bluuebunny/crossref_metadata_2025_split huggingface dataset:
IL-36γ prevents immunopathology during influenza infection
Authors: Wein Alexander N , Dunbar Paul , McMaster Sean R , Kumar Nivedha , Hayward Sarah L , Denning Timothy L , Kohlmeier Jacob E 
Published: January 2023

Abstract
Influenza infection is a disease of high importance for public health, but the roles of individual cytokines in the pathogenesis of influenza infection remains to be elucidated. The IL-36 cytokine family is a relative of IL-1 and functions and signals in an analogous fashion. Despite their roles in many inflammatory conditions, the impact of IL-36 family cytokines on influenza pathogenesis and immunity remain largely undefined. To better understand the roles of IL-36 cytokines during influenza infection, we investigated IL-36 cytokine expression during low (x31) and high (PR8) pathogenesis influenza infection. We observed that IL-36γ is significantly upregulated during both low (x31) and high (PR8) pathogenesis influenza infection and has immune and non-immune cell sources. Unexpectedly, we observed that deletion of IL-36γ causes greater morbidity and mortality compared to WT mice, suggesting that the IL-36γ has a previously unknown protective function in addition to its pro-inflammatory roles. This increased morbidity correlates with a significant decrease in the number of alveolar macrophages in IL-36γ−/− mice during the early stages of influenza infection, and the rate of viral clearance varies between the WT and IL-36γ−/− mice based on the strain and dose of virus. We are currently performing RNA-Seq analysis to identify the protective immune mechanisms induced by IL-36γ signaling during highly pathogenic influenza infection. Overall, our results suggest a novel, protective role for IL-36γ during influenza infection and may suggest potential therapeutic approaches for ameliorating influenza pathogenesis.
The White adipose tissue represents a major hub for memory T cells endowed with potent effector function
Authors: Han Seong-Ji , Zaretsky Arielle Glatman , Collins Nicholas , Oliviera Vinicius , da Fonseca Denise Morais , Belkaid Yasmine 
Published: January 2023

Abstract
The white adipose tissue represents 15% of healthy mammalian hosts. In addition to serving as a scaffold for the lymphatic and blood vasculature, this compartment plays a fundamental role in the control of host metabolism. To which extent the adipose tissue also contributes to immune surveillance and long-term protective defense remains largely unknown. Our studies show that under steady state conditions, the white adipose tissue is home to abundant and diverse effector and memory lymphocyte populations. Following infection, the adipose tissue accumulates large numbers of pathogen-specific memory T cells, including tissue-resident (TRM) cells characterized by a defined phenotypic profile and enhanced proliferative capacity. Thus, the white adipose tissue develops immune responses in parallel with, but distinct from, its connected tissue site. Local reactivation of adipose tissue TRM leads to rapid and broad responses with systemic impact on immune pathways. Together, these results uncover the adipose tissue as a reservoir of memory T cells endowed with long-term protective functions, positioning this compartment as an immunological shield between infected tissues and the periphery.
Candida albicans colonization exacerbates skin inflammation in a murine model of psoriasis
Authors: Nakajima Saeko , Harrison Oliver , Linehan Jonathan L , Belkaid Yasmine 
Published: January 2023

Abstract
In addition to being a primary site of exposure to pathogens, the skin is also home to a complex microbiota that modulate skin immune homeostasis. Notably, our previous work revealed that defined microbes differentially regulate the skin immune landscape. In clinical settings, shifts in skin microbiota composition have been shown in the context of skin inflammatory disorders, such as atopic dermatitis, acne vulgaris and psoriasis. However, the precise role of cutaneous microbiota in the initiation, control or promotion of skin inflammatory states remains unclear. To clarify the mechanisms by which the skin microbiota influence host immunity under inflammatory conditions, we focused on psoriasis, a common inflammatory skin disorder mediated by both innate and adaptive immune systems.
Murine studies have shown that topical application of imiquimod, a TLR7 agonist, can induce psoriasis-like skin inflammation, mediated by the IL-23/IL-17 axis. Using this experimental model, we found that previous skin association of mice with C.albicans but not other skin microbes (e.g., S.aureus), significantly enhanced skin inflammation. Notably, C.albicans topical association promoted IL-17A production from CD4+ effector T cells in the skin and skin draining lymph nodes. Our work currently explores how adaptive immunity directed against C.albicans could contribute to the etiology of this important skin disorder. This work aims to define the causative association between defined microbes and the development of skin inflammatory disorders and may allow for the development of tailored clinical interventions aiming at controlling skin microbiota and/or aberrant responses to these microbes.
Specific interaction between defined skin commensal and dermal IL-17A-producing gamma delta T cells.
Authors: Bouladoux Nicolas , Ridaura Vanessa , Claesen Jaen , Fischbach Michael , Belkaid Yasmine 
Published: January 2023

