BCL6 corepressor contributes to Th17 cell formation by inhibiting Th17 fate suppressors

CD4+ T helper 17 (Th17) cells protect vertebrate hosts from extracellular pathogens at mucosal surfaces. Th17 cells form from naive precursors when signals from the T cell antigen receptor (TCR) and certain cytokine receptors induce the expression of the RORγt transcription factor, which activates a set of Th17-specific genes. Using T cell–specific loss-of-function experiments, we find that two components of the Polycomb repressive complex 1.1 (PRC1.1), BCL6 corepressor (BCOR) and KDM2B, which helps target the complex to unmethylated CpG DNA islands, are required for optimal Th17 cell formation in mice after Streptococcus pyogenes infection. Genome-wide expression and BCOR chromatin immunoprecipitation studies revealed that BCOR directly represses Lef1, Runx2, and Dusp4, whose products inhibit Th17 differentiation. Together, the results suggest that the PRC1.1 components BCOR and KDM2B work together to enhance Th17 cell formation by repressing Th17 fate suppressors.

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The epigenetic regulator ATF7ip inhibits Il2 expression, regulating Th17 responses

Journal of Experimental Medicine ◽

10.1084/jem.20182316 ◽

2019 ◽

Vol 216 (9) ◽

pp. 2024-2037 ◽

Cited By ~ 1

Author(s):

Jun Hyung Sin ◽

Cassandra Zuckerman ◽

Jessica T. Cortez ◽

Walter L. Eckalbar ◽

David J. Erle ◽

...

Keyword(s):

T Cell ◽

Cell Receptor ◽

T Helper 17 ◽

Interacting Protein ◽

Mucosal Surfaces ◽

Repressive Histone Mark ◽

Th17 Differentiation ◽

Activating Transcription Factor ◽

Autoimmune Pathogenesis

T helper 17 cells (Th17) are critical for fighting infections at mucosal surfaces; however, they have also been found to contribute to the pathogenesis of multiple autoimmune diseases and have been targeted therapeutically. Due to the role of Th17 cells in autoimmune pathogenesis, it is important to understand the factors that control Th17 development. Here we identify the activating transcription factor 7 interacting protein (ATF7ip) as a critical regulator of Th17 differentiation. Mice with T cell–specific deletion of Atf7ip have impaired Th17 differentiation secondary to the aberrant overproduction of IL-2 with T cell receptor (TCR) stimulation and are resistant to colitis in vivo. ChIP-seq studies identified ATF7ip as an inhibitor of Il2 gene expression through the deposition of the repressive histone mark H3K9me3 in the Il2-Il21 intergenic region. These results demonstrate a new epigenetic pathway by which IL-2 production is constrained, and this may open up new avenues for modulating its production.

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T cell derived HB-EGF prevents Th17 cell differentiation in an autocrine way

10.1101/2021.02.09.430418 ◽

2021 ◽

Author(s):

Felicity Macdonald ◽

Jorg van Loosdregt ◽

Dietmar M W Zaiss

Keyword(s):

T Cells ◽

T Cell ◽

Growth Factor ◽

Autoimmune Diseases ◽

T Cell Activation ◽

Cd4 T Cells ◽

Th17 Cell ◽

Th17 Cells ◽

Cell Activation ◽

T Helper 17

ABSTRACTCD4 T cells critically contribute to host immunity against infections, but can also contribute to the development of autoimmune diseases. The underlying mechanisms that govern differentiation of naïve CD4 T cells into different effector populations remain poorly understood. Here, we show that the expression of the Epidermal Growth Factor (EGF)-like growth factor HB-EGF by CD4 T cells sustained their expression of Interleukin (IL)-2 and reduced their capacity to differentiate into T Helper 17 (Th17) cells. Concordantly, mice with a T cell specific deficiency of HB-EGF showed an enhanced differentiation of naïve CD4 T cells into Th17 cells and a more rapid onset of experimental autoimmune encephalomyelitis (EAE). Furthermore, transfer of naïve HB-EGF-deficient CD4 T cells into Rag1-/- mice led to the rapid induction of multi-organ inflammation in recipient mice. Together, our data reveal a novel mechanism by which an HB-EGF-mediated constrain on Th17 differentiation prevents the development of autoimmune diseases.SUMMARYCD4 T cell activation induces the expression of the EGFR and its high-affinity ligand HB-EGF. HB-EGF sustains IL-2 expression in an autocrine manner, preventing the differentiation of Th17 cells and the subsequent induction of Th17 cell-mediated autoimmune diseases.

