1461-1463.

5 Wellcome Trust Case Control Consortium, Australo-Anglo-American Spondylitis Consortium (TASC), Burton, P. R., Clayton, D. G., Cardon, L. R., Craddock, N., Deloukas, P., Duncanson, A., Kwiatkowski, D. P. et al., Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. *Nat. Genet.* 2007. 39: 1329-1337.

6 Cargill, M., Schrodi, S. J., Chang, M., Garcia, V. E., Brandon, R., Callis, K. P., Matsunami, N. et al., A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. *Am. J. Hum. Genet.* 2007. 80: 273-290.

7 Teng, M. W. L., Bowman, E. P., Mcelwee, J. J., Smyth, M. J., Casanova, J.-L., Cooper, A. M. and Cua, D. J., IL-12 and IL-23 cytokines: from discovery

to targeted therapies for immune-mediated inflammatory diseases. *Nat. Med.* 2015. 21: 719-729.

8 Schinocca, C., Rizzo, C., Fasano, S., Grasso, G., La Barbera, L., Ciccia, F. et al., Role of the IL-23/IL-17 pathway in rheumatic diseases: an overview. *Front. Immunol.* 2021 [cited 2023 May 30];12. Available from: https://www.frontiersin.org/articles/10.3389/fimmu.2021.637829

9 Parham, C., Chirica, M., Timans, J., Vaisberg, E., Travis, M., Cheung, J., Pflanz, S. et al., A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R. *J. Immunol.* 2002. 168: 5699-5708.

10 Rosine, N., Rowe, H., Koturan, S., Yahia-Cherbal, H., Leloup, C., Watad, A., Berenbaum, F. et al., Characterization of blood mucosal-associated invariant t cells in patients with axial spondyloarthritis and of resident mucosal-associated invariant t cells from the axial endheses of non-axial spondyloarthritis control patients. *Arthritis Rheumatol.* 2022. 74: 1786-1795.

11 Philippot, Q., Ogishi, M., Bohlen, J., Puchan, J., Arias, A. A., Nguyen, T., Martin-Fernandez, M. et al., Human IL-23 is essential for IFN-γ-dependent immunity to mycobacteria. *Sci. Immunol.* 2023. 8: eabq5204.

12 Trinchieri, G., Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity. *Annu. Rev. Immunol.* 1995. 13: 251-276.

13 Sinigaglia, F., D'ambrosio, D., Panina-Bordignon, P. and Rogge, L., Regulation of the IL-12/IL-12R axis: a critical step in T-helper cell differentiation and effector function. *Immunol. Rev.* 1999. 170: 65-72.

14 Presky, D. H., Yang, H., Minetti, L. J., Chua, A. O., Nabavi, N., Wu, C.-Y., Gately, M. K. et al., A functional interleukin 12 receptor complex is composed of two β-type cytokine receptor subunits. *Proc. Natl. Acad. Sci.* 1996. 93: 14002-14007.

15 Schröder, J., Moll, J. M., Baran, P., Grötzinger, J., Scheller, J. and Floss, D. M., Non-canonical interleukin 23 receptor complex assembly. *J. Biol. Chem.* 2015. 290: 359-370.

16 Pastor-Fernández, G., Mariblanca, I. R. and Navarro, M. N., Decoding IL-23 signaling cascade for new therapeutic opportunities. *Cells*. 2020. 9: 2044.

17 Bloch, Y., Bouchareychas, L., Merceron, R., Skladanowska, K., Van Den Bossche, L., Detry, S., Govindarajan, S. et al., Structural activation of pro-inflammatory human cytokine IL-23 by cognate IL-23 receptor enables recruitment of the shared receptor IL-12Rβ1. *Immunity*. 2018. 48: 45-58. e6.

18 Zou, J., Presky, D. H., Wu, C.-Y. and Gubler, U., Differential associations between the cytoplasmic regions of the interleukin-12 receptor subunits beta1 and beta2 and JAK kinases. *J. Biol. Chem.* 1997. 272: 6073-6077.

19 Floss, D. M., Klöcker, T., Schröder, J., Lamertz, L., Mrotzek, S., Strobl, B., Hermanns, H. et al., Defining the functional binding sites of interleukin 12 receptor β1 and interleukin 23 receptor to Janus kinases. *Mol. Biol. Cell.* 2016. 27: 2301-2316.

20 Rogge, L., Barberis-Maino, L., Biffi, M., Passini, N., Presky, D. H., Gubler, U. and Sinigaglia, F., Selective expression of an interleukin-12 receptor component by human T helper 1 cells. *J. Exp. Med.* 1997. 185: 825-831.

21 Gollob, J. A., Murphy, E. A., Mahajan, S., Schnipper, C. P., Ritz, J. and Frank, D. A., Altered interleukin-12 responsiveness in Th1 and Th2 cells is associated with the differential activation of STAT5 and STAT1. *Blood*. 1998. 91: 1341-1354.

22 Lee, P. W., Smith, A. J., Yang, Y., Selhorst, A. J., Liu, Y., Racke, M. K. and Lovett-Racke, A. E., IL-23R-activated STAT3/STAT4 is essential for Th1/Th17-mediated CNS autoimmunity. *JCI Insight*. [cited 2020 Dec 21];2. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5621925/
today indicate that most immune cells need to be activated in order to acquire responsiveness to IL-23. The stimuli and the transcriptional pathways that induce the IL-23R in the different cell types are variable, depend on the cell type and the environmental context, and are still poorly characterized. Additionally, future efforts should also focus on understanding the downstream effects of IL-23 signaling in the different cell types, and their role in disease settings.

**Acknowledgements:** IM was supported by a stipend from the Pasteur-Paris University (PPU) International PhD Program. HYC is supported by Janssen Research and Development and LR and EB are supported by Institut Pasteur.

**Conflict of interest:** The authors declare no conflict of interest.

**Data availability statement:** Data sharing is not applicable to this article as no datasets were generated or analysed during the current study

**Peer review:** The peer review history for this article is available at https://publons.com/publon/10.1002/eji.202250348

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3 Cua, D. J., Sherlock, J., Chen, Y., Murphy, C. A., Joyce, B., Seymour, B., Lucian, L. et al., Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. *Nature*. 2003. 421: 744-748.

4 Duerr, R. H., Taylor, K. D., Brant, S. R., Rioux, J. D., Silverberg, M. S., Daly, M. J., Steinhart, A. H. et al., A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. *Science*. 2006. 314: 1461-1463.

5 Wellcome Trust Case Control Consortium, Australo-Anglo-American Spondylitis Consortium (TASC), Burton, P. R., Clayton, D. G., Cardon, L. R., Craddock, N., Deloukas, P., Duncanson, A., Kwiatkowski, D. P. et al., Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. *Nat. Genet.* 2007. 39: 1329-1337.

6 Cargill, M., Schrodi, S. J., Chang, M., Garcia, V. E., Brandon, R., Callis, K. P., Matsunami, N. et al., A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. *Am. J. Hum. Genet.* 2007. 80: 273-290.

7 Teng, M. W. L., Bowman, E. P., Mcelwee, J. J., Smyth, M. J., Casanova, J.-L., Cooper, A. M. and Cua, D. J., IL-12 and IL-23 cytokines: from discovery

to targeted therapies for immune-mediated inflammatory diseases. *Nat. Med.* 2015. 21: 719-729.

8 Schinocca, C., Rizzo, C., Fasano, S., Grasso, G., La Barbera, L., Ciccia, F. et al., Role of the IL-23/IL-17 pathway in rheumatic diseases: an overview. *Front. Immunol.* 2021 [cited 2023 May 30];12. Available from: https://www.frontiersin.org/articles/10.3389/fimmu.2021.637829

9 Parham, C., Chirica, M., Timans, J., Vaisberg, E., Travis, M., Cheung, J., Pflanz, S. et al., A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R. *J. Immunol.* 2002. 168: 5699-5708.

10 Rosine, N., Rowe, H., Koturan, S., Yahia-Cherbal, H., Leloup, C., Watad, A., Berenbaum, F. et al., Characterization of blood mucosal-associated invariant t cells in patients with axial spondyloarthritis and of resident mucosal-associated invariant t cells from the axial endheses of non-axial spondyloarthritis control patients. *Arthritis Rheumatol.* 2022. 74: 1786-1795.

11 Philippot, Q., Ogishi, M., Bohlen, J., Puchan, J., Arias, A. A., Nguyen, T., Martin-Fernandez, M. et al., Human IL-23 is essential for IFN-γ-dependent immunity to mycobacteria. *Sci. Immunol.* 2023. 8: eabq5204.

