scholarly journals Microbiota-induced IL-1β, but not IL-6, is critical for the development of steady-state TH17 cells in the intestine

2012 ◽  
Vol 209 (2) ◽  
pp. 251-258 ◽  
Author(s):  
Michael H. Shaw ◽  
Nobuhiko Kamada ◽  
Yun-Gi Kim ◽  
Gabriel Núñez
Keyword(s):  
T Cells ◽  
Small Intestine ◽  
Steady State ◽  
Th17 Cells ◽  
Retinoic Acid Receptor ◽  
Selective Reduction ◽  
Orphan Receptor ◽  
Therapeutic Implications ◽  
Myd88 Signaling ◽  
Myeloid Differentiation Factor

TH17 cells are a lineage of CD4+ T cells that are critical for host defense and autoimmunity by expressing the cytokines IL-17A, IL-17F, and IL-22. A feature of TH17 cells at steady state is their ubiquitous presence in the lamina propria of the small intestine. The induction of these steady-state intestinal TH17 (sTH17) cells is dependent on the presence of the microbiota. However, the signaling pathway linking the microbiota to the development of intestinal sTH17 cells remains unclear. In this study, we show that IL-1β, but not IL-6, is induced by the presence of the microbiota in intestinal macrophages and is required for the induction of sTH17 cells. In the absence of IL-1β–IL-1R or MyD88 signaling, there is a selective reduction in the frequency of intestinal sTH17 cells and impaired production of IL-17 and IL-22. Myeloid differentiation factor 88–deficient (MyD88−/−) and germ-free (GF) mice, but not IL-1R−/− mice, exhibit impairment in IL-1β induction. Microbiota-induced IL-1β acts directly on IL-1R–expressing T cells to drive the generation of sTH17 cells. Furthermore, administration of IL-1β into GF mice induces the development of retinoic acid receptor–related orphan receptor γt–expressing sTH17 cells in the small intestine, but not in the spleen. Thus, commensal-induced IL-1β production is a critical step for sTH17 differentiation in the intestine, which may have therapeutic implications for TH17-mediated pathologies.

scholarly journals Role of Th17 Cells in Skin Inflammation of Allergic Contact Dermatits

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Matthias Peiser
Keyword(s):  
T Cells ◽  
Th17 Cells ◽  
Skin Diseases ◽  
Inflammatory Diseases ◽  
Retinoic Acid Receptor ◽  
Contact Hypersensitivity ◽  
Orphan Receptor ◽  
Th2 Cells ◽  
Th Cells ◽  
Allergic Contact

Extending the classical concept considering an imbalance exclusively of T helper(h) 1 and Th2 cells on the bottom of many inflammatory diseases, Th17 cells were recently described. Today, there is sufficient experimental evidence to classify psoriasis and allergic contact dermatitis (ACD) amongst other inflammatory skin disorders as IL-17 associated diseases. In several human studies, T-cell-clones could be isolated from eczema biopsies, and high IL-17 levels were observed after challenge with allergen. In the last years, the phenotype of these IL-17 releasing T cells was in the focus of discussion. It has been suggested that Th17 could be identified by expression of retinoic acid receptor-related orphan receptor (ROR)C (humans) or RORγt (mice) and IL-17, accompanied by the absence of IFN-γand IL-22. In cells from skin biopsies, contact allergens elevate IL-17A, IL-23, and RORC within the subset of Th cells. The indications for a participation of Th17 in the development of ACD are supported by data from IL-17 deficient mice with reduced contact hypersensitivity (CHS) reactions that could be restored after transplantation of wild type CD4+T cells. In addition to Th17 cells, subpopulations of CD8+T cells and regulatory T cells are further sources of IL-17 that play important roles in ACD as well. Finally, the results from Th17 cell research allow today identification of different skin diseases by a specific profile of signature cytokines from Th cells that can be used as a future diagnostic tool.

scholarly journals Xianfanghuomingyin, a Chinese Compound Medicine, Modulates the Proliferation and Differentiation of T Lymphocyte in a Collagen-Induced Arthritis Mouse Model