Abstract
The skin is home to a diverse and complex microbiota that play an important role in tissue homeostasis and local immunity. We have previously shown that Staphylococcus epidermidis promotes IL-17A-producing CD8+ T cells that enhance innate barrier immunity and limit pathogen invasion. However, the ability of other defined skin microbes and/or microbes-derived products to modulate skin immunity is still poorly characterized. T cells expressing low level of gamma delta TCR (gdT) are a dermal population of T lymphocytes that are committed to produce IL-17A and can mediate both innate and adaptive-like immune responses. Here, we show that cutaneous colonization with Corynebacterium accolens, a dominant member of the human and murine skin microbiota, induces IL-17A-producing gdT cells in the skin of specific-pathogen free mice. Intriguingly this ability is conserved amongst other species from the same genus supporting the idea that a canonical constituent shared by members of this taxon may be mediating this effect. Using a mutant strain of C. accolens lacking the corynemycolic acid synthase enzyme, we found that corynemycolic acids, a major component of the cell envelope, are important for the induction of IL-17A-producing gdT cells. Furthermore, mice associated with C. accolens displayed increased skin inflammation in an experimental model of psoriasis, a disease associated with an increase of IL-17A-producing gdT cells. Together these results uncover a novel mode of interaction between the skin microbiota and the skin immune system and highlight the important role that the skin microbiota may have in the pathogenesis of skin inflammatory disorders.
NF-κB-inducing kinase (NIK): A novel modulator of eosinophilic esophagitis (EoE) in mouse models and human patients
Authors: Eden Kristin , McDaniel Dylan , Heid Bettina , Allen Irving C 
Published: January 2023

Abstract
Eosinophilic esophagitis (EoE) is an allergic disease of the esophagus driven by T cell and eosinophil responses to dietary allergens resulting in chronic mucosal inflammation and fibrosis. NF-κB inducing kinase (NIK) is a key signaling molecule of the noncanonical NF-κB pathway, an alternative signaling cascade producing chemokines involved in lymphoid stroma development and leukocyte trafficking. Nik−/− mice have been shown to develop a spontaneous hypereosinophilic syndrome in major organs; however, the gastrointestinal mucosa of these mice have not been evaluated. Here we show that Nik−/− mice develop significant eosinophilic esophagitis that mimics human EoE, including intraepithelial eosinophil accumulation, degranulation, mucosal thickening, fibrosis, and basal cell hyperplasia. Additionally, these mice display mucosal hyperplasia in the cranial glandular stomach surrounding the gastroesophageal junction. Interestingly, the remainder of the gastrointestinal tract including the caudal stomach, small intestine, and colon are unaffected, also similar to human EoE. Esophageal tissue from Nik−/− mice contains elevations in Th2 cytokines as well as TSLP, a gene implicated in human EoE. Retrospective metadata analysis of biopsies from human EoE patients shows many significant changes in gene expression throughout the noncanonical NF-κB pathway that are consistent with our murine model. Given that current models of this disease involve artificial sensitization or infectious agents, we conclude that Nik−/− mice may a useful spontaneous model of eosinophilic disease of the esophageal mucosa with improved physiologic relevance. These findings also highlight a novel role for noncanonical NF-κB signaling in EoE.
Gap Junction Mediated Antigen Transport in Epithelium Promotes Amplification of CD8 T Cell Mediated Bystander Pathology Following Chlamydial Infection
Authors: Murthy Ashlesh K , Manam Srikanth , La Salle Sophie , Holtzman Michael J , Zhang Yong , Ramsey Kyle H , Nicholson Bruce J 
Published: January 2023