12 Trinchieri, G., Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity. *Annu. Rev. Immunol.* 1995. 13: 251-276.

13 Sinigaglia, F., D'ambrosio, D., Panina-Bordignon, P. and Rogge, L., Regulation of the IL-12/IL-12R axis: a critical step in T-helper cell differentiation and effector function. *Immunol. Rev.* 1999. 170: 65-72.

14 Presky, D. H., Yang, H., Minetti, L. J., Chua, A. O., Nabavi, N., Wu, C.-Y., Gately, M. K. et al., A functional interleukin 12 receptor complex is composed of two β-type cytokine receptor subunits. *Proc. Natl. Acad. Sci.* 1996. 93: 14002-14007.

15 Schröder, J., Moll, J. M., Baran, P., Grötzinger, J., Scheller, J. and Floss, D. M., Non-canonical interleukin 23 receptor complex assembly. *J. Biol. Chem.* 2015. 290: 359-370.

16 Pastor-Fernández, G., Mariblanca, I. R. and Navarro, M. N., Decoding IL-23 signaling cascade for new therapeutic opportunities. *Cells*. 2020. 9: 2044.

17 Bloch, Y., Bouchareychas, L., Merceron, R., Skladanowska, K., Van Den Bossche, L., Detry, S., Govindarajan, S. et al., Structural activation of pro-inflammatory human cytokine IL-23 by cognate IL-23 receptor enables recruitment of the shared receptor IL-12Rβ1. *Immunity*. 2018. 48: 45-58. e6.

18 Zou, J., Presky, D. H., Wu, C.-Y. and Gubler, U., Differential associations between the cytoplasmic regions of the interleukin-12 receptor subunits beta1 and beta2 and JAK kinases. *J. Biol. Chem.* 1997. 272: 6073-6077.

19 Floss, D. M., Klöcker, T., Schröder, J., Lamertz, L., Mrotzek, S., Strobl, B., Hermanns, H. et al., Defining the functional binding sites of interleukin 12 receptor β1 and interleukin 23 receptor to Janus kinases. *Mol. Biol. Cell.* 2016. 27: 2301-2316.

20 Rogge, L., Barberis-Maino, L., Biffi, M., Passini, N., Presky, D. H., Gubler, U. and Sinigaglia, F., Selective expression of an interleukin-12 receptor component by human T helper 1 cells. *J. Exp. Med.* 1997. 185: 825-831.

21 Gollob, J. A., Murphy, E. A., Mahajan, S., Schnipper, C. P., Ritz, J. and Frank, D. A., Altered interleukin-12 responsiveness in Th1 and Th2 cells is associated with the differential activation of STAT5 and STAT1. *Blood*. 1998. 91: 1341-1354.

22 Lee, P. W., Smith, A. J., Yang, Y., Selhorst, A. J., Liu, Y., Racke, M. K. and Lovett-Racke, A. E., IL-23R-activated STAT3/STAT4 is essential for Th1/Th17-mediated CNS autoimmunity. *JCI Insight*. [cited 2020 Dec 21];2. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5621925/
23 Zhang, X.-Y., Zhang, H.-J., Zhang, Y., Fu, Y.-J., He, J., Zhu, L. P., Wang, S.-H. et al., Identification and expression analysis of alternatively spliced isoforms of human interleukin-23 receptor gene in normal lymphoid cells and selected tumor cells. *Immunogenetics*. 2006. 57: 934–943.

24 Kan, S.-H., Mancini, G. and Gallagher, G., Identification and characterization of multiple splice forms of the human interleukin-23 receptor alpha chain in mitogen-activated leukocytes. *Genes Immun*. 2008. 9: 631–639.

25 Zhang, W., Ferguson, J., Ng, S. M., Hui, K., Goh, G., Lin, A., Esplugues, E. et al., Effector CD4+ T cell expression signatures and immune-mediated disease associated genes. *PLoS One*. 2012. 7: e38510.

26 Floss, D. M., Moll, J. M. and Scheller, J., IL-12 and IL-23—Close relatives with structural homologies but distinct immunological functions. *Cells*. 2020. 9: 2184.

27 Leshinsky-Silver, E., Karban, A., Dalal, I., Eliakim, R., Shirin, H., Tzofi, T., Boaz, M. et al., Evaluation of the interleukin-23 receptor gene coding variant R381Q in pediatric and adult Crohn disease. *J. Pediatr. Gastroenterol. Nutr*. 2007. 45: 405–408.

28 Roberts, R. L., Gearry, R. B., Hollis-Moffatt, J. E., Miller, A. L., Reid, J., Abkevich, V., Timms, K. M. et al., IL23R R381Q and ATG16L1 T300A are strongly associated with Crohn's disease in a study of New Zealand Caucasians with inflammatory bowel disease. *Am. J. Gastroenterol*. 2007. 102: 2754–2761.

29 Silverberg, M. S., Cho, J. H., Rioux, J. D., Mcgovern, D. P. B., Wu, J., Annese, V., Achkar, J.-P. et al., Ulcerative colitis-risk loci on chromosomes 1p36 and 12q15 found by genome-wide association study. *Nat. Genet*. 2009. 41: 216–220.

30 Liu, Y., Helms, C., Liao, W., Zaba, L. C., Duan, S., Gardner, J., Wise, C. et al., A genome-wide association study of psoriasis and psoriatic arthritis identifies new disease loci. *PLoS Genet*. 2008. 4: e1000041.

31 Rahman, P., Inman, R. D., Gladman, D. D., Reeve, J. P., Peddle, L. and Maksymowych, W. P., Association of interleukin-23 receptor variants with ankylosing spondylitis. *Arthritis Rheum*. 2008. 58: 1020–1025.

32 Australo-Anglo-American Spondyloarthritis Consortium (TASC), Reveille, J. D., Sims, A. M., Danoy, P., Evans, D. M., Leo, P. et al., Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci. *Nat. Genet*. 2010. 42: 123–127.

33 Sarin, R., Wu, X. and Abraham, C., Inflammatory disease protective R381Q IL23 receptor polymorphism results in decreased primary CD4+ and CD8+ human T-cell functional responses. *Proc Natl Acad Sci USA*. 2011. 108: 9560–9565.

34 Pidasheva, S., Trifari, S., Phillips, A., Hackney, J. A., Ma, Y., Smith, A., Sohn, S. J. et al., Functional studies on the IBD susceptibility gene IL23R implicate reduced receptor function in the protective genetic variant R381Q. *PLoS One*. 2011. 6: e25038.

35 Di Meglio, P., Di Cesare, A., Laggner, U., Chu, C.-C., Napolitano, L., Vilianova, F., Tosi, I. et al., The IL23R R381Q gene variant protects against immune-mediated diseases by impairing IL-23-induced Th17 effector response in humans. *PLoS One*. 2011. 6: e17160.

36 Coffre, M., Roumier, M., Rybczynska, M., Sechet, E., Law, H. K. W., Gossec, L., Dougados, M. et al., Combinatorial control of Th17 and Th1 cell functions by genetic variations in genes associated with the interleukin-23 signaling pathway in spondyloarthritis. *Arthritis Rheum*. 2013. 65: 1510–1521.

37 Sivanesan, D., Beauchamp, C., Quinou, C., Lee, J., Lesage, S., Chemtob, S., Rioux, J. D. et al., IL23R (interleukin 23 receptor) variants protective against inflammatory bowel diseases (IBD) display loss of function due to impaired protein stability and intracellular trafficking*. *J. Biol. Chem*. 2016. 291: 8673–8685.

38 Bauquet, A. T., Jin, H., Paterson, A. M., Mitsdoerffer, M., Ho, I.-C., Sharpe, A. H. and Kuchroo, V. K., Costimulatory molecule ICOS plays a critical role in the development of TH-17 and follicular T-helper cells by regulating c-Maf expression and IL-21 production. *Nat. Immunol*. 2009. 10: 167–175.

39 Wines, B. D., Yap, M. L., Powell, M. S., Tan, P. S., Ko, K. K., Orlowski, E. and Hogarth, P. M., Distinctive expression of interleukin-23 receptor subunits on human Th17 and γδ T cells. *Immunol. Cell Biol*. 2017. 95: 272–279.

40 Chen, Z., Tato, C. M., Muul, L., Laurence, A. and O'Shea, J. J., Distinct regulation of interleukin-17 in human T helper lymphocytes. *Arthritis Rheum*. 2007. 56: 2936–2946.

41 Li, H., Hsu, H.-C., Wu, Q., Yang, P., Li, J., Luo, B., Oukka, M. et al., IL-23 promotes TCR-mediated negative selection of thymocytes through the upregulation of IL-23 receptor and RORγt. *Nat. Commun*. 2014. 5: 4259.

