scholarly journals Balancing Inflammation: The Link between Th17 and Regulatory T Cells

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Maggie L. Diller ◽  
Ragini R. Kudchadkar ◽  
Keith A. Delman ◽  
David H. Lawson ◽  
Mandy L. Ford
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Th17 Cells ◽  
Cell Lineage ◽  
Effector Functions ◽  
Inflammatory Conditions ◽  
Cell Compartments ◽  
Th17 Cell Differentiation ◽  
And Function

CD4+T cell compartments in mouse and man are composed of multiple distinct subsets each possessing unique phenotypic and functional characteristics. IL-17-producing CD4+T cells (Th17 cells) represent a distinct subset of the CD4+T cell lineage. Recent evidence suggests that Th17 cells carry out effector functions similar to cytotoxic CD8+T cells and play an important role in the clearance of extracellular pathogens and fungi. Th17 cell differentiation and function are closely related to the development and function of regulatory T cells(TREG). The balance between these two cell populations is essential for immune homeostasis and dysregulation of this balance has been implicated in a variety of inflammatory conditions including autoimmunity, allograft rejection, and tumorigenesis. Emerging evidence reports a significant amount of plasticity between the