Abstract
Chlamydia-specific CD8 T cells play a significant role in oviduct pathology, not bacterial clearance. We hypothesized that gap junction mediated antigen transport (GMAT) from infected to uninfected cells could explain the apparent targeting of uninfected epithelial cells by Chlamydia-specific CD8 T cells. Since gap junction protein connexin 43 is highly expressed in oviduct epithelium, we generated Foxj1Cre-Cx43flox mice with a conditional deficiency of CX43 only in ciliated columnar epithelia in oviducts. Foxj1Cre-Cx43flox mice displayed similar chlamydial infection, but reduced splenic Ag-specific CD8 T cell response and oviduct pathology when compared to WT mice, suggesting that CX43-mediates chlamydial pathogenesis. To evaluate the role of GMAT via CX43 in pathogenesis, HeLa S3 cells were engineered to express functional CX43 or a closed channel point-mutant CX43 (T154A). Chlamydial peptides were observed in neighboring uninfected cells at mid-developmental cycle upon infection of HeLa-CX43, not HeLa S3 or HeLa-CX43-T154A cells. Naïve mouse antigen-presenting cells (APC) optimally activated Chlamydia-specific mouse CD8 T cells upon co-culture with Chlamydia-infected HeLa-CX43, when compared to HeLa S3 or HeLa-CX43-T154A cells, demonstrating that GMAT is involved in activation of CD8 T cells. Furthermore, naïve mouse APC optimally activated Chlamydia-specific mouse CD8 T cells upon co-culture with a 1:4 mixture of Chlamydia-infected HeLa-CX43 and uninfected HeLa-CX43 cells, when compared to mixtures of infected HeLa-CX43 with uninfected HeLa-S3 or HeLa-CX43-T154A cells. These results demonstrate that GMAT via uninfected epithelial cells amplifies pathogenic Chlamydia-specific CD8 T cell response.
Notch signaling is required for the generation and function of follicular T helper cells in settings of Type-2 inflammation.
Authors: Aringa Mark Dell , Reinhardt R. Lee 
Published: January 2023

Abstract
The presence of IgE and IgG1 antibodies are hallmarks of allergic responses. The generation of high affinity, class-switched antibodies is reliant on interactions of B cells with T follicular helper (Tfh) cells in germinal centers. IL-4 produced by Tfh cells plays a critical role in B cell maturation and survival. The mechanisms controlling IL-4 production by Tfh cells remain largely unknown. Given that Notch signaling is required for the differentiation of Tfh cells and is known to influence cytokine production in T cells, we hypothesized that Notch signaling also plays an important role in regulating the function and maintenance of Tfh cells. Intestinal helminth infection was used to characterize whether persistent Notch signaling is required to maintain Tfh cell fate and function during allergic immunity. The use of intestinal helminths also allows us to assess the role of Notch signaling in lung Th2 cells. Deletion of Notch receptors on T cells of infected mice results in reduced IL-4 production by Tfh and Th2 cells. Despite similar reductions in IL-4 production, Th2 immunity remains intact while Tfh functionality is lost. Overexpression of Notch signaling in CD4+ T cells leads to increased IL-4 production by Tfh cells, but not Th2 cells. While it has been shown that Notch signaling is critical for Tfh differentiation, it is not known if Notch signaling plays a continued role after Tfh differentiation. Inhibition of Notch signaling after Tfh differentiation results in decreased expression of CXCR5 and aberrant localization of IL-4 producing T-cells in the lymph node. These findings suggest that Notch signaling is not only important for Tfh differentiation, but that it is also important for regulating Tfh cell fate, function, and maintenance.
A long-noncoding RNA, Gata3-AS1, is a positive transcriptional regulator of transcription factor Gata3 in TH2 cells.
Authors: Gibbons Hunter Ramsdell , Spurlock Charles F , Aune Thomas M 
Published: January 2023