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SIRT1 deacetylates RORγt and enhances Th17 cell generation

Journal of Experimental Medicine ◽

10.1084/jem.20132378 ◽

2015 ◽

Vol 212 (5) ◽

pp. 607-617 ◽

Cited By ~ 73

Author(s):

Hyung W. Lim ◽

Seung Goo Kang ◽

Jae Kyu Ryu ◽

Birgit Schilling ◽

Mingjian Fei ◽

...

Keyword(s):

Multiple Sclerosis ◽

T Cell ◽

Th17 Cell ◽

Th17 Cells ◽

Cell Function ◽

Cell Generation ◽

Sirtuin 1 ◽

T Helper 17 ◽

Effector Cells ◽

And Function

The balance of effector and regulatory T cell function, dependent on multiple signals and epigenetic regulators, is critical to immune self-tolerance. Dysregulation of T helper 17 (Th17) effector cells is associated with multiple autoimmune diseases, including multiple sclerosis. Here, we report that Sirtuin 1 (SIRT1), a protein deacetylase previously reported to have an antiinflammatory function, in fact promotes autoimmunity by deacetylating RORγt, the signature transcription factor of Th17 cells. SIRT1 increases RORγt transcriptional activity, enhancing Th17 cell generation and function. Both T cell–specific Sirt1 deletion and treatment with pharmacologic SIRT1 inhibitors suppress Th17 differentiation and are protective in a mouse model of multiple sclerosis. Moreover, analysis of infiltrating cell populations during disease induction in mixed hematopoietic chimeras shows a marked bias against Sirt1-deficient Th17 cells. These findings reveal an unexpected proinflammatory role of SIRT1 and, importantly, support the possible therapeutic use of SIRT1 inhibitors against autoimmunity.

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Evidence for Associations Between Th1/Th17 “Hybrid” Phenotype and Altered Lipometabolism in Very Severe Graves Orbitopathy

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa124 ◽

2020 ◽

Vol 105 (6) ◽

pp. 1851-1867 ◽

Cited By ~ 2

Author(s):

Sijie Fang ◽

Shuo Zhang ◽

Yazhuo Huang ◽

Yu Wu ◽

Yi Lu ◽

...

Keyword(s):

T Cell ◽

Th17 Cell ◽

Th17 Cells ◽

T Cell Subsets ◽

Th1 Cell ◽

Effector T Cell ◽

Cell Lineages ◽

Graves Orbitopathy ◽

Ifn Γ

Abstract Purpose The purpose of this article is to investigate the characteristics of Th1-cell and Th17-cell lineages for very severe Graves orbitopathy (GO) development. Methods Flow cytometry was performed with blood samples from GO and Graves disease (GD) patients and healthy controls, to explore effector T-cell phenotypes. Lipidomics was conducted with serum from very severe GO patients before and after glucocorticoid (GC) therapy. Immunohistochemistry and Western blotting were used to examine orbital-infiltrating Th17 cells or in vitro models of Th17 polarization. Results In GD, Th1 cells predominated in peripheral effector T-cell subsets, whereas in GO, Th17-cell lineage predominated. In moderate-to-severe GO, Th17.1 cells expressed retinoic acid receptor-related orphan receptor-γt (RORγt) independently and produced interleukin-17A (IL-17A), whereas in very severe GO, Th17.1 cells co-expressed RORγt and Tbet and produced interferon-γ (IFN-γ). Increased IFN-γ–producing Th17.1 cells positively correlated with GO activity and were associated with the development of very severe GO. Additionally, GC therapy inhibited both Th1-cell and Th17-cell lineages and modulated a lipid panel consisting of 79 serum metabolites. However, in GC-resistant, very severe GO, IFN-γ–producing Th17.1 cells remained at a high level, correlating with increased serum triglycerides. Further, retro-orbital tissues from GC-resistant, very severe GO were shown to be infiltrated by CXCR3+ Th17 cells expressing Tbet and STAT4 and rich in triglycerides that promoted Th1 phenotype in Th17 cells in vitro. Conclusions Our findings address the importance of Th17.1 cells in GO pathogenesis, possibly promoting our understanding of the association between Th17-cell plasticity and disease severity of GO.

