Tissue-Specific Features of Innate Lymphoid Cells
Authors: Isabel Meininger, Anna Carrasco, Anna Rao, Tea Soini, Efthymia Kokkinou, Jenny Mjösberg
Journal: Trends in Immunology (2020)

Recent progress in the characterization of innate lymphoid cells (ILCs) across various organs in mice and humans has revealed distinct ILC phenotypes and functionalities depending on their localization.Transcriptional profiling and genetic engineering have identified tissue-specific functions of ILC1 cells in mice. In humans, the definition of ILC1 cells is controversial and poorly understood, which complicates their characterization and comparison between organs.ILC2 cells display a relatively homogeneous phenotype across different tissues in mice and humans. Tissue variations are restricted to receptors involved in sensing environmental signals such as cytokines.ILC3 cells differ in their homing receptor expression patterns, antigen-presentation ability, and cytokine responsiveness not only across tissues but also across distinct niches within tissues. Although the function of the circulating immune cell compartment has been studied in detail for decades, limitations in terms of access and cell yields from peripheral tissues have restricted our understanding of tissue-based immunity, particularly in humans. Recent advances in high-throughput protein analyses, transcriptional profiling, and epigenetics have partially overcome these obstacles. Innate lymphoid cells (ILCs) are predominantly tissue-resident, and accumulating data indicate that they have significant tissue-specific functions. We summarize current knowledge of ILC phenotypes in various tissues in mice and humans, aiming to clarify ILC immunity in distinct anatomical locations. Although the function of the circulating immune cell compartment has been studied in detail for decades, limitations in terms of access and cell yields from peripheral tissues have restricted our understanding of tissue-based immunity, particularly in humans. Recent advances in high-throughput protein analyses, transcriptional profiling, and epigenetics have partially overcome these obstacles. Innate lymphoid cells (ILCs) are predominantly tissue-resident, and accumulating data indicate that they have significant tissue-specific functions. We summarize current knowledge of ILC phenotypes in various tissues in mice and humans, aiming to clarify ILC immunity in distinct anatomical locations. Innate lymphoid cells (ILCs) comprise non-T, non-B, lymphoid cells in mice and humans. A universal nomenclature proposed in 2018 [1.Vivier E. et al.Innate lymphoid cells: 10 years on.Cell. 2018; 174: 1054-1066Abstract Full Text Full Text PDF PubMed Scopus (346) Google Scholar] segregated ILCs into five distinct subsets: natural killer (NK) cells, ILC1, ILC2, ILC3, and lymphoid tissue inducer cells (LTi, see Glossary), of which only NK cells and ILC1, the latter in some tissues, demonstrate cytotoxic activity [2.Riggan L. et al.True detective: unraveling group 1 innate lymphocyte heterogeneity.Trends Immunol. 2019; 40: 909-921Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar]. Although cytotoxic CD56dim NK cells lack the interleukin (IL)-7 receptor subunit α (IL-7R-α, also known as CD127), and CD56bright NK cells express intermediate amounts, ILCs show high expression of CD127 [3.Spits H. et al.NK cells and type 1 innate lymphoid cells: partners in host defense.Nat. 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Moreover, although ILCs lack antigen-specific receptors, they share phenotypic and functional characteristics with CD4+ T helper (Th) cells, where ILC1 mirror Th1, ILC2 mirror Th2, and ILC3 mirror Th17 cells [7.Colonna M. Innate lymphoid cells: diversity, plasticity, and unique functions in immunity.Immunity. 