Abstract
Long non-coding RNAs (lncRNAs) are RNAs transcribed by the genome, are &gt;200 base pairs long, but are not translated into protein due to presence of multiple translational stop codons. LncRNAs possess a diverse array of regulatory functions including activation and silencing of gene transcription, regulation of splicing, and coordinating epigenetic modifications. Divergent lncRNAs are noncoding genes, which produce a lncRNA in the antisense orientation to an mRNA gene, and may share a promoter region. These lncRNAs may regulate their neighbor mRNA by direct RNA interactions or through the process of their own transcription. Gata3-AS1 is a divergent lncRNA gene in humans neighboring Gata3. The GATA3 transcription factor initiates transcription of genes encoding cytokines IL-4, IL-5, and IL-13, the hallmarks of TH2 polarization. Gata3-AS1 and Gata3 are exclusively expressed in the TH2 lineage of lymphocytes. In this study, we show that GATA3-AS1 is selectively expressed in human TH2 cells, resides solely in the nucleus, and is required for expression of GATA3, IL5, and IL13. Further, GATA3-AS1 RNA is required to establish H3K4-methyation and H3K27-acetylation ‘marks’ at the GATA3 genomic locus under TH2 differentiation conditions and directly binds the WDR5 DNA binding subunit of the MLL methyltransferase. Thus, GATA3-AS1 is a functional lncRNA and positive transcriptional regulator of GATA3 and commitment to the TH2 lineage.
Regulatory action of multiple AP-1 transcription factors balances Th17 lineage stability and plasticity
Authors: Wheaton Joshua D , Carr Tiffany M , Ciofani Maria 
Published: January 2023

Abstract
During an immune response, naïve CD4+ T cells encounter their cognate antigen and are induced to differentiate into one of several distinct T helper (Th) subsets. Although previously regarded as lineage-committed, these differentiated subsets are now appreciated to exhibit a degree of plasticity, whereby certain environmental stimuli permit inter-subset conversion. In particular, Th17 cells have been demonstrated to exhibit a high degree of intrinsic plasticity and are capable of “reprogramming” towards phenotypes typical of both pro- and anti-inflammatory T cell subsets. Despite the suggested importance of this phenomenon in the etiology of autoimmune and inflammatory disorders, the mechanisms underlying Th17 cell plasticity are poorly understood. We have recently identified the AP-1 transcription factor family as a central controller of both Th17 cell stability and plasticity, with different AP-1 family members exhibiting both overlapping and unique control of distinct aspects of the Th17 transcriptional program. Using a combined strategy employing transcriptomics and global analysis of TF occupancy for multiple AP-1 family members, we have identified novel regulatory modules defined by distinct modes of AP-1-mediated activation. These findings provide new insights into the mechanism by which environmentally-regulated transcription factors collaborate for the maintenance of T cell identity.
Unraveling how T cell antigen receptor signaling strength determines T cell differentiation using a combined experimental and computational approach
Authors: Faeder James , Sheehan Robert P , Hawse William F , Gable Matthew J , Lee Robin E C , Morel Penelope A 
Published: January 2023

Abstract
Antigen stimulation of the T cell receptor in a naïve cell triggers a complex network of signaling pathways that collectively determine whether it adopts a tolerogenic, Treg, or immunogenic, Th, phenotype. The complexity of this network presents a major barrier to the development of computational models, but such efforts hold the promise for increased understanding and the development of therapies based on selective T cell differentiation. We previously developed a Boolean model of T cell differentiation that predicted an optimal TCR signal duration for the production of Tregs, a strategy that we implemented and confirmed using an in vitro system. This model suggested that the dynamics of PTEN, a lipid phosphatase that opposes the activation the Akt/mTOR signaling pathway, were predictive of cell fate. Subsequent experiments revealed a critical positive feedback loop for Akt activation acting through the transcription factor FoxO1, a substrate of Akt that regulates PTEN. Here, we present a detailed computational model of Akt signaling during T cell differentiation that tracks the dynamics of numerous protein phosphoforms and complexes. The model is developed using the BioNetGen modeling language and simulated using ordinary differential equations. The calibrated model reproduces dose-dependent kinetics of phosphorylation of Akt at T308 and S473 measured experimentally, and predicts the existence of a sharp threshold in signal strength, which we have confirmed experimentally using Nur77-GFP reporter mice. The model also predicts a reduction in this threshold with reduction in PTEN expression, which we confirmed in mice heterozygous for PTEN deficiency.
Dancing with PKCθ: Fine-tuning T cell fate via cell-penetrating antibodies
Authors: Ozay E. Ilker , Tew Gregory N. , Minter Lisa M. 
Published: January 2023