42 Tan, Z. Y., Bealgey, K. W., Fang, Y., Gong, Y. M. and Bao, S., Interleukin-23: Immunological roles and clinical implications. *Int. J. Biochem. Cell Biol*. 2009. 41: 733–735.

43 Ivanov, I. I., Mckenzie, B. S., Zhou, L., Tadokoro, C. E., Lepelley, A., Lafaille, J. J., Cua, D. J. et al., RORγt directs the differentiation program of proinflammatory Th17 Cells. *Cell*. 2006. 126: 1121–1133.

44 Lee, Y., Awasthi, A., Yosef, N., Quintana, F. J., Xiao, S., Peters, A., Wu, C. et al., Induction and molecular signature of pathogenic TH17 cells. *Nat. Immunol*. 2012. 13: 991–999.

45 Jain, R., Chen, Y., Kanno, Y., Joyce-Shaikh, B., Vahedi, G., Hirahara, K., Blumenschein, W. M. et al., Interleukin-23-induced transcription factor blimp-1 promotes pathogenicity of T helper 17 cells. *Immunity*. 2016. 44: 131–142.

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47 Razawy, W., Asmawidjaja, P. S., Mus, A. M., Salioska, N., Davelaar, N., Kops, N., Oukka, M. et al., CD4+ CCR6+ T cells, but not γδ T cells, are important for the IL-23R-dependent progression of antigen-induced inflammatory arthritis in mice. *Eur. J. Immunol*. 2020. 50: 245–255.

48 Pawlak, M., Detomaso, D., Schnell, A., Meyer Zu Horste, G., Lee, Y., Nyman, J., Dionne, D. et al., Induction of a colitogenic phenotype in Th1-like cells depends on interleukin-23 receptor signaling. *Immunity*. 2022. 55: 1663–1679. e6.

49 Whitley, S. K., Li, M., Kashem, S. W., Hirai, T., Igyártó, B. Z., Knizner, K., Ho, J. et al., Local IL-23 is required for proliferation and retention of skin-resident memory TH17 cells. *Sci. Immunol*. 2022. 7: eabq3254.

50 Hong, H., Gao, M., Wu, Q., Yang, P., Liu, S., Li, H., Burrows, P. D. et al., IL-23 promotes a coordinated B cell germinal center program for class-switch recombination to IgG2b in BXD2 Mice. *J. Immunol*. 2020. 205: 346–358.

51 Yang, B.-H., Hagemann, S., Mamareli, P., Lauer, U., Hoffmann, U., Beckstette, M., Föhse, L. et al., Foxp3(+) T cells expressing RORγt represent a stable regulatory T-cell effector lineage with enhanced suppressive capacity during intestinal inflammation. *Mucosal Immunol*. 2016. 9: 444–457.

52 Jacobse, J., Brown, R. E., Li, J., Pilat, J. M., Pham, L., Short, S. P., Peek, C. T. et al., Interleukin-23 receptor signaling impairs the stability and function of colonic regulatory T cells. *Cell Rep*. 2023. 42: 112128.

53 Wei, Y.-L., Han, A., Glanville, J., Fang, F., Zuniga, L. A., Lee, J. S., Cua, D. J. et al., A highly focused antigen receptor repertoire characterizes γδ T cells that are poised to make IL-17 rapidly in naive animals. *Front. Immunol*. 2015 [cited 2023 Mar 16];6. Available from: https://www.frontiersin.org/articles/10.3389/fimmu.2015.00118
23 Zhang, X.-Y., Zhang, H.-J., Zhang, Y., Fu, Y.-J., He, J., Zhu, L. P., Wang, S.-H. et al., Identification and expression analysis of alternatively spliced isoforms of human interleukin-23 receptor gene in normal lymphoid cells and selected tumor cells. *Immunogenetics*. 2006. 57: 934–943.

24 Kan, S.-H., Mancini, G. and Gallagher, G., Identification and characterization of multiple splice forms of the human interleukin-23 receptor alpha chain in mitogen-activated leukocytes. *Genes Immun*. 2008. 9: 631–639.

25 Zhang, W., Ferguson, J., Ng, S. M., Hui, K., Goh, G., Lin, A., Esplugues, E. et al., Effector CD4+ T cell expression signatures and immune-mediated disease associated genes. *PLoS One*. 2012. 7: e38510.

26 Floss, D. M., Moll, J. M. and Scheller, J., IL-12 and IL-23—Close relatives with structural homologies but distinct immunological functions. *Cells*. 2020. 9: 2184.

27 Leshinsky-Silver, E., Karban, A., Dalal, I., Eliakim, R., Shirin, H., Tzofi, T., Boaz, M. et al., Evaluation of the interleukin-23 receptor gene coding variant R381Q in pediatric and adult Crohn disease. *J. Pediatr. Gastroenterol. Nutr*. 2007. 45: 405–408.

28 Roberts, R. L., Gearry, R. B., Hollis-Moffatt, J. E., Miller, A. L., Reid, J., Abkevich, V., Timms, K. M. et al., IL23R R381Q and ATG16L1 T300A are strongly associated with Crohn's disease in a study of New Zealand Caucasians with inflammatory bowel disease. *Am. J. Gastroenterol*. 2007. 102: 2754–2761.

29 Silverberg, M. S., Cho, J. H., Rioux, J. D., Mcgovern, D. P. B., Wu, J., Annese, V., Achkar, J.-P. et al., Ulcerative colitis-risk loci on chromosomes 1p36 and 12q15 found by genome-wide association study. *Nat. Genet*. 2009. 41: 216–220.

30 Liu, Y., Helms, C., Liao, W., Zaba, L. C., Duan, S., Gardner, J., Wise, C. et al., A genome-wide association study of psoriasis and psoriatic arthritis identifies new disease loci. *PLoS Genet*. 2008. 4: e1000041.

31 Rahman, P., Inman, R. D., Gladman, D. D., Reeve, J. P., Peddle, L. and Maksymowych, W. P., Association of interleukin-23 receptor variants with ankylosing spondylitis. *Arthritis Rheum*. 2008. 58: 1020–1025.

32 Australo-Anglo-American Spondyloarthritis Consortium (TASC), Reveille, J. D., Sims, A. M., Danoy, P., Evans, D. M., Leo, P. et al., Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci. *Nat. Genet*. 2010. 42: 123–127.

33 Sarin, R., Wu, X. and Abraham, C., Inflammatory disease protective R381Q IL23 receptor polymorphism results in decreased primary CD4+ and CD8+ human T-cell functional responses. *Proc Natl Acad Sci USA*. 2011. 108: 9560–9565.

34 Pidasheva, S., Trifari, S., Phillips, A., Hackney, J. A., Ma, Y., Smith, A., Sohn, S. J. et al., Functional studies on the IBD susceptibility gene IL23R implicate reduced receptor function in the protective genetic variant R381Q. *PLoS One*. 2011. 6: e25038.

35 Di Meglio, P., Di Cesare, A., Laggner, U., Chu, C.-C., Napolitano, L., Vilianova, F., Tosi, I. et al., The IL23R R381Q gene variant protects against immune-mediated diseases by impairing IL-23-induced Th17 effector response in humans. *PLoS One*. 2011. 6: e17160.

36 Coffre, M., Roumier, M., Rybczynska, M., Sechet, E., Law, H. K. W., Gossec, L., Dougados, M. et al., Combinatorial control of Th17 and Th1 cell functions by genetic variations in genes associated with the interleukin-23 signaling pathway in spondyloarthritis. *Arthritis Rheum*. 2013. 65: 1510–1521.

37 Sivanesan, D., Beauchamp, C., Quinou, C., Lee, J., Lesage, S., Chemtob, S., Rioux, J. D. et al., IL23R (interleukin 23 receptor) variants protective against inflammatory bowel diseases (IBD) display loss of function due to impaired protein stability and intracellular trafficking*. *J. Biol. Chem*. 2016. 291: 8673–8685.

38 Bauquet, A. T., Jin, H., Paterson, A. M., Mitsdoerffer, M., Ho, I.-C., Sharpe, A. H. and Kuchroo, V. K., Costimulatory molecule ICOS plays a critical role in the development of Th17 and follicular T-helper cells by regulating c-Maf expression and IL-21 production. *Nat. Immunol*. 2009. 10: 167–175.

39 Wines, B. D., Yap, M. L., Powell, M. S., Tan, P. S., Ko, K. K., Orlowski, E. and Hogarth, P. M., Distinctive expression of interleukin-23 receptor subunits on human Th17 and γδ T cells. *Immunol. Cell Biol*. 2017. 95: 272–279.

40 Chen, Z., Tato, C. M., Muul, L., Laurence, A. and O'Shea, J. J., Distinct regulation of interleukin-17 in human T helper lymphocytes. *Arthritis Rheum*. 2007. 56: 2936–2946.