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Abstract MP50: Time Restricted Feeding Reduces Interleukin 17a Production Associated With Western Diets

Hypertension ◽

10.1161/hyp.78.suppl_1.mp50 ◽

2021 ◽

Vol 78 (Suppl_1) ◽

Author(s):

Gwendolyn K Davis ◽

Daniel Fehrenbach ◽

Charles D Smart ◽

Claudia Edell ◽

Jennifer Pollock ◽

...

Keyword(s):

T Cell ◽

Circadian Rhythms ◽

Th17 Cell ◽

Th17 Cells ◽

Fold Increase ◽

Organ Damage ◽

High Salt ◽

Restricted Feeding ◽

High Fat ◽

Interleukin 17A

Circadian rhythms govern our daily physiological processes. However, disruption of circadian rhythms, as can occur with ad libitum Western diets, disrupt these processes leading to cardiometabolic diseases. Our lab and others have shown that Th17 cells, which produce interleukin 17A (IL-17A), are implicated in the development of cardiovascular and renal end-organ damage associated with high fat and/or high salt diets. Th17 cell differentiation and trafficking is regulated by the circadian clock and influenced by light-dark cycles. However, whether feeding-fasting rhythms influence Th17 cell responses is poorly understood. We tested the hypothesis that limiting food intake to the 12-hr active period (time-restricted feeding, TRF) mitigates high fat and high salt (HF/HS) diet induced T cell IL-17A production and target organ damage. Beginning at 8 weeks of age, male C57Bl/6J mice were placed on either a normal chow/normal salt (NC/NS) or a HF/HS diet for 20 weeks, with TRF intervention occurring during the last two weeks in the HF/HS + TRF group. Body weight was similarly significantly increased in the HF/HS and HF/HS + TRF groups in comparison to the NC/NS group. Th17 cells were significantly increased (2.6-fold increase, p = 0.02) in the Peyer’s patches (lymphoid aggregates found in the small intestines) of mice on HF/HS diet in comparison to those on NC/NS. Importantly, TRF abolished this increase. Renal CD4 + T cell IL-17A production, as measured by flow cytometry, was increased by HF/HS diet compared to NC/NS (3-fold increase, p = 0.02). Similarly, TRF abolished this increase. This study highlights how Western diets exacerbate intestinal and renal IL-17A production and the potential beneficial impact of a behavioral intervention, TRF, to mitigate the Th17 mediated inflammation associated with diet-induced obesity.

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Pivotal Roles of T-Helper 17-Related Cytokines, IL-17, IL-22, and IL-23, in Inflammatory Diseases

Clinical and Developmental Immunology ◽

10.1155/2013/968549 ◽

2013 ◽

Vol 2013 ◽

pp. 1-13 ◽

Cited By ~ 75

Author(s):

Ning Qu ◽

Mingli Xu ◽

Izuru Mizoguchi ◽

Jun-ichi Furusawa ◽

Kotaro Kaneko ◽

...

Keyword(s):

Th17 Cell ◽

Th17 Cells ◽

Functional Role ◽

Inflammatory Diseases ◽

Interleukin 17 ◽

T Helper ◽

T Helper 17 ◽

Autoimmune Encephalomyelitis ◽

Experimental Autoimmune

T-helper 17 (Th17) cells are characterized by producing interleukin-17 (IL-17, also called IL-17A), IL-17F, IL-21, and IL-22 and potentially TNF-α and IL-6 upon certain stimulation. IL-23, which promotes Th17 cell development, as well as IL-17 and IL-22 produced by the Th17 cells plays essential roles in various inflammatory diseases, such as experimental autoimmune encephalomyelitis, rheumatoid arthritis, colitis, and Concanavalin A-induced hepatitis. In this review, we summarize the characteristics of the functional role of Th17 cells, with particular focus on the Th17 cell-related cytokines such as IL-17, IL-22, and IL-23, in mouse models and human inflammatory diseases.