2018; 48: 1104-1117Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar]. However, despite these similarities, ILCs and T cells arise from distinct developmental pathways and display unique epigenetic and transcriptional programs, suggestive of their nonredundant roles [8.Shih H.Y. et al.Developmental acquisition of regulomes underlies innate lymphoid cell functionality.Cell. 2016; 165: 1120-1133Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar, 9.Koues O.I. et al.Distinct gene regulatory pathways for human innate versus adaptive lymphoid cells.Cell. 2016; 165: 1134-1146Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar, 10.Ercolano G. et al.Distinct and shared gene expression for human innate versus adaptive helper lymphoid cells.J. Leukoc. Biol. 2020; 108: 723-737Crossref PubMed Scopus (0) Google Scholar]. Similarly to Th subsets, ILC1 are regulated by the transcription factor (TF) T-bet and produce interferon (IFN)-γ, whereas ILC2 are governed by Gata-binding protein (GATA)-3 and mainly secrete IL-5 and IL-13. ILC3 are dependent on the retinoid-related orphan receptor γt (RORγt) and aryl hydrocarbon receptor (AHR), and release IL-17 and IL-22 [7.Colonna M. Innate lymphoid cells: diversity, plasticity, and unique functions in immunity.Immunity. 2018; 48: 1104-1117Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar,11.Spits H. et al.Innate lymphoid cells-a proposal for uniform nomenclature.Nat. Rev. Immunol. 2013; 13: 145-149Crossref PubMed Scopus (0) Google Scholar]. Similarly to ILC3, LTi cells, that are involved in the formation of secondary lymphoid organs (SLOs) during embryogenesis, also depend on RORγt [12.Eberl G. et al.An essential function for the nuclear receptor RORγt in the generation of fetal lymphoid tissue inducer cells.Nat. Immunol. 2004; 5: 64-73Crossref PubMed Scopus (689) Google Scholar]. ILCs mostly reside within tissues, particularly in mucosal linings, where they might play tissue-protective or inflammatory roles [1.Vivier E. et al.Innate lymphoid cells: 10 years on.Cell. 2018; 174: 1054-1066Abstract Full Text Full Text PDF PubMed Scopus (346) Google Scholar]. Parabiosis experiments in mice have demonstrated that ILCs, but not NK cells, are predominantly tissue-resident immune cells [13.Gasteiger G. et al.Tissue residency of innate lymphoid cells in lymphoid and nonlymphoid organs.Science. 2015; 350: 981-985Crossref PubMed Scopus (327) Google Scholar], even under inflammatory conditions, a concept that has been challenged by other reports [14.Huang Y. et al.S1P-dependent interorgan trafficking of group 2 innate lymphoid cells supports host defense.Science. 2018; 359: 114-119Crossref PubMed Scopus (134) Google Scholar]. From further mouse studies, it is nonetheless becoming increasingly clearer that the ILC pool residing in a given tissue is the result of waves of development from fetal to adult life – a phenomenon that has been termed layered ontogeny [15.Schneider C. et al.Tissue-resident group 2 innate lymphoid cells differentiate by layered ontogeny and in situ perinatal priming.Immunity. 2019; 50: 1425-1438Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar,16.Oherle K. et al.Insulin-like growth factor 1 supports a pulmonary niche that promotes type 3 innate lymphoid cell development in newborn lungs.Immunity. 2020; 52: 275-294Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar]. Nevertheless, how the ontogeny of ILCs differs between tissues remains obscure. Although the origin of tissue-resident ILCs in humans is technically challenging to address, there is evidence that the local ILC pool can at least partially be replenished by infiltration and in situ differentiation of circulating naïve ILCs – so-called innate lymphoid cell precursors (ILCP) [17.Lim A.I. et al.Systemic human ILC precursors provide a substrate for tissue ILC differentiation.Cell. 2017; 168: 1086-1100Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar,18.Nagasawa M. et al.KLRG1 and NKp46 discriminate subpopulations of human CD117+CRTH2− ILCs biased toward ILC2 or ILC3.J. Exp. Med. 2019; 216: 1762-1776Crossref PubMed Scopus (0) Google Scholar]. Reflecting their tissue residency and the impact of the microenvironment on ILC function, recent studies have revealed profound tissue-specific transcriptional signatures and heterogeneity for human [19.Yudanin N.A. et al.Spatial and temporal mapping of human innate lymphoid cells reveals elements of tissue specificity.Immunity. 