41 Li, H., Hsu, H.-C., Wu, Q., Yang, P., Li, J., Luo, B., Oukka, M. et al., IL-23 promotes TCR-mediated negative selection of thymocytes through the upregulation of IL-23 receptor and RORγt. *Nat. Commun*. 2014. 5: 4259.

42 Tan, Z. Y., Bealgey, K. W., Fang, Y., Gong, Y. M. and Bao, S., Interleukin-23: Immunological roles and clinical implications. *Int. J. Biochem. Cell Biol*. 2009. 41: 733–735.

43 Ivanov, I. I., Mckenzie, B. S., Zhou, L., Tadokoro, C. E., Lepelley, A., Lafaille, J. J., Cua, D. J. et al., RORγt directs the differentiation program of proinflammatory Th17 Cells. *Cell*. 2006. 126: 1121–1133.

44 Lee, Y., Awasthi, A., Yosef, N., Quintana, F. J., Xiao, S., Peters, A., Wu, C. et al., Induction and molecular signature of pathogenic TH17 cells. *Nat. Immunol*. 2012. 13: 991–999.

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55 Izcue, A., Hue, S., Buonocore, S., Arancibia-Cárcamo, C. V., Ahern, P. P., Iwakura, Y., Maloy, K. J. et al., Interleukin-23 restrains regulatory T cell activity to drive T cell-dependent colitis. *Immunity*. 2008. 28: 559–570.

56 Wu, C., Chen, Z., Xiao, S., Thalhamer, T., Madi, A., Han, T. and Kuchroo, V., SGK1 governs the reciprocal development of Th17 and regulatory T cells. *Cell Rep*. 2018. 22: 653–665.

57 Kannan, A. K., Su, Z., Gauvin, D. M., Paulsboe, S. E., Duggan, R., Lasko, L. M., Honore, P. et al., IL-23 induces regulatory T cell plasticity with implications for inflammatory skin diseases. *Sci. Rep*. 2019. 9: 17675.

58 Dong, S., Maiella, S., Xhaard, A., Pang, Y., Wenandy, L., Larghero, J., Becavin, C. et al., Multiparameter single-cell profiling of human CD4+FOXP3+ regulatory T-cell populations in homeostatic conditions and during graft-versus-host disease. *Blood*. 2013. 122: 1802–1812.

59 Alfen, J. S., Larghi, P., Facciotti, F., Gagliani, N., Bosotti, R., Paroni, M., Maglie, S. et al., Intestinal IFN-γ-producing type 1 regulatory T cells coexpress CCR5 and programmed cell death protein 1 and downregulate IL-10 in the inflamed guts of patients with inflammatory bowel disease. *J. Allergy Clin. Immunol*. 2018. 142: 1537–1547. e8.

60 Curtis, M. M., Way, S. S. and Wilson, C. B., IL-23 promotes the production of IL-17 by antigen-specific CD8 T cells in the absence of IL-12 and type-I interferons. *J. Immunol*. 2009. 183: 381–387.

61 Chognard, G., Bellemare, L., Pelletier, A.-N., Dominguez-Punaro, M. C., Beauchamp, C., Guyon, M.-J., Charron, G. et al., The dichotomous pattern of IL-12R and IL-23R expression elucidates the role of IL-12 and IL-23 in inflammation. *PLoS One*. 2014. 9: e89092.

62 Shen, H., Zhang, W., Abraham, C. and Cho, J. H., Age and CD161 expression contribute to inter-individual variation in interleukin-23 response in CD8+ memory human T cells. *PLoS One*. 2013. 8: e57746.

63 Steel, K. J. A., Srenathan, U., Ridley, M., Durham, L. E., Wu, S. Y., Ryan, S. E., Hughes, C. D. et al., Polyfunctional, proinflammatory, tissue-resident memory phenotype and function of synovial interleukin-17A+CD8+ T cells in psoriatic arthritis. *Arthritis Rheumatol*. 2020. 72: 435–447.

64 Ball, J. A., Clear, A., Aries, J., Charrot, S., Besley, C., Mee, M., Stagg, A. et al., Retinoic acid-responsive CD8 effector T cells are selectively increased in IL-23-rich tissue in gastrointestinal GVHD. *Blood*. 2021. 137: 702–717.

65 Ben Youssef, G., Tourret, M., Salou, M., Ghazarian, L., Houdouin, V., Montdot, S., Mburu, Y. et al., Ontogeny of human mucosal-associated invariant T cells and related T cell subsets. *J. Exp. Med*. 2018. 215: 459–479.

66 Wang, H., Kjer-Nielsen, L., Shi, M., D'souza, C., Pediongco, T. J., Cao, H., Kostenko, L. et al., IL-23 costimulates antigen-specific MAIT cell activation and enables vaccination against bacterial infection. *Sci. Immunol*. 2019. 4: eaaw0402.

67 Leng, T., Akther, H. D., Hackstein, C.-P., Powell, K., King, T., Friedrich, M., Christoforidou, Z. et al., TCR and inflammatory signals tune human MAIT cells to exert specific tissue repair and effector functions. *Cell Rep*. 2019. 28: 3077–3091. e5.

68 Salou, M., Legoux, F., Gilet, J., Darbois, A., Du Halgouet, A., Alonso, R., Richer, W. et al., A common transcriptomic program acquired in the thymus defines tissue residency of MAIT and NKT subsets. *J. Exp. Med*. 2019. 216: 133–151.

69 Chen, L., He, Z., Slinger, E., Bongers, G., Lapenda, T. L., Pacer, M. E., Jiao, J. et al., IL-23 activates innate lymphoid cells to promote neonatal intestinal pathology. *Mucosal Immunol*. 2015. 8: 390–402.

70 Beckstette, M., Lu, C.-W., Herppich, S., Diem, E. C., Ntalli, A., Ochel, A., Kruse, F. et al., Profiling of epigenetic marker regions in murine ILCs

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71 Garner, L. C., Amini, A., Fitzpatrick, M. E. B., Lett, M. J., Hess, G. F., Filipowicz Sinnreich, M., Provine, N. M. et al., Single-cell analysis of human MAIT cell transcriptional, functional and clonal diversity. *Nat. Immunol*. 2023. 24: 1565–1578.

72 Slichter, C. K., Mcdavid, A., Miller, H. W., Finak, G., Seymour, B. J., Mcnevin, J. P., Diaz, G. et al., Distinct activation thresholds of human conventional and innate-like memory T cells. *JCI Insight*. 2016 Jun 2 [cited 2023 May 25];1. Available from: https://insight.jci.org/articles/view/86292

73 Constantinides, M. G., Link, V. M., Tamoutounour, S., Wong, A. C., Perez-Chaparro, P. J., Han, S.-J., Chen, Y. E. et al., MAIT cells are imprinted by the microbiota in early life and promote tissue repair. *Science*. 2019. 366: eaax6624.

74 Meermeier, E. W., Zheng, C. L., Tran, J. G., Soma, S., Worley, A. H., Weiss, D. I., Modlin, R. L. et al., Human lung-resident mucosal-associated invariant T cells are abundant, express antimicrobial proteins, and are cytokine responsive. *Commun. Biol*. 2022. 5: 1–13.

75 Raychaudhuri, S. K., Abria, C., Mitra, A. and Raychaudhuri, S. P., Functional significance of MAIT cells in psoriatic arthritis. *Cytokine*. 2020. 125: 154855.

76 Petermann, F., Rothhammer, V., Claussen, M. C., Haas, J. D., Blanco, L. R., Heink, S., Prinz, I. et al., γδ T cells enhance autoimmunity by restraining regulatory T cell responses via an interleukin-23-dependent mechanism. *Immunity*. 2010. 33: 351–363.

77 Moens, E., Brouwer, M., Dimova, T., Goldman, M., Willems, F. and Vermijlen, D., IL-23R and TCR signaling drives the generation of neonatal Vγ9Vδ2 T cells expressing high levels of cytotoxic mediators and producing IFN-γ and IL-17. *J. Leukocyte Biol*. 2011. 89: 743–752.

78 Awasthi, A., Rolblanco, L., Jäger, A., Korn, T., Pot, C., Galileos, G., Bettelli, E. et al., Cutting edge: IL-23 receptor GFP reporter mice reveal distinct populations of IL-17-producing cells. *J. Immunol*. 2009. 182: 5904–5908.

79 Lockhart, E., Green, A. M. and Flynn, J. L., IL-17 Production is dominated by γδ T cells rather than CD4 T cells during mycobacterium tuberculosis infection. *J. Immunol*. 2006. 177: 4662–4669.