2016 ◽  
Vol 2016 ◽  
pp. 1-14 ◽  
Author(s):  
Bo Nie ◽  
Xue Li ◽  
Yi Wei ◽  
Meng Chen ◽  
Jingwei Zhou ◽  
...  
Keyword(s):  
Mouse Model ◽  
Th17 Cells ◽  
Retinoic Acid Receptor ◽  
Treg Cells ◽  
Immunological Tolerance ◽  
Cartilage Destruction ◽  
Orphan Receptor ◽  
Th2 Cells ◽  
Collagen Induced Arthritis ◽  
Proliferation And Differentiation

In traditional Chinese medicine (TCM), xianfanghuomingyin (XFHM) is used to treat autoimmune diseases, including rheumatoid arthritis (RA). Here, we studied the mechanisms underlying its treatment effects, especially its anti-inflammatory effects in a collagen-induced arthritis (CIA) mouse model. We found that cartilage destruction and pannus formation were alleviated by treatment with XFHM. The abnormal differentiation of Th1 and Th17 cells was downregulated significantly by XFHM, and Th2 and Treg cells were upregulated. Moreover, the expression levels of specific cytokines and transcription factors related to Th1 cells (interferonγ[IFNγ], T-bet) and Th17 cells (interleukin- [IL-] 17) and the nuclear receptor retinoic acid receptor-related orphan receptor-gamma (RORγ) were downregulated. Serum IL-4 and GATA-3, which contribute to Th2 cells differentiation, increased significantly after XFHM administration. These results indicate that XFHM can restore the balance of T lymphocytes and reestablish the immunological tolerance to inhibit autoinflammatory disorder of RA. Taken together, XFHM can be used as a complementary or alternative traditional medicine to treat RA.

scholarly journals CD69 Association with Jak3/Stat5 Proteins Regulates Th17 Cell Differentiation

2010 ◽  
Vol 30 (20) ◽  
pp. 4877-4889 ◽  
Author(s):  
Pilar Martín ◽  
Manuel Gómez ◽  
Amalia Lamana ◽  
Arantxa Cruz-Adalia ◽  
Marta Ramírez-Huesca ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Th17 Cells ◽  
T Cell Differentiation ◽  
Orphan Receptor ◽  
Interleukin 17 ◽  
Deficient Mice

ABSTRACT T-cell differentiation involves the early decision to commit to a particular pattern of response to an antigen. Here, we show that the leukocyte activation antigen CD69 limits differentiation into proinflammatory helper T cells (Th17 cells). Upon antigen stimulation in vitro, CD4+ T cells from CD69-deficient mice generate an expansion of Th17 cells and the induction of greater mRNA expression of interleukin 17 (IL-17), IL 23 receptor (IL-23R), and the nuclear receptor retinoic acid-related orphan receptor γt (RORγt). In vivo studies with CD69-deficient mice bearing OTII T-cell receptors (TCRs) specific for OVA peptide showed a high proportion of antigen-specific Th17 subpopulation in the draining lymph nodes, as well as in CD69-deficient mice immunized with type II collagen. Biochemical analysis demonstrated that the CD69 cytoplasmic tail associates with the Jak3/Stat5 signaling pathway, which regulates the transcription of RORγt and, consequently, differentiation toward the Th17 lineage. Functional experiments in Th17 cultures demonstrated that the selective inhibition of Jak3 activation enhanced the transcription of RORγt. Moreover, the addition of exogenous IL-2 restored Stat5 phosphorylation and inhibited the enhanced Th17 differentiation in CD69-deficient cells. These results support the early activation receptor CD69 as an intrinsic modulator of the T-cell differentiation program that conditions immune inflammatory processes.

scholarly journals In vivo equilibrium of proinflammatory IL-17+ and regulatory IL-10+ Foxp3+ RORγt+ T cells

2008 ◽  
Vol 205 (6) ◽  
pp. 1381-1393 ◽  
Author(s):  
Matthias Lochner ◽  
Lucie Peduto ◽  
Marie Cherrier ◽  
Shinichiro Sawa ◽  
Francina Langa ◽  
...  
Keyword(s):  
T Cells ◽  
Retinoic Acid Receptor ◽  
Cell Receptor ◽  
Nuclear Hormone Receptor ◽  
Orphan Receptor ◽  
T Helper ◽  
T Helper 17 ◽  
Infection And Inflammation ◽  
And Function