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Myelin-specific T helper 17 cells promote adult hippocampal neurogenesis through indirect mechanisms

F1000Research ◽

10.12688/f1000research.4439.2 ◽

2017 ◽

Vol 3 ◽

pp. 169 ◽

Cited By ~ 2

Author(s):

Johannes Niebling ◽

Annette E. Rünker ◽

Sonja Schallenberg ◽

Karsten Kretschmer ◽

Gerd Kempermann

Keyword(s):

T Cell ◽

Th17 Cell ◽

Th17 Cells ◽

Precursor Cells ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Lymphoid Tissues ◽

Base Line ◽

T Helper ◽

Th Cell

CD4+ T cells provide a neuro-immunological link in the regulation of adult hippocampal neurogenesis, but the exact mechanisms underlying enhanced neural precursor cell proliferation and the relative contribution of different T helper (Th) cell subsets have remained unclear. Here, we explored the pro-proliferative potential of interleukin 17-producing T helper (Th17) cells, a developmentally and functionally distinct Th cell subset that is a key mediator of autoimmune neurodegeneration. We found that base-line proliferation of hippocampal precursor cells in a T cell-deficient mouse model of impaired hippocampal neurogenesis can be restored upon adoptive transfer with homogeneous Th17 populations enriched for myelin-reactive T cell receptors (TCR). In these experiments, enhanced proliferation was independent of direct interactions of infiltrating Th17 cells with precursor cells or neighboring cells in the hippocampal neurogenic niche. Complementary studies in immunocompetent mice identified several receptors for Th17 cell-derived cytokines with mRNA expression in hippocampal precursor cells and dentate gyrus tissue, suggesting that Th17 cell activity in peripheral lymphoid tissues might promote hippocampal neurogenesis through secreted cytokines.

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Differential Levels of Regulatory T Cells and T-Helper-17 Cells in Women With Early and Advanced Endometriosis

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2019-00350 ◽

2019 ◽

Vol 104 (10) ◽

pp. 4715-4729 ◽

Cited By ~ 8

Author(s):

Khaleque N Khan ◽

Kazuo Yamamoto ◽

Akira Fujishita ◽

Hideki Muto ◽

Akemi Koshiba ◽

...

Keyword(s):

T Cell ◽

Th17 Cells ◽

Treg Cells ◽

Lower Percentage ◽

T Helper ◽

T Helper 17 ◽

Control Subjects ◽

Cell Subpopulations ◽

American Society ◽

T Cell Subpopulations

Abstract Context Regulatory T (Treg) cells and T-helper-17 (Th17) cells may be involved in endometriosis. Information on the pattern of change in the percentages of Treg and Th17 cells in the peripheral blood (PB) and peritoneal fluid (PF) of women with early and advanced endometriosis is unclear. Objective To investigate the pattern of change in the percentages of Treg and Th17 cells in the PB and PF of women with early and advanced endometriosis. Methods We recruited 31 women with laparoscopically and histologically confirmed, revised American Society of Reproductive Medicine stage I-II endometriosis, 39 women with stage III-IV endometriosis, and 36 control subjects without visible endometriosis. PB and PF samples were collected and T-cell subpopulations analyzed by flow cytometry using specific monoclonal antibodies recognizing CD4+, CD25+, FOXP3+, and IL-17A+ markers. PF concentrations of TGF-β and IL-17 were measured by ELISA. Results The percentages of CD25+FOXP3+ Treg cells within the CD4+ T-cell population were significantly higher in the PF of women with advanced endometriosis than in either early endometriosis or in control subjects (P < 0.05 for both). A persistently lower percentage of CD4+IL-17A+ Th17 cells was found in both PB and PF of women with early and advanced endometriosis. Compared with IL-17 levels, PF levels of TGF-β were significantly higher in women with endometriosis (P = 0.01). Conclusion Our findings reconfirmed the current speculation that endometriosis is related to alteration of Treg and Th17 cells in the pelvis causing survival and implantation of ectopic endometrial lesions.