80 Sutton, C. E., Lalor, S. J., Sweeney, C. M., Brereton, C. F., Lavelle, E. C. and Mills, K. H. G., Interleukin-1 and IL-23 induce innate IL-17 production from γδ T cells, amplifying Th17 responses and autoimmunity. *Immunity*. 2009. 31: 331–341.

81 Liang, D., Zuo, A., Shao, H., Born, W. K., O'Brien, R. L., Kaplan, H. J. and Sun, D., IL-23 receptor expression on γδ T cells correlates with their enhancing or suppressive effects on autoreactive T cells in experimental autoimmune uveitis. *J. Immunol*. 2013. 191: 1118–1125.

82 Cai, Y., Xue, F., Fleming, C., Yang, J., Ding, C., Ma, Y., Liu, M. et al., Differential developmental requirement and peripheral regulation for dermal Vγ4 and Vγ6T17 cells in health and inflammation. *Nat. Commun*. 2014. 5: 3986.

83 Rolblanco, L., Lazarevic, V., Awasthi, A., Mitsdoerffer, M., Wilson, B. S., Croxford, A. et al., IL-23 receptor regulates unconventional IL-17-producing T cells that control bacterial infections. *JL*. 2010. 184: 1710–1720.

84 Cuthbert, R. J., Watad, A., Fragkakis, E. M., Dunsmuir, R., Loughenbury, P., Khan, A., Millner, P. A. et al., Evidence that tissue resident human enthesis γδT-cells can produce IL-17A independently of IL-23R transcript expression. *Ann. Rheum. Dis*. 2019. 78: 1559–1565.

85 Venken, K., Jacques, P., Mortier, C., Labadia, M. E., Decruy, T., Coudenys, J., Hoyt, K. et al., RORγt inhibition selectively targets IL-17 producing
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55 Izcue, A., Hue, S., Buonocore, S., Arancibia-Cárcamo, C. V., Ahern, P. P., Iwakura, Y., Maloy, K. J. et al., Interleukin-23 restrains regulatory T cell activity to drive T cell-dependent colitis. *Immunity*. 2008. **28**: 559–570.

56 Wu, C., Chen, Z., Xiao, S., Thalhamer, T., Madi, A., Han, T. and Kuchroo, V., SGK1 governs the reciprocal development of Th17 and regulatory T cells. *Cell Rep*. 2018. **22**: 653–665.

57 Kannan, A. K., Su, Z., Gauvin, D. M., Paulsboe, S. E., Duggan, R., Lasko, L. M., Honore, P. et al., IL-23 induces regulatory T cell plasticity with implications for inflammatory skin diseases. *Sci. Rep*. 2019. **9**: 17675.

58 Dong, S., Maiella, S., Xhaard, A., Pang, Y., Wenandy, L., Larghero, J., Becavin, C. et al., Multiparameter single-cell profiling of human CD4+FOXP3+ regulatory T-cell populations in homeostatic conditions and during graft-versus-host disease. *Blood*. 2013. **122**: 1802–1812.

59 Alfen, J. S., Larghi, P., Facciotti, F., Gagliani, N., Bosotti, R., Paroni, M., Maglie, S. et al., Intestinal IFN-γ-producing type 1 regulatory T cells coexpress CCR5 and programmed cell death protein 1 and downregulate IL-10 in the inflamed guts of patients with inflammatory bowel disease. *J. Allergy Clin. Immunol*. 2018. **142**: 1537–1547. e8.

60 Curtis, M. M., Way, S. S. and Wilson, C. B., IL-23 promotes the production of IL-17 by antigen-specific CD8 T cells in the absence of IL-12 and type-I interferons. *J. Immunol*. 2009. **183**: 381–387.

61 Chognard, G., Bellemare, L., Pelletier, A.-N., Dominguez-Punaro, M. C., Beauchamp, C., Guyon, M.-J., Charron, G. et al., The dichotomous pattern of IL-12R and IL-23R expression elucidates the role of IL-12 and IL-23 in inflammation. *PLoS One*. 2014. **9**: e89092.

62 Shen, H., Zhang, W., Abraham, C. and Cho, J. H., Age and CD161 expression contribute to inter-individual variation in interleukin-23 response in CD8+ memory human T cells. *PLoS One*. 2013. **8**: e57746.

63 Steel, K. J. A., Srenathan, U., Ridley, M., Durham, L. E., Wu, S. Y., Ryan, S. E., Hughes, C. D. et al., Polyfunctional, proinflammatory, tissue-resident memory phenotype and function of synovial interleukin-17A+CD8+ T cells in psoriatic arthritis. *Arthritis Rheumatol*. 2020. **72**: 435–447.

64 Ball, J. A., Clear, A., Aries, J., Charrot, S., Besley, C., Mee, M., Stagg, A. et al., Retinoic acid-responsive CD8 effector T cells are selectively increased in IL-23-rich tissue in gastrointestinal GVHD. *Blood*. 2021. **137**: 702–717.

65 Ben Youssef, G., Tourret, M., Salou, M., Ghazarian, L., Houdouin, V., Montdot, S., Mburu, Y. et al., Ontogeny of human mucosal-associated invariant T cells and related T cell subsets. *J. Exp. Med*. 2018. **215**: 459–479.

66 Wang, H., Kjer-Nielsen, L., Shi, M., D'souza, C., Pediongco, T. J., Cao, H., Kostenko, L. et al., IL-23 costimulates antigen-specific MAIT cell activation and enables vaccination against bacterial infection. *Sci. Immunol*. 2019. **4**: eaaw0402.

67 Leng, T., Akther, H. D., Hackstein, C.-P., Powell, K., King, T., Friedrich, M., Christoforidou, Z. et al., TCR and inflammatory signals tune human MAIT cells to exert specific tissue repair and effector functions. *Cell Rep*. 2019. **28**: 3077–3091. e5.

68 Salou, M., Legoux, F., Gilet, J., Darbois, A., Du Halgouet, A., Alonso, R., Richer, W. et al., A common transcriptomic program acquired in the thymus defines tissue residency of MAIT and NKT subsets. *J. Exp. Med*. 2019. **216**: 133–151.

69 Chen, L., He, Z., Slinger, E., Bongers, G., Lapenda, T. L., Pacer, M. E., Jiao, J. et al., IL-23 activates innate lymphoid cells to promote neonatal intestinal pathology. *Mucosal Immunol*. 2015. **8**: 390–402.

70 Beckstette, M., Lu, C.-W., Herppich, S., Diem, E. C., Ntalli, A., Ochel, A., Kruse, F. et al., Profiling of epigenetic marker regions in murine ILCs

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71 Garner, L. C., Amini, A., Fitzpatrick, M. E. B., Lett, M. J., Hess, G. F., Filipowicz Sinnreich, M., Provine, N. M. et al., Single-cell analysis of human MAIT cell transcriptional, functional and clonal diversity. *Nat. Immunol*. 2023. **24**: 1565–1578.

72 Slichter, C. K., Mcdavid, A., Miller, H. W., Finak, G., Seymour, B. J., Mcnevin, J. P., Diaz, G. et al., Distinct activation thresholds of human conventional and innate-like memory T cells. *JCI Insight*. 2016 Jun 2 [cited 2023 May 25];1. Available from: https://insight.jci.org/articles/view/86292

73 Constantinides, M. G., Link, V. M., Tamoutounour, S., Wong, A. C., Perez-Chaparro, P. J., Han, S.-J., Chen, Y. E. et al., MAIT cells are imprinted by the microbiota in early life and promote tissue repair. *Science*. 2019. **366**: eaax6624.

74 Meermeier, E. W., Zheng, C. L., Tran, J. G., Soma, S., Worley, A. H., Weiss, D. I., Modlin, R. L. et al., Human lung-resident mucosal-associated invariant T cells are abundant, express antimicrobial proteins, and are cytokine responsive. *Commun. Biol*. 2022. **5**: 1–13.

75 Raychaudhuri, S. K., Abria, C., Mitra, A. and Raychaudhuri, S. P., Functional significance of MAIT cells in psoriatic arthritis. *Cytokine*. 2020. **125**: 154855.

76 Petermann, F., Rothhammer, V., Claussen, M. C., Haas, J. D., Blanco, L. R., Heink, S., Prinz, I. et al., γδ T cells enhance autoimmunity by restraining regulatory T cell responses via an interleukin-23-dependent mechanism. *Immunity*. 2010. **33**: 351–363.

77 Moens, E., Brouwer, M., Dimova, T., Goldman, M., Willems, F. and Vermijlen, D., IL-23R and TCR signaling drives the generation of neonatal Vγ9Vδ2 T cells expressing high levels of cytotoxic mediators and producing IFN-γ and IL-17. *J. Leukocyte Biol*. 2011. **89**: 743–752.