The nuclear hormone receptor retinoic acid receptor–related orphan receptor γt (RORγt) is required for the generation of T helper 17 cells expressing the proinflammatory cytokine interleukin (IL)-17. In vivo, however, less than half of RORγt+ T cells express IL-17. We report here that RORγt+ Tαβ cells include Foxp3+ cells that coexist with IL-17–producing RORγt+ Tαβ cells in all tissues examined. The Foxp3+ RORγt+ Tαβ express IL-10 and CCL20, and function as regulatory T cells. Furthermore, the ratio of Foxp3+ to IL-17–producing RORγt+ Tαβ cells remains remarkably constant in mice enduring infection and inflammation. This equilibrium is tuned in favor of IL-10 production by Foxp3 and CCL20, and in favor of IL-17 production by IL-6 and IL-23. In the lung and skin, the largest population of RORγt+ T cells express the γδ T cell receptor and produce the highest levels of IL-17 independently of IL-6. Thus, potentially antagonistic proinflammatory IL-17–producing and regulatory Foxp3+ RORγt+ T cells coexist and are tightly controlled, suggesting that a perturbed equilibrium in RORγt+ T cells might lead to decreased immunoreactivity or, in contrast, to pathological inflammation.

scholarly journals Interleukin (IL)-12 and IL-18 Synergize to Promote MAIT Cell IL-17A and IL-17F Production Independently of IL-23 Signaling

2020 ◽  
Vol 11 ◽  
Author(s):  
Suzanne Cole ◽  
Janine Murray ◽  
Catherine Simpson ◽  
Remi Okoye ◽  
Kerry Tyson ◽  
...  
Keyword(s):  
Th17 Cells ◽  
Cell Activation ◽  
Retinoic Acid Receptor ◽  
Γδ T Cells ◽  
Lymphoid Cells ◽  
Orphan Receptor ◽  
Mait Cells ◽  
Activation Assay ◽  
Mait Cell

IL-23 is considered a critical regulator of IL-17 in Th17 cells; however, its requirement for inducing IL-17 production in other human immune subsets remains incompletely understood. Mucosal associated invariant T (MAIT) cells uniformly express retinoic acid receptor-related orphan receptor gamma t (RORγt) but only a minor population have been shown to produce IL-17A. Here we show that IL-17F is the dominant IL-17 isoform produced by MAIT cells, not IL-17A. For optimal MAIT cell derived IL-17A and IL-17F production, T cell receptor (TCR) triggering, IL-18 and monocyte derived IL-12 signaling is required. Unlike Th17 cells, this process is independent of IL-23 signaling. Using an in vitro skin cell activation assay, we demonstrate that dual neutralization of both IL-17A and IL-17F resulted in greater suppression of inflammatory proteins than inhibition of IL-17A alone. Finally, we extend our findings by showing that other innate-like lymphocytes such as group 3 innate lymphoid cells (ILC3) and gamma delta (γδ) T cells are also capable of IL-23 independent IL-17A and IL-17F production. These data indicate both IL-17F and IL-17A production from MAIT cells may contribute to tissue inflammation independently of IL-23, in part explaining the therapeutic disconnect between targeting IL-17 or IL-23 in certain inflammatory diseases.

scholarly journals Origin, trafficking, and intraepithelial fate of gut-tropic T cells

2013 ◽  
Vol 210 (9) ◽  
pp. 1839-1854 ◽  
Author(s):  
Delphine Guy-Grand ◽  
Pierre Vassalli ◽  
Gerard Eberl ◽  
Pablo Pereira ◽  
Odile Burlen-Defranoux ◽  
...  
Keyword(s):  
T Cells ◽  
Small Intestine ◽  
Steady State ◽  
Cd4 T Cells ◽  
Lymphoid Tissue ◽  
Granzyme B ◽  
Intraepithelial Lymphocytes ◽  
Recent Thymic Emigrants ◽  
Developmentally Regulated