2019; 50: 505-519Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar] and mouse ILCs [20.Gury-BenAri M. et al.The spectrum and regulatory landscape of intestinal innate lymphoid cells are shaped by the microbiome.Cell. 2016; 166: 1231-1246Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar], respectively. Accumulating evidence suggests that ILCs are shaped by the microenvironment and exert tissue-specific functions depending on the signals they receive. In this review we summarize recent studies on the tissue-specific features of ILCs across organs in mice and humans. We discuss in detail the phenotypic and transcriptional differences that contribute to distinct ILC profiles in different tissues, highlighting the parallels between mice and humans. Understanding how ILCs are impacted by various tissue microenvironments is important for improving therapeutic strategies in pathologies that affect specific tissues. Numerous mouse studies over the past 10 years have revealed that Lin−NK1.1+NKp46+ NK cells or ILC1 display a highly heterogeneous expression pattern of cell-surface markers and TFs in different tissue environments [3.Spits H. et al.NK cells and type 1 innate lymphoid cells: partners in host defense.Nat. Immunol. 2016; 17: 758-764Crossref PubMed Google Scholar]. In this review we do not unravel the heterogeneity of ILC1 and NK cells, which has been excellently reviewed elsewhere [2.Riggan L. et al.True detective: unraveling group 1 innate lymphocyte heterogeneity.Trends Immunol. 2019; 40: 909-921Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar], but instead focus on the tissue-specific features reported for ILC1. Although ILCs are defined as tissue-resident lymphocytes, migratory ILCs have been reported. CD62L+CCR7+ ILC1 is the most prevalent subset in the blood of mice (CD127+Lin−NK1.1+NKp46+T-bet+) [21.Dutton E.E. et al.Peripheral lymph nodes contain migratory and resident innate lymphoid cell populations.Sci. Immunol. 2019; 4eaau8082Crossref PubMed Scopus (11) Google Scholar], possibly representing an immature precursor of more mature subsets in tissues. In the liver, ILC1 are defined as CD49a+CD49b− cells that do not express the TF Eomes (Figure 1). These ILC1 produce high amounts of IFN-γ, granzyme C, and tumor necrosis factor ligand superfamily member 10 (TNFSF10, also known as TRAIL) for target cell killing [22.Peng H. et al.Liver-resident NK cells confer adaptive immunity in skin-contact inflammation.J. Clin. Invest. 2013; 123: 1444-1456Crossref PubMed Scopus (291) Google Scholar, 23.Daussy C. et al.T-bet and Eomes instruct the development of two distinct natural killer cell lineages in the liver and in the bone marrow.J. Exp. Med. 2014; 211: 563-577Crossref PubMed Scopus (284) Google Scholar, 24.Sojka D.K. et al.Tissue-resident natural killer (NK) cells are cell lineages distinct from thymic and conventional splenic NK cells.elife. 2014; 3: e01659Crossref PubMed Scopus (283) Google Scholar, 25.Robinette M.L. et al.Transcriptional programs define molecular characteristics of innate lymphoid cell classes and subsets.Nat. Immunol. 2015; 16: 306-317Crossref PubMed Scopus (329) Google Scholar, 26.Weizman O. El et al.ILC1 confer early host protection at initial sites of viral infection.Cell. 2017; 171: 795-808Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar, 27.Gordon S.M. et al.The transcription factors T-bet and Eomes control key checkpoints of natural killer cell maturation.Immunity. 2012; 36: 55-67Abstract Full Text Full Text PDF PubMed Scopus (394) Google Scholar, 28.Takeda K. et al.TRAIL identifies immature natural killer cells in newborn mice and adult mouse liver.Blood. 2005; 105: 2082-2089Crossref PubMed Scopus (186) Google Scholar]. There are discrepancies in the observed expression levels of granzyme A/B/C in ILC1 in liver and intestine [23.Daussy C. et al.T-bet and Eomes instruct the development of two distinct natural killer cell lineages in the liver and in the bone marrow.J. Exp. Med. 2014; 211: 563-577Crossref PubMed Scopus (284) Google Scholar,25.Robinette M.L. et al.Transcriptional programs define molecular characteristics of innate lymphoid cell classes and subsets.Nat. Immunol. 