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Faecalibacterium prausnitzii produces butyrate to decrease c-Myc-related metabolism and Th17 differentiation by inhibiting histone deacetylase 3

International Immunology ◽

10.1093/intimm/dxz022 ◽

2019 ◽

Vol 31 (8) ◽

pp. 499-514 ◽

Cited By ~ 7

Author(s):

Mingming Zhang ◽

Lixing Zhou ◽

Yuming Wang ◽

Robert Gregory Dorfman ◽

Dehua Tang ◽

...

Keyword(s):

Histone Deacetylase ◽

Th17 Cells ◽

Inflammatory Diseases ◽

T Helper 17 ◽

Histone Deacetylase 3 ◽

Faecalibacterium Prausnitzii ◽

Other Substances ◽

Th17 Differentiation ◽

Anti Inflammatory ◽

Inflammatory Effect

Abstract Decreased levels of Faecalibacterium prausnitzii (F. prausnitzii), whose supernatant plays an anti-inflammatory effect, are frequently found in inflammatory bowel disease (IBD) patients. However, the anti-inflammatory products in F. prausnitzii supernatant and the mechanism have not been fully investigated. Here we found that F. prausnitzii and F. prausnitzii-derived butyrate were decreased in the intestines of IBD patients. Supplementation with F. prausnitzii supernatant and butyrate could ameliorate colitis in an animal model. Butyrate, but not other substances produced by F. prausnitzii, exerted an anti-inflammatory effect by inhibiting the differentiation of T helper 17 (Th17) cells. The mechanism underlying the anti-inflammatory effects of the butyrate produced by F. prausnitzii involved the enhancement of the acetylation-promoted degradation of c-Myc through histone deacetylase 3 (HDAC3) inhibition. In conclusion, F. prausnitzii produced butyrate to decrease Th17 differentiation and attenuate colitis through inhibiting HDAC3 and c-Myc-related metabolism in T cells. The use of F. prausnitzii may be an effective new approach to decrease the level of Th17 cells in the treatment of inflammatory diseases.

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Fenofibrate Inhibited the Differentiation of T Helper 17 CellsIn Vitro

PPAR Research ◽

10.1155/2012/145654 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10 ◽

Cited By ~ 2

Author(s):

Zhou Zhou ◽

Weiliang Sun ◽

Ying Liang ◽

Yanxiang Gao ◽

Wei Kong ◽

...

Keyword(s):

Multiple Sclerosis ◽

Autoimmune Diseases ◽

Th17 Cells ◽

Transforming Growth Factor ◽

Inflammatory Diseases ◽

Lipid Lowering ◽

Interleukin 17 ◽

T Helper ◽

T Helper 17 ◽

Th17 Differentiation

Uncontrolled activity of T cells mediates autoimmune and inflammatory diseases such as multiple sclerosis, inflammatory bowel diseases, rheumatoid arthritis, type 1 diabetes, and atherosclerosis. Recent findings suggest that enhanced activity of interleukin-17 (IL-17) producing T helper 17 cells (Th17 cells) plays an important role in autoimmune diseases and inflammatory diseases. Previous papers have revealed that a lipid-lowering synthetic ligand of peroxisome proliferator-activated receptorα(PPARα), fenofibrate, alleviates both atherosclerosis and a few nonlipid-associated autoimmune diseases such as autoimmune colitis and multiple sclerosis. However, the link between fenofibrate and Th17 cells is lacking. In the present study, we hypothesized that fenofibrate inhibited the differentiation of Th17 cells. Our results showed that fenofibrate inhibited transforming growth factor-β(TGF-β) and IL-6-induced differentiation of Th17 cellsin vitro. However, other PPARαligands such as WY14643, GW7647 and bezafibrate did not show any effect on Th17 differentiation, indicating that this effect of fenofibrate might be PPARαindependent. Furthermore, our data showed that fenofibrate reduced IL-21 production and STAT3 activation, a critical signal in the Th17 differentiation. Thus, by ameliorating the differentiation of Th17 cells, fenofibrate might be beneficial for autoimmunity and inflammatory diseases.

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