The small intestine epithelium (SI-Ep) harbors millions of unconventional (γδ and CD4− CD8− NK1.1− TCRαβ) and conventional (CD8αβ and CD4) T cells, designated intraepithelial lymphocytes (IELs). Here, we identified the circulating pool of SI-Ep–tropic T cells and studied their capacity to colonize the SI-Ep under steady-state conditions in SPF mice. Developmentally regulated levels of α4β7 endowed recent thymic emigrants (RTEs) of unconventional types with higher SI-Ep tropism than their conventional homologues. SI-Ep–tropic RTEs, which in all lineages emerged naive, homed to the SI-Ep, but this environment was inadequate to stimulate them to cycle. In contrast, conventional and, unexpectedly, unconventional T cells, particularly Vγ7+ (hallmark of γδ IELs), previously stimulated to cycle in the gut-associated lymphoid tissue (GALT), proliferated in the SI-Ep. Cycling unconventional SI-Ep immigrants divided far more efficiently than their conventional homologues, thereby becoming predominant. This difference impacted on acquisition of high Granzyme B content, which required extensive proliferation. In conclusion, SI-Ep–tropic T cells follow a thymus–SI-Ep or a GALT–SI-Ep pathway, the latter generating highly competitive immigrants that are the sole precursors of cytotoxic IELs. These events occur continuously as part of the normal IEL dynamics.

scholarly journals Prostaglandin E2 regulates Th17 cell differentiation and function through cyclic AMP and EP2/EP4 receptor signaling

2009 ◽  
Vol 206 (3) ◽  
pp. 535-548 ◽  
Author(s):  
Katia Boniface ◽  
Kristian S. Bak-Jensen ◽  
Ying Li ◽  
Wendy M. Blumenschein ◽  
Mandy J. McGeachy ◽  
...  
Keyword(s):  
Cyclic Amp ◽  
Prostaglandin E2 ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Retinoic Acid Receptor ◽  
Receptor Expression ◽  
Orphan Receptor ◽  
Antiinflammatory Drugs ◽  
Inflammatory Microenvironment ◽  
Ep4 Receptor

Prostaglandins, particularly prostaglandin E2 (PGE2), play an important role during inflammation. This is exemplified by the clinical use of cyclooxygenase 2 inhibitors, which interfere with PGE2 synthesis, as effective antiinflammatory drugs. Here, we show that PGE2 directly promotes differentiation and proinflammatory functions of human and murine IL-17–producing T helper (Th17) cells. In human purified naive T cells, PGE2 acts via prostaglandin receptor EP2- and EP4-mediated signaling and cyclic AMP pathways to up-regulate IL-23 and IL-1 receptor expression. Furthermore, PGE2 synergizes with IL-1β and IL-23 to drive retinoic acid receptor–related orphan receptor (ROR)-γt, IL-17, IL-17F, CCL20, and CCR6 expression, which is consistent with the reported Th17 phenotype. While enhancing Th17 cytokine expression mainly through EP2, PGE2 differentially regulates interferon (IFN)-γ production and inhibits production of the antiinflammatory cytokine IL-10 in Th17 cells predominantly through EP4. Furthermore, PGE2 is required for IL-17 production in the presence of antigen-presenting cells. Hence, the combination of inflammatory cytokines and noncytokine immunomodulators, such as PGE2, during differentiation and activation determines the ultimate phenotype of Th17 cells. These findings, together with the altered IL-12/IL-23 balance induced by PGE2 in dendritic cells, further highlight the crucial role of the inflammatory microenvironment in Th17 cell development and regulation.

scholarly journals Oxidative Stress in SLE T Cells, Is NRF2 Really the Target to Treat?

2021 ◽  
Vol 12 ◽  
Author(s):  
Kim Ohl ◽  
Klaus Tenbrock
Keyword(s):  
Oxidative Stress ◽  
Systemic Lupus Erythematosus ◽  
T Cells ◽  
Lupus Erythematosus ◽  
Th17 Cells ◽  
Cellular Damage ◽  
Systemic Lupus ◽  
Therapeutic Implications ◽  
Nrf2 Expression ◽  
Stress Activation

Oxidative stress is a major component of cellular damage in T cells from patients with systemic lupus erythematosus (SLE) resulting amongst others in the generation of pathogenic Th17 cells. The NRF2/Keap1 pathway is the most important antioxidant system protecting cells from damage due to oxidative stress. Activation of NRF2 therefore seems to represent a putative therapeutic target in SLE, which is nevertheless challenged by several findings suggesting tissue and cell specific differences in the effect of NRF2 expression. This review focusses on the current understanding of oxidative stress in SLE T cells and its pathophysiologic and therapeutic implications.

scholarly journals Effect of interleukin (IL)-35 on IL-17 expression and production by human CD4+ T cells