2015; 16: 306-317Crossref PubMed Scopus (329) Google Scholar,26.Weizman O. El et al.ILC1 confer early host protection at initial sites of viral infection.Cell. 2017; 171: 795-808Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar,29.Klose C.S.N. et al.Differentiation of type 1 ILCs from a common progenitor to all helper-like innate lymphoid cell lineages.Cell. 2014; 157: 340-356Abstract Full Text Full Text PDF PubMed Scopus (588) Google Scholar], with more cytolytic activity being reported for liver ILC1 [24.Sojka D.K. et al.Tissue-resident natural killer (NK) cells are cell lineages distinct from thymic and conventional splenic NK cells.elife. 2014; 3: e01659Crossref PubMed Scopus (283) Google Scholar]. Of note, different surface markers have been employed to separate ILC1 and NK cells in the liver and small intestine, which might identify ILC1/NK cell populations with different features [25.Robinette M.L. et al.Transcriptional programs define molecular characteristics of innate lymphoid cell classes and subsets.Nat. Immunol. 2015; 16: 306-317Crossref PubMed Scopus (329) Google Scholar]. Because NK cells and ILC1 show different but overlapping phenotypes and functions, especially in the liver, there is so far no clear distinction between the two cell types. Single-cell RNA sequencing (scRNA-seq) of small intestinal lamina propria (siLP) ILC1 revealed the presence of four distinct transcriptional ILC1 states, ILC1a–d [20.Gury-BenAri M. et al.The spectrum and regulatory landscape of intestinal innate lymphoid cells are shaped by the microbiome.Cell. 2016; 166: 1231-1246Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar], that are characterized by graded expression of Tbx21 (encoding T-bet). Whereas ILC1a express the lowest amounts of Tbx21 and Ifng, ILC1d show the highest expression of Tbx21, Gzmb (granzyme B), and Gzmc, suggesting a high degree of functional specialization among ILC1 in the small intestine [20.Gury-BenAri M. et al.The spectrum and regulatory landscape of intestinal innate lymphoid cells are shaped by the microbiome.Cell. 2016; 166: 1231-1246Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar]. Compared with spleen and liver, siLP ILC1 showed a more activated and heterogeneous profile, perhaps because the microbial environment modulates ILC1 responsiveness and can lead to versatile responses within distinct transcriptional states (ILC1a–d) [20.Gury-BenAri M. et al.The spectrum and regulatory landscape of intestinal innate lymphoid cells are shaped by the microbiome.Cell. 2016; 166: 1231-1246Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar,25.Robinette M.L. et al.Transcriptional programs define molecular characteristics of innate lymphoid cell classes and subsets.Nat. Immunol. 2015; 16: 306-317Crossref PubMed Scopus (329) Google Scholar]. siLP subsets express high amounts of the TF Nfil3, that is required for the development of intestinal intraepithelial ILC1 (ieILC1)/NK cells (NKp46+NK1.1+CD160+) as well as of CD49b−Eomes− ILC1 in adipose tissue [25.Robinette M.L. et al.Transcriptional programs define molecular characteristics of innate lymphoid cell classes and subsets.Nat. Immunol. 2015; 16: 306-317Crossref PubMed Scopus (329) Google Scholar,30.Fuchs A. et al.Intraepithelial type 1 innate lymphoid cells are a unique subset of IL-12- and IL-15-responsive IFN-γ-producing cells.Immunity. 2013; 38: 769-781Abstract Full Text Full Text PDF PubMed Scopus (492) Google Scholar, 31.Geiger T.L. et al.Nfil3 is crucial for development of innate lymphoid cells and host protection against intestinal pathogens.J. Exp. Med. 2014; 211: 1723-1731Crossref PubMed Scopus (158) Google Scholar, 32.O'Sullivan T.E. et al.Adipose-resident group 1 innate lymphoid cells promote obesity-associated insulin resistance.Immunity. 2016; 45: 428-441Abstract Full Text Full Text PDF PubMed Google Scholar]. Because ILC1 in liver, skin, salivary glands, and uterus do not depend on Nfil3 [24.Sojka D.K. et al.Tissue-resident natural killer (NK) cells are cell lineages distinct from thymic and conventional splenic NK cells.elife. 