Abstract
Previously, we showed that PKCθ signaling is neutralized in human T cells when anti-pPKCθ (against Thr538 phosphorylation) is delivered intracellularly, using a cell-penetrating peptide mimic (PTDM). Using a humanized model of graft-vs-host disease, we further demonstrated these effects were durable and provided a survival benefit when anti-pPKCθ-treated human PBMCs were used to induce disease. Of note, intracellular delivery of anti-pPKCθ altered PKCθ cellular localization compared to mock-treated cells. In the present study, we show that PKCθ localization is modulated in TH1, TH2, TH17, and iTregs following anti-pPKCθ delivery, and this modulation influences TH cell fate in vitro. It has been reported that PKCθ stimulates STAT3 transcription via the NF-κB pathway and has differential effects on STAT4 and STAT6. We found that, through its cellular localization, pPKCθ may differentially regulate the expression and translocation of STAT proteins, as well as master transcription factors, to ultimately control T cell differentiation programs. Altogether, we demonstrate that we can change the subcellular localization of PKCθ using a cell-penetrating antibody and as a result, can redirect the differentiation potential of T helper cells.
Sepsis inhibits pre-existing Ag-specific memory CD4 T cell-mediated immunity
Authors: Griffith Thomas S , Sjaastad Frances V , Murphy Katherine A , Kucaba Tamara A , Badovinac Vladimir P 
Published: January 2023

Abstract
Sepsis strikes 750,000 Americans annually. Patients who survive severe sepsis display prolonged immune dysfunction with deficits in innate and adaptive immune responses. Thus, the most common cause of death of septic patients is the not from the initial septic event, but from a subsequent secondary infection. CD4 T cells support the function of a variety of immune cells needed during a productive and protective immune response, and perturbations in the CD4 T cell compartment can dramatically affect overall immune system fitness. Sepsis patients have defects in the DTH response, marked by a failure to respond to skin testing with Ag to which previous exposure is known to have occurred. Using the cecal ligation and puncture (CLP) mouse model of sepsis, we replicated this observation in CLP-treated mice. DTH is predominately mediated by CD4 T cells, bringing into question to what extent memory CD4 T cells are affected by sepsis. We observed rapid apoptosis of persisting memory Ag-specific CD4 T cells after sepsis induction. In addition to the numerical change in Agspecific CD4 T cells, sepsis altered Ag-specific functions of memory CD4 T cells. Specifically, Ag-specific CD4 T cells from CLP-treated mice produced significantly less effector cytokines (IFNγ, TNF, and IL-2) on a per cell basis after restimulation and their proliferative capacity was significantly decreased compared to the same Ag-specific population in sham-treated mice. These numerical and functional deficiencies in Ag-specific CD4 T cells in CLP-treated mice corresponded to a loss in CD4 T cell-mediated protection. Together, our data show CLP-induced sepsis impairs adaptive cellular immunity (in part) by affecting the number and function of Ag-specific memory CD4 T cells.
Unique Properties of Long-lived Effector CD8 T cells
Authors: Renkema Kristin , Jameson Stephen , Hamilton Sara 
Published: January 2023

Abstract
Long-lived effector CD8 T cells (LLEC) are generated post infection and persist months after the infection has cleared. LLEC retain a “terminally differentiated” phenotype (CD62L-, CD27-, KLRG1+), which distinguishes them from other long-lived memory CD8 T cell populations. Upon pathogen re-challenge, these cells potently clear viral and bacterial pathogens more effectively than other memory CD8 T cell populations. Unlike other circulating effector memory cells, LLEC express many NK cell markers and are capable of produce IFNγ within hours after in vitro exposure to IL-12 and IL-18, suggesting that they uniquely possess innate-like, rapid effector mechanisms that aide in swift pathogen clearance and survival of the host. Interestingly, LLEC-phenotype CD8 T cells are prevalent in humans, and represent the predominant T cell population in “dirty” mice, that have naturally acquired environmental microbes. Our studies, focused on the establishment, maintenance, and functional properties of protective memory CD8 T cells, reveal LLEC as a distinct effector memory population that shares many characteristics with NK cells and suggest that vaccine approaches that expand the LLEC pool may be beneficial for protective CD8 T cell responses.