PeerJ ◽  
2017 ◽  
Vol 5 ◽  
pp. e2999 ◽  
Author(s):  
Kosuke Okada ◽  
Takeki Fujimura ◽  
Takeshi Kikuchi ◽  
Makoto Aino ◽  
Yosuke Kamiya ◽  
...  
Keyword(s):  
T Cells ◽  
Mrna Expression ◽  
Th17 Cells ◽  
Mononuclear Cells ◽  
Transforming Growth Factor ◽  
Quantitative Polymerase Chain Reaction ◽  
Orphan Receptor ◽  
Enzyme Linked Immunosorbent Assay ◽  
Healthy Controls ◽  
Cytokine Cocktail

Background Interleukin (IL)-17 produced by mainly T helper 17 (Th17) cells may play an important destructive role in chronic periodontitis (CP). Thus, anti-inflammatory cytokines, such as IL-35, might have a beneficial effect in periodontitis by inhibiting differentiation of Th17 cells. Th17 differentiation is regulated by the retinoic acid receptor-related orphan receptor (ROR) α (encoded by RORA) and RORγt (encoded by RORC). However, the role of IL-35 in periodontitis is not clear and the effect of IL-35 on the function of Th17 cells is still incompletely understood. Therefore, we investigated the effects of IL-35 on Th17 cells. Methods Peripheral blood mononuclear cells (PBMCs) were sampled from three healthy volunteers and three CP patients and were analyzed by flow cytometry for T cell population. Th17 cells differentiated by a cytokine cocktail (recombinant transforming growth factor-β, rIL-6, rIL-1β, anti-interferon (IFN)-γ, anti-IL-2 and anti-IL-4) from PBMCs were cultured with or without rIL-35. IL17A (which usually refers to IL-17), RORA and RORCmRNA expression was analyzed by quantitative polymerase chain reaction, and IL-17A production was determined by enzyme-linked immunosorbent assay. Results The proportion of IL-17A+CD4+ slightly increased in CP patients compared with healthy controls, however, there were no significant differences in the percentage of IL-17A+CD4+ as well as IFN-γ+CD4+ and Foxp3+CD4+ T cells between healthy controls and CP patients. IL17A, RORA and RORC mRNA expression was significantly increased in Th17 cells induced by the cytokine cocktail, and the induction was significantly inhibited by addition of rIL-35 (1 ng/mL). IL-17A production in Th17 cells was significantly inhibited by rIL-35 addition (1 ng/mL). Discussion The present study suggests that IL-35 could directly suppress IL-17 expression via RORα and RORγt inhibition and might play an important role in inflammatory diseases such as periodontitis.

scholarly journals Increased CXCR3+ T Cells Impairs Recruitment of T-Helper Type 17 Cells via Interferon γ and Interleukin 18 in the Small Intestine Mucosa During Treated HIV-1 Infection

2019 ◽  
Vol 220 (5) ◽  
pp. 830-840 ◽  
Author(s):  
C Loiseau ◽  
M Requena ◽  
M Nayrac ◽  
M Mavigner ◽  
M Cazabat ◽  
...  
Keyword(s):  
T Cells ◽  
Small Intestine ◽  
Cd8 T Cells ◽  
Th17 Cells ◽  
Ex Vivo ◽  
Interferon Γ ◽  
Interleukin 18 ◽  
T Helper ◽  
Hiv 1 ◽  
Helper Type

Abstract The restoration of CD4+ T cells, especially T-helper type 17 (Th17) cells, remains incomplete in the gut mucosa of most human immunodeficiency virus type 1 (HIV-1)–infected individuals despite sustained antiretroviral therapy (ART). Herein, we report an increase in the absolute number of CXCR3+ T cells in the duodenal mucosa during ART. The frequencies of Th1 and CXCR3+ CD8+ T cells were increased and negatively correlated with CCL20 and CCL25 expression in the mucosa. In ex vivo analyses, we showed that interferon γ, the main cytokine produced by Th1 and effector CD8+ T cells, downregulates the expression of CCL20 and CCL25 by small intestine enterocytes, while it increases the expression of CXCL9/10/11, the ligands of CXCR3. Interleukin 18, a pro-Th1 cytokine produced by enterocytes, also contributes to the downregulation of CCL20 expression and increases interferon γ production by Th1 cells. This could perpetuate an amplification loop for CXCR3-driven Th1 and effector CD8+ T cells recruitment to the gut, while impairing Th17 cells homing through the CCR6-CCL20 axis in treated HIV-1–infected individuals.

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