2014; 3: e01659Crossref PubMed Scopus (283) Google Scholar,33.Cortez V.S. et al.Salivary gland NK cells sevelop independently of Nfil3 in steady-state.J. Immunol. 2014; 192: 4487-4491Crossref PubMed Scopus (0) Google Scholar], one could speculate that ILC1 in different tissues arise from different progenitors and/or execute a different maturation program depending on the tissue environment. This theory is supported by the fact that only liver ILC1 are dramatically reduced in Zfp683−/− mice (Zfp683 encodes the TF Hobit) relative to wild-type (WT) mice [26.Weizman O. El et al.ILC1 confer early host protection at initial sites of viral infection.Cell. 2017; 171: 795-808Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar,34.Mackay L.K. et al.Hobit and Blimp1 instruct a universal transcriptional program of tissue residency in lymphocytes.Science. 2016; 352: 459-463Crossref PubMed Scopus (278) Google Scholar]. More fate-mapping studies in mice will be necessary to unravel the developmental programs that account for organ-specific ILC1 origins and features. Several cell-surface markers including CD90, CD69, CD49a, Ly6C, CD103, and CD61 were found to be differentially expressed by ILC1 in different tissues [24.Sojka D.K. et al.Tissue-resident natural killer (NK) cells are cell lineages distinct from thymic and conventional splenic NK cells.elife. 2014; 3: e01659Crossref PubMed Scopus (283) Google Scholar,26.Weizman O. El et al.ILC1 confer early host protection at initial sites of viral infection.Cell. 2017; 171: 795-808Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar,29.Klose C.S.N. et al.Differentiation of type 1 ILCs from a common progenitor to all helper-like innate lymphoid cell lineages.Cell. 2014; 157: 340-356Abstract Full Text Full Text PDF PubMed Scopus (588) Google Scholar,30.Fuchs A. et al.Intraepithelial type 1 innate lymphoid cells are a unique subset of IL-12- and IL-15-responsive IFN-γ-producing cells.Immunity. 2013; 38: 769-781Abstract Full Text Full Text PDF PubMed Scopus (492) Google Scholar,35.Cortez V.S. et al.Transforming growth factor-β signaling guides the differentiation of innate lymphoid cells in salivary glands.Immunity. 2016; 44: 1127-1139Abstract Full Text Full Text PDF PubMed Google Scholar,36.Park E. et al.Toxoplasma gondii infection drives conversion of NK cells into ILC1-like cells.eLife. 2019; 8: e47605Crossref PubMed Scopus (8) Google Scholar]. In addition to tissue-specific ILC1 phenotypes, their definition becomes even more complex given that NK cells can upregulate CD49a, Ly6C, CD69, TRAIL, and CD90, and decrease Eomes, upon transfer into murine cytomegalovirus (MCMV)-infected mice, or in response to proinflammatory cytokines in vivo and in vitro [26.Weizman O. El et al.ILC1 confer early host protection at initial sites of viral infection.Cell. 2017; 171: 795-808Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar,37.Bezman N.A. et al.Molecular definition of the identity and activation of natural killer cells.Nat. Immunol. 2012; 13: 1000-1008Crossref PubMed Scopus (158) Google Scholar,38.Sheppard S. et al.The murine natural cytotoxic receptor NKp46/NCR1 controls TRAIL protein expression in NK cells and ILC1s.Cell Rep. 2018; 22: 3385-3392Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar]. However, the inhibitory receptor CD200r1 could represent a stable ILC1 marker in several tissues such as adipose tissue, liver, spleen, and peritoneal cavity [26.Weizman O. El et al.ILC1 confer early host protection at initial sites of viral infection.Cell. 2017; 171: 795-808Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar]. Although several ILC1/NK cell-related surface markers have been reported, tissue- and cell type-specific markers need to be identified to enable an organ-specific definition of ILC1 that serves to distinguish them from NK cells. A more distinct population of NKp46+NK1.1+ ILC1 has been found in salivary glands [33.Cortez V.S. et al.Salivary gland NK cells sevelop independently of Nfil3 in steady-state.J. Immunol. 2014; 192: 4487-4491Crossref PubMed Scopus (0) Google Scholar,35.Cortez V.S. et al.Transforming growth factor-β signaling guides the differentiation of innate lymphoid cells in salivary glands.Immunity. 