78 Awasthi, A., Rolblanco, L., JäGer, A., Korn, T., Pot, C., Galileos, G., Bettelli, E. et al., Cutting edge: IL-23 receptor GFP reporter mice reveal distinct populations of IL-17-producing cells. *J. Immunol*. 2009. **182**: 5904–5908.

79 Lockhart, E., Green, A. M. and Flynn, J. L., IL-17 Production is dominated by γδ T cells rather than CD4 T cells during mycobacterium tuberculosis infection. *J. Immunol*. 2006. **177**: 4662–4669.

80 Sutton, C. E., Lalor, S. J., Sweeney, C. M., Brereton, C. F., Lavelle, E. C. and Mills, K. H. G., Interleukin-1 and IL-23 induce innate IL-17 production from γδ T cells, amplifying Th17 responses and autoimmunity. *Immunity*. 2009. **31**: 331–341.

81 Liang, D., Zuo, A., Shao, H., Born, W. K., O'Brien, R. L., Kaplan, H. J. and Sun, D., IL-23 receptor expression on γδ T cells correlates with their enhancing or suppressive effects on autoreactive T cells in experimental autoimmune uveitis. *J. Immunol*. 2013. **191**: 1118–1125.

82 Cai, Y., Xue, F., Fleming, C., Yang, J., Ding, C., Ma, Y., Liu, M. et al., Differential developmental requirement and peripheral regulation for dermal Vγ4 and Vγ6T17 cells in health and inflammation. *Nat. Commun*. 2014. **5**: 3986.

83 Rolblanco, L., Lazarevic, V., Awasthi, A., Mitsdoerffer, M., Wilson, B. S., Croxford, A. et al., IL-23 receptor regulates unconventional IL-17-producing T cells that control bacterial infections. *J. 2010. **184**: 1710–1720.

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85 Venken, K., Jacques, P., Mortier, C., Labadia, M. E., Decruy, T., Coudenys, J., Hoyt, K. et al., RORγt inhibition selectively targets IL-17 producing
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106 Bao, S., Zheng, J., Li, N., Huang, C., Chen, M., Cheng, Q., Li, Q. et al., Role of interleukin-23 in monocyte-derived dendritic cells of HBV-related acute-on-chronic liver failure and its correlation with the severity of liver damage. *Clin. Res. Hepatol. Gastroenterol.* 2017. 41: 147–155.

107 Belladonna, M. L., Renauld, J.-C., Bianchi, R., Vacca, C., Fallarino, F., Orabona, C., Fioretti, M. C. et al., IL-23 and IL-12 have overlapping, but distinct, effects on murine dendritic cells. *J. Immunol.* 2002. 168: 5448–5454.

108 Li, Y., Zhu, L., Chu, Z., Yang, T., Sun, H.-X., Yang, F., Wang, W. et al., Characterization and biological significance of IL-23-induced neutrophil polarization. *Cell Mol Immunol.* 2018. 15: 518–530.

109 Yadav, B., Specht, C. A., Lee, C. K., Pokrovskii, M., Huh, J. R., Littman, D. R. and Levitz, S. M., Lung eosinophils elicited during allergic and acute aspergillosis express RORγt and IL-23R but do not require IL-23 for IL-17 production. *PLoS Pathog.* 2021. 17: e1009891.

110 Glasmacher, E., Agrawal, S., Chang, A. B., Murphy, T. L., Zeng, W., Vander Lugt, B., Khan, A. A. et al., A genomic regulatory element that directs assembly and function of immune-specific AP-1-IRF complexes. *Science.* 2012. 338: 975–980.

111 Li, P., Spolski, R., Liao, W., Wang, L., Murphy, T. L., Murphy, K. M. and Leonard, W. J., BATF-JUN is critical for IRF4-mediated transcription in T cells. *Nature.* 2012. 490: 543–546.

112 Giofani, M., Madar, A., Galan, C., Sellars, M., Mace, K., Pauli, F., Agarwal, A. et al., A validated regulatory network for Th17 cell specification. *Cell.* 2012. 151: 289–303.

113 Pham, D., Moseley, C. E., Gao, M., Savic, D., Winstead, C. J., Sun, M., Kee, B. L. et al., Batf pioneers the reorganization of chromatin in developing effector T cells via Ets1-dependent recruitment of Cctf. *Cell Rep.* 2019. 29: 1203–1220. e7.

114 Hall, J. A., Pokrovskii, M., Kroehling, L., Kim, Bo-R, Kim, S. Y., Wu, L., Lee, J.-Y. et al., Transcription factor RORα enforces stability of the Th17 cell effector program by binding to a Rorc cis-regulatory element. *Immunity.* 2022. 55: 2027–2043. e9.

115 Xiao, S., Yosef, N., Yang, J., Wang, Y., Zhou, L., Zhu, C., Wu, C. et al., Small-molecule RORγt antagonists inhibit T helper 17 cell transcriptional network by divergent mechanisms. *Immunity.* 2014. 40: 477–489.

116 Gocke, A. R., Cravens, P. D., Ben, L.-H., Hussain, R. Z., Northrop, S. C., Racke, M. K. and Lovett-Racke, A. E., T-bet regulates the fate of Th1 and Th17 lymphocytes in autoimmunity. *J. Immunol.* 2007. 178: 1341–1348.

117 Krausgruber, T., Schiering, C., Adelmann, K., Harrison, O. J., Chomka, A., Pearson, C., Ahern, P. P. et al., T-bet is a key modulator of IL-23-driven
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86 Zhang, L., Yan, J., Yang, B., Zhang, G., Wang, M., Dong, S., Liu, W. et al., IL-23 activated γδ T cells affect Th17 cells and regulatory T cells by secreting IL-21 in children with primary nephrotic syndrome. *Scand. J. Immunol.* 2018. 87: 36–45.

87 Edwards, S. C., Sutton, C. E., Ladell, K., Grant, E. J., McIaren, J. E., Roche, F., Dash, P. et al., A population of proinflammatory T cells coexpresses αβ and γδ T cell receptors in mice and humans. *J. Exp. Med.* 2020. 217: e20190834.

88 Rachitskaya, A. V., Hansen, A. M., Horai, R., Li, Z., Villasmil, R., Luger, D., Nussenblatt, R. B. et al., Cutting edge: NKT cells constitutively express IL-23 receptor and RORγt and rapidly produce IL-17 upon receptor ligation in an IL-6-independent fashion. *J. Immunol.* 2008. 180: 5167–5171.

89 Van De Wetering, D., De Paus, R. A., Van Dissel, J. T. and Van De Vosse, E., IL-23 modulates CD56+/CD3- NK cell and CD56+/CD3+ NK-like T cell function differentially from IL-12. *Int. Immunol.* 2009. 21: 145–153.

90 Buonocore, S., Ahern, P. P., Uhlig, H. H., Ivanov, I. I., Littman, D. R., Maloy, K. J. and Powrie, F., Innate lymphoid cells drive IL-23 dependent innate intestinal pathology. *Nature*. 2010. 464: 1371–1375.

91 Bauché, D., Joyce-Shaikh, B., Fong, J., Villarino, A. V., Ku, K. S., Jain, R., Lee, Y.-C. et al., IL-23 and IL-2 activation of STAT5 is required for optimal IL-22 production in ILC3s during colitis. *Sci. Immunol.* 2020. 5: eaav1080.

92 Eken, A., Singh, A. K., Treuting, P. M. and Oukka, M., IL-23R+ innate lymphoid cells induce colitis via interleukin-22-dependent mechanism. *Mucosal Immunol.* 2014. 7: 143–154.

93 Blijdorp, I. C. J., Menegatti, S., Van Mens, L. J. J., Van De Sande, M. G. H., Chen, S., Hreggvidsdottir, H. S., Noordenbos, T. et al., Expansion of interleukin-22- and granulocyte-macrophage colony-stimulating factor-expressing, but not interleukin-17A-expressing, group 3 innate lymphoid cells in the inflamed joints of patients with spondyloarthritis. *Arthritis Rheumatol.* 2019. 71: 392–402.

94 Bernink, J. H., Ohne, Y., Teunissen, M. B. M., Wang, J., Wu, J., Krabbendam, L., Guntermann, C. et al., c-Kit-positive ILC2s exhibit an ILC3-like signature that may contribute to IL-17-mediated pathologies. *Nat. Immunol.* 2019. 20: 992–1003.

95 Croft, C. A., Thaller, A., Marie, S., Doisne, J.-M., Surace, L., Yang, R., Puel, A. et al., Notch, RORC and IL-23 signals cooperate to promote multi-lineage human innate lymphoid cell differentiation. *Nat. Commun.* 2022. 13: 4344.

96 Ziblat, A., Nuñez, S. Y., Raffo Iraolagoitia, X. L., Spallanzani, R. G., Torres, N. I., Sierra, J. M., Secchiari, F. et al., Interleukin (IL)-23 stimulates IFN-γ secretion by CD56bright natural killer cells and enhances IL-18-driven dendritic cells activation. *Front. Immunol.* 2018. 8: 1959.

97 Cocco, C., Canale, S., Frasson, C., Di Carlo, E., Ognio, E., Ribatti, D., Prigione, I. et al., Interleukin-23 acts as antitumor agent on childhood B-acute lymphoblastic leukemia cells. *Blood.* 2010. 116: 3887–3898.

98 Cutrona, G., Tripodo, C., Matis, S., Recchia, A. G., Massucco, C., Fabbi, M., Colombo, M. et al., Microenvironmental regulation of the IL-23R/IL-23 axis overrides chronic lymphocytic leukemia indolence. *Sci. Transl. Med.* 2018. 10: eaal1571.

99 Cocco, C., Morandi, F. and Airoldi, I., Interleukin-27 and interleukin-23 modulate human plasma cell functions. *J Leukoc Biol.* 2011. 89: 729–734.

100 Leitner, M., Heck, S., Nguyen, K., Nguyen, P. Q., Harfoush, S., Rosenkranz, E., Bals, R. et al., Allergic airway inflammation induces upregulation of the expression of IL-23R by macrophages and not in CD3+T cells and CD11c+F4/80- dendritic cells of the lung. *Cell Tissue Res.* 2022. 389: 85–98.

101 Schmiedel, B. J., Singh, D., Madrigal, A., Valdovino-Gonzalez, A. G., White, B. M., Zapardiel-Gonzalo, J., Ha, B. et al., Impact of genetic poly-

morphisms on human immune cell gene expression. *Cell.* 2018. 175: 1701–1715. e16.

102 Uhlén, M., Fagerberg, L., Hallström, B. M., Lindskog, C., Oksvold, P., Mardinoglu, A., Sivertsson, Å. et al., Proteomics. Tissue-based map of the human proteome. *Science.* 2015. 347: 1260419.

103 Sun, R. and Abraham, C., IL23 promotes antimicrobial pathways in human macrophages, which are reduced with the IBD-protective IL23R R381Q variant. *Cell Mol Gastroenterol Hepatol.* 2020. 10: 673–697.

104 Sun, R., Hedl, M. and Abraham, C., IL23 induces IL23R recycling and amplifies innate receptor-induced signalling and cytokines in human macrophages, and the IBD-protective IL23R R381Q variant modulates these outcomes. *Gut.* 2020. 69: 264–273.

105 Wang, C., Liu, T., Wang, Z., Li, W., Zhao, Q., Mi, Z. et al., IL-23/IL23R promote macrophage pyroptosis and Th1/Th17 cell differentiation in mycobacterial infection. *J. Invest. Dermatol.* 2023 May 12 [cited 2023 May 19];0(0). Available from: https://www.jidonline.org/article/S0022-202X(23)02062-6/fulltext

106 Bao, S., Zheng, J., Li, N., Huang, C., Chen, M., Cheng, Q., Li, Q. et al., Role of interleukin-23 in monocyte-derived dendritic cells of HBV-related acute-on-chronic liver failure and its correlation with the severity of liver damage. *Clin. Res. Hepatol. Gastroenterol.* 2017. 41: 147–155.

107 Belladonna, M. L., Renauld, J.-C., Bianchi, R., Vacca, C., Fallarino, F., Orabona, C., Fioretti, M. C. et al., IL-23 and IL-12 have overlapping, but distinct, effects on murine dendritic cells. *J. Immunol.* 2002. 168: 5448–5454.

108 Li, Y., Zhu, L., Chu, Z., Yang, T., Sun, H.-X., Yang, F., Wang, W. et al., Characterization and biological significance of IL-23-induced neutrophil polarization. *Cell Mol Immunol.* 2018. 15: 518–530.

109 Yadav, B., Specht, C. A., Lee, C. K., Pokrovskii, M., Huh, J. R., Littman, D. R. and Levitz, S. M., Lung eosinophils elicited during allergic and acute aspergillosis express RORγt and IL-23R but do not require IL-23 for IL-17 production. *PLoS Pathog.* 2021. 17: e1009891.

110 Glasmacher, E., Agrawal, S., Chang, A. B., Murphy, T. L., Zeng, W., Vander Lugt, B., Khan, A. A. et al., A genomic regulatory element that directs assembly and function of immune-specific AP-1-IRF complexes. *Science.* 2012. 338: 975–980.

111 Li, P., Spolski, R., Liao, W., Wang, L., Murphy, T. L., Murphy, K. M. and Leonard, W. J., BATF-JUN is critical for IRF4-mediated transcription in T cells. *Nature.* 2012. 490: 543–546.

112 Giofani, M., Madar, A., Galan, C., Sellars, M., Mace, K., Pauli, F., Agarwal, A. et al., A validated regulatory network for Th17 cell specification. *Cell.* 2012. 151: 289–303.

113 Pham, D., Moseley, C. E., Gao, M., Savic, D., Winstead, C. J., Sun, M., Kee, B. L. et al., Batf pioneers the reorganization of chromatin in developing effector T cells via Ets1-dependent recruitment of Cctf. *Cell Rep.* 2019. 29: 1203–1220. e7.

114 Hall, J. A., Pokrovskii, M., Kroehling, L., Kim, Bo-R, Kim, S. Y., Wu, L., Lee, J.-Y. et al., Transcription factor RORα enforces stability of the Th17 cell effector program by binding to a Rorc cis-regulatory element. *Immunity.* 2022. 55: 2027–2043. e9.

115 Xiao, S., Yosef, N., Yang, J., Wang, Y., Zhou, L., Zhu, C., Wu, C. et al., Small-molecule RORγt antagonists inhibit T helper 17 cell transcriptional network by divergent mechanisms. *Immunity.* 2014. 40: 477–489.

116 Gocke, A. R., Cravens, P. D., Ben, L.-H., Hussain, R. Z., Northrop, S. C., Racke, M. K. and Lovett-Racke, A. E., T-bet regulates the fate of Th1 and Th17 lymphocytes in autoimmunity. *J. Immunol.* 2007. 178: 1341–1348.

117 Krausgruber, T., Schiering, C., Adelmann, K., Harrison, O. J., Chomka, A., Pearson, C., Ahern, P. P. et al., T-bet is a key modulator of IL-23-driven
pathogenic CD4 + T cell responses in the intestine. *Nat. Commun.* 2016. 7: 11627.

118 Gökmen, M. R., Dong, R., Kanhere, A., Powell, N., Perucha, E., Jackson, I., Howard, J. K. et al., Genome-wide regulatory analysis reveals that T-bet controls Th17 lineage differentiation through direct suppression of IRF4. *J. Immunol.* 2013. **191**: 5925–5932.

119 Moon, Y.-M., Lee, S.-Y., Kwok, S.-K., Lee, S. H., Kim, D., Kim, W. K., Her, Y.-M. et al., The Fos-related antigen 1-JUNB/activator protein 1 transcription complex, a downstream target of signal transducer and activator of transcription 3, induces T helper 17 differentiation and promotes experimental autoimmune arthritis. *Front. Immunol.* 2017. **8**: 1793.

120 Shetty, A., Tripathi, S. K., Junttila, S., Buchacher, T., Biradar, R., Bhosale, S. D., Envall, T. et al., A systematic comparison of FOSL1, FOSL2 and BATF-mediated transcriptional regulation during early human Th17 differentiation. *Nucleic Acids. Res.* 2022. **50**: 4938–4958.

121 Ghoreschi, K., Laurence, A., Yang, X.-P., Tato, C. M., Mcgeachy, M. J., Konkel, J. E., Ramos, H. L. et al., Generation of pathogenic Th17 cells in the absence of TGF-β Signaling. *Nature*. 2010. **467**: 967–971.

122 Newcomb, D. C., Cephus, J. Y., Boswell, M. G., Fahrenholz, J. M., Langley, E. W., Feldman, A. S., Zhou, W. et al., Estrogen and progesterone decrease let-7f microRNA expression and increase IL-23/IL-23 receptor signaling and IL-17A production in patients with severe asthma. *J. Allergy Clin. Immunol.* 2015. **136**: 1025–1034. e11.

123 Fuseini, H., Cephus, J.-Y., Wu, P., Davis, J. B., Contreras, D. C., Gandhi, V. D., Rathmell, J. C. et al., ERα signaling increased IL-17A production in Th17 cells by upregulating IL-23R expression, mitochondrial respiration, and proliferation. *Front. Immunol.* 2019. **10**: 2740.

124 Angelou, C. C., Wells, A. C., Vijayaraghavan, J., Dougan, C. E., Lawlor, R., Iverson, E., Lazarevic, V. et al., Differentiation of pathogenic Th17 cells is negatively regulated by Let-7 MicroRNAs in a mouse model of multiple sclerosis. *Front. Immunol.* 2019. **10**: 3125.

125 Wang, L., Wang, E., Wang, Y., Mines, R., Xiang, K., Sun, Z., Zhou, G. et al., miR-34a is a microRNA safeguard for Citrobacter-induced inflammatory colon oncogenesis. *eLife*. 2018. **7**: e39479.

126 Matis, S., Grazia Recchia, A., Colombo, M., Cardillo, M., Fabbi, M., Todoerti, K., Bossio, S. et al., MiR-146b-5p regulates IL-23 receptor com-

plex expression in chronic lymphocytic leukemia cells. *Blood Adv.* 2022. 6: 5593–5612.

127 Hasan, Z., Koizumi, S.-I., Sasaki, D., Yamada, H., Arakaki, N., Fujihara, Y., Okitsu, S. et al., JunB is essential for IL-23-dependent pathogenicity of Th17 cells. *Nat. Commun.* 2017. **8**: 15628.

128 Carr, T. M., Wheaton, J. D., Houtz, G. M. and Giofani, M., JunB promotes Th17 cell identity and restrains alternative CD4+ T-cell programs during inflammation. *Nat. Commun.* 2017. **8**: 301.

129 Dang, E. V., Barbi, J., Yang, H.-Y., Jinasena, D., Yu, H., Zheng, Y., Bordman, Z. et al., Control of TH17/Treg balance by hypoxia-inducible factor 1. *Cell*. 2011. **146**: 772–784.

130 Meyer Zu Horste, G., Wu, C., Wang, C., Cong, L., Pawlak, M., Lee, Y., Elyaman, W. et al., RBPJ controls development of pathogenic Th17 cells by regulating IL-23 receptor expression. *Cell Rep.* 2016. **16**: 392–404.

131 Ando, N., Nakamura, Y., Aoki, R., Ishimaru, K., Ogawa, H., Okumura, Ko, Shibata, S. et al., Circadian gene clock regulates psoriasis-like skin inflammation in mice. *J. Invest. Dermatol.* 2015. **135**: 3001–3008.

132 Snyder, K. J., Choe, H. K., Gao, Y., Sell, N. E., Braunreiter, K. M., Zitzer, N. C., Neidemire-Colley, L. et al., Inhibition of bromodomain and extra terminal (BET) domain activity modulates the IL-23R/IL-17 axis and suppresses acute graft-versus-host disease. *Front. Oncol.* 2021. **11**: 760789.

**Abbreviations:** DC: dendritic cells · ILC: innate lymphoid cells · MAIT: mucosal-associated invariant T cells · Tfh: T-follicular helper cells

**Full correspondence:** Dr. Ikram Mezghiche, Institut Pasteur Paris, Immunoregulation unit, 25 Rue du Dr ROUX, 75724 Paris Cedex 15, Paris, France

e-mail: ikram.mezghiche@pasteur.fr

Received: 31/5/2023

Revised: 11/10/2023

Accepted: 12/10/2023

Accepted article online: 14/10/2023
pathogenic CD4 + T cell responses in the intestine. *Nat. Commun.* 2016. 7: 11627.

118 Gökmen, M. R., Dong, R., Kanhere, A., Powell, N., Perucha, E., Jackson, I., Howard, J. K. et al., Genome-wide regulatory analysis reveals that T-bet controls Th17 lineage differentiation through direct suppression of IRF4. *J. Immunol.* 2013. **191**: 5925–5932.

119 Moon, Y.-M., Lee, S.-Y., Kwok, S.-K., Lee, S. H., Kim, D., Kim, W. K., Her, Y.-M. et al., The Fos-related antigen 1-JUNB/activator protein 1 transcription complex, a downstream target of signal transducer and activator of transcription 3, induces T helper 17 differentiation and promotes experimental autoimmune arthritis. *Front. Immunol.* 2017. **8**: 1793.

120 Shetty, A., Tripathi, S. K., Junttila, S., Buchacher, T., Biradar, R., Bhosale, S. D., Envall, T. et al., A systematic comparison of FOSL1, FOSL2 and BATF-mediated transcriptional regulation during early human Th17 differentiation. *Nucleic Acids. Res.* 2022. **50**: 4938–4958.

121 Ghoreschi, K., Laurence, A., Yang, X.-P., Tato, C. M., Mcgeachy, M. J., Konkel, J. E., Ramos, H. L. et al., Generation of pathogenic Th17 cells in the absence of TGF-β Signaling. *Nature*. 2010. **467**: 967–971.

122 Newcomb, D. C., Cephus, J. Y., Boswell, M. G., Fahrenholz, J. M., Langley, E. W., Feldman, A. S., Zhou, W. et al., Estrogen and progesterone decrease let-7f microRNA expression and increase IL-23/IL-23 receptor signaling and IL-17A production in patients with severe asthma. *J. Allergy Clin. Immunol.* 2015. **136**: 1025–1034. e11.

123 Fuseini, H., Cephus, J.-Y., Wu, P., Davis, J. B., Contreras, D. C., Gandhi, V. D., Rathmell, J. C. et al., ERα signaling increased IL-17A production in Th17 cells by upregulating IL-23R expression, mitochondrial respiration, and proliferation. *Front. Immunol.* 2019. **10**: 2740.

124 Angelou, C. C., Wells, A. C., Vijayaraghavan, J., Dougan, C. E., Lawlor, R., Iverson, E., Lazarevic, V. et al., Differentiation of pathogenic Th17 cells is negatively regulated by Let-7 MicroRNAs in a mouse model of multiple sclerosis. *Front. Immunol.* 2019. **10**: 3125.

125 Wang, L., Wang, E., Wang, Y., Mines, R., Xiang, K., Sun, Z., Zhou, G. et al., miR-34a is a microRNA safeguard for Citrobacter-induced inflammatory colon oncogenesis. *eLife*. 2018. **7**: e39479.

126 Matis, S., Grazia Recchia, A., Colombo, M., Cardillo, M., Fabbi, M., Todoerti, K., Bossio, S. et al., MiR-146b-5p regulates IL-23 receptor com-

plex expression in chronic lymphocytic leukemia cells. *Blood Adv.* 2022. 6: 5593–5612.

127 Hasan, Z., Koizumi, S.-I., Sasaki, D., Yamada, H., Arakaki, N., Fujihara, Y., Okitsu, S. et al., JunB is essential for IL-23-dependent pathogenicity of Th17 cells. *Nat. Commun.* 2017. **8**: 15628.

128 Carr, T. M., Wheaton, J. D., Houtz, G. M. and Giofani, M., JunB promotes Th17 cell identity and restrains alternative CD4+ T-cell programs during inflammation. *Nat. Commun.* 2017. **8**: 301.

129 Dang, E. V., Barbi, J., Yang, H.-Y., Jinasena, D., Yu, H., Zheng, Y., Bordman, Z. et al., Control of TH17/Treg balance by hypoxia-inducible factor 1. *Cell*. 2011. **146**: 772–784.

130 Meyer Zu Horste, G., Wu, C., Wang, C., Cong, L., Pawlak, M., Lee, Y., Elyaman, W. et al., RBPJ controls development of pathogenic Th17 cells by regulating IL-23 receptor expression. *Cell Rep.* 2016. **16**: 392–404.

131 Ando, N., Nakamura, Y., Aoki, R., Ishimaru, K., Ogawa, H., Okumura, Ko, Shibata, S. et al., Circadian gene clock regulates psoriasis-like skin inflammation in mice. *J. Invest. Dermatol.* 2015. **135**: 3001–3008.

132 Snyder, K. J., Choe, H. K., Gao, Y., Sell, N. E., Braunreiter, K. M., Zitzer, N. C., Neidemire-Colley, L. et al., Inhibition of bromodomain and extra terminal (BET) domain activity modulates the IL-23R/IL-17 axis and suppresses acute graft-versus-host disease. *Front. Oncol.* 2021. **11**: 760789.

**Abbreviations:** DC: dendritic cells · ILC: innate lymphoid cells · MAIT: mucosal-associated invariant T cells · Tfh: T-follicular helper cells

**Full correspondence:** Dr. Ikram Mezghiche, Institut Pasteur Paris, Immunoregulation unit, 25 Rue du Dr ROUX, 75724 Paris Cedex 15, Paris, France

e-mail: ikram.mezghiche@pasteur.fr

Received: 31/5/2023

Revised: 11/10/2023

Accepted: 12/10/2023

Accepted article online: 14/10/2023