2016; 44: 1127-1139Abstract Full Text Full Text PDF PubMed Google Scholar] that share features with tumor-associated ILC1 [39.Dadi S. et al.Cancer immunosurveillance by tissue-resident innate lymphoid cells and innate-like T cells.Cell. 2016; 164: 365-377Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar]. Salivary gland ILC1 express CD49a, CD103, and CD69 that all promote retention within tissues [33.Cortez V.S. et al.Salivary gland NK cells sevelop independently of Nfil3 in steady-state.J. Immunol. 2014; 192: 4487-4491Crossref PubMed Scopus (0) Google Scholar]. These cells exhibit characteristic features of both NK cells and ILCs: salivary gland ILC1 express Eomes and T-bet as well as CD49b, but show no CD127 expression, and exhibit low IFN-γ production and cytotoxic granule release, suggesting that they represent a distinct subset of ILC1 [33.Cortez V.S. et al.Salivary gland NK cells sevelop independently of Nfil3 in steady-state.J. Immunol. 2014; 192: 4487-4491Crossref PubMed Scopus (0) Google Scholar,40.Tessmer M.S. et al.Salivary gland NK cells are phenotypically and functionally unique.PLoS Pathog. 2011; 7: e1001254Crossref PubMed Scopus (0) Google Scholar]. One key factor reported to support the acquisition of an ILC1-like phenotype in salivary glands and in the tumor microenvironment is the cytokine TGF-β [35.Cortez V.S. et al.Transforming growth factor-β signaling guides the differentiation of innate lymphoid cells in salivary glands.Immunity. 2016; 44: 1127-1139Abstract Full Text Full Text PDF PubMed Google Scholar,41.Gao Y. et al.Tumor immunoevasion by the conversion of effector NK cells into type 1 innate lymphoid cells.Nat. Immunol. 2017; 18: 1004-1015Crossref PubMed Scopus (182) Google Scholar]. In a methylcholanthrene (MCA)-induced fibrosarcoma mouse model, TGF-β signaling promoted the conversion of NK cells (CD49a−CD49b+) into an intermediate ILC1 state (CD49a+CD49b+), and finally into noncytotoxic ILC1 (CD49a+CD49b−) [41.Gao Y. et al.Tumor immunoevasion by the conversion of effector NK cells into type 1 innate lymphoid cells.Nat. Immunol. 2017; 18: 1004-1015Crossref PubMed Scopus (182) Google Scholar]. Because NK cells were shown to be essential for preventing fibrosarcoma formation and melanoma growth in MCA-tumor bearing mice, TGF-β-driven conversion of NK cells into ILC1 might represent a putative mechanism by which tumors escape immune surveillance. Similarly, in salivary glands, ablation of TGF-β receptor type 2 (TGF-βR2, encoded by Tgfbr2) in ILC1-like cells in Tgfbr2fl/fl × Ncr1cre mice led to reduced expression of CD49a, CD103, CD69, and TRAIL, and upregulation of NK cell markers, relative to WT mice [35.Cortez V.S. et al.Transforming growth factor-β signaling guides the differentiation of innate lymphoid cells in salivary glands.Immunity. 2016; 44: 1127-1139Abstract Full Text Full Text PDF PubMed Google Scholar] – findings that were not seen in liver or gut. However, TGF-β only partially mediated NK cell to ILC1 conversion in the obese liver environment in a model comparing lean and obese mice [42.Cuff A.O. et al.The obese liver environment mediates conversion of nk cells to a less cytotoxic ILC1-like phenotype.Front. Immunol. 2019; 10: 2180Crossref PubMed Scopus (4) Google Scholar], suggesting that the combination of TGF-β with liver-specific features might promote the acquisition of an ILC1-like phenotype. Thus, a more detailed analysis of ILC1-specific signaling pathways in various tissues would be highly beneficial to understand distinct ILC1 phenotypes and functions in different organs, and might reveal tissue-specific targets to enable the development of selective candidate therapeutics to treat ILC1/NK cell-mediated disease. Compared with mouse ILC1, the definition of ILC1 in humans is highly controversial. The existence of prototypical helper CD127+ ILC1, NK cells with low cytotoxic activity and a subset of cytotoxic ieILC1 complicates a uniform nomenclature for ILC1 and their comparison between studies [3.Spits H. et al.NK cells and type 1 innate lymphoid cells: partners in host defense.Nat. Immunol. 2016; 17: 758-764Crossref PubMed Google Scholar]. In addition to the conventional CD56dim and CD56bright NK subsets in humans [43.Cooper M.A. et al.The biology of human natural killer-cell subsets.Trends Immunol. 2001; 22: 633-640Abstract Full Text Full Text PDF PubMed Scopus (1846) Google Scholar], several organ-specific subsets of NK cells have been described, including the liver CD49a+ NK cells and ieILC1 in the intestine (Table 1) [30.Fuchs A. et al.Intraepithelial type 1 innate lymphoid cells are a unique subset of IL-12- and IL-15-responsive IFN-γ-producing cells.Immunity. 2013; 38: 769-781Abstract Full Text Full Text PDF PubMed Scopus (492) Google Scholar,44.Cella M. et al.Subsets of ILC3−ILC1-like cells generate a diversity spectrum of innate lymphoid cells in human mucosal tissues.Nat. Immunol. 2019; 20: 980-991Crossref PubMed Scopus (0) Google Scholar,45.Marquardt N. et al.Identification and characterization of human intrahepatic CD49a+ NK cells.J. Immunol. 2015; 194: 2467-2471Crossref PubMed Scopus (0) Google Scholar]. The human liver-unique subset displays low cytotoxicity and high capacity for cytokine production [45.Marquardt N. et al.Identification and characterization of human intrahepatic CD49a+ NK cells.J. Immunol. 2015; 194: 2467-2471Crossref PubMed Scopus (0) Google Scholar], and has been proposed to be the human counterpart of the intrahepatic tissue-resident NK cells in the mouse [22.Peng H. et al.Liver-resident NK cells confer adaptive immunity in skin-contact inflammation.J. Clin. Invest. 2013; 123: 1444-1456Crossref PubMed Scopus (291) Google Scholar, 23.Daussy C. et al.T-bet and Eomes instruct the development of two distinct natural killer cell lineages in the liver and in the bone marrow.J. Exp. Med. 2014; 211: 563-577Crossref PubMed Scopus (284) Google Scholar, 24.Sojka D.K. et al.Tissue-resident natural killer (NK) cells are cell lineages distinct from thymic and conventional splenic NK cells.elife. 2014; 3: e01659Crossref PubMed Scopus (283) Google Scholar,27.Gordon S.M. et al.The transcription factors T-bet and Eomes control key checkpoints of natural killer cell maturation.Immunity. 2012; 36: 55-67Abstract Full Text Full Text PDF PubMed Scopus (394) Google Scholar]. ieILC1 were described in human tonsil and gut, and were increased in the gut during Crohn's disease [30.Fuchs A. et al.Intraepithelial type 1 innate lymphoid cells are a unique subset of IL-12- and IL-15-responsive IFN-γ-producing cells.Immunity. 2013; 38: 769-781Abstract Full Text Full Text PDF PubMed Scopus (492) Google Scholar]. Similarly to conventional NK cells, ieILC1 lack CD127, are cytotoxic, and express T-bet and Eomes [30.Fuchs A. et al.Intraepithelial type 1 innate lymphoid cells are a unique subset of IL-12- and IL-15-responsive IFN-γ-producing cells.Immunity. 2013; 38: 769-781Abstract Full Text Full Text PDF PubMed Scopus (492) Google Scholar]. In line with this, SPADE-tree analysis of intestinal flow cytometry data clustered ieILC1 with NK cells, separately from CD127+ ILCs [46.Sagebiel A.F. et al.Tissue-resident Eomes+ NK cells are the major innate lymphoid cell population in human infant intestine.Nat. Commun. 2019; 10: 975Crossref PubMed Scopus (5) Google Scholar]. The presence of ieILC1 in gut and intestinal draining lymph nodes (LN), and their absence in blood, bone marrow (BM), lung, and spleen, has recently been confirmed by high-dimensional flow cytometry profiling of NK cells from healthy organ donors [47.Dogra P. et al.Tissue determinants of human NK cell development, function, and residence.Cell. 2020; 180: 749-763Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar]. Hence, NK cells and cytotoxic ILC1 (ieILC1) show tissue-specific distributions, possibly reflecting their divergent and microenvironment-dependent roles.Table 1Reported Human ILC1 Markers with Differential Expression in Various TissuesaKey: + positive; – negative; +/– heterogeneous; * reported RNA expression [19]., bAbbreviations: CD127, IL-7 receptor subunit α (IL-7R-α); ILC1, innate lymphoid cell type 1; ieILC1, intraepithelial ILC1; LN, lymph node; n.d., not determined..ILC1TissueT-betEomesCD56CD127CD49aCD103NKp44CD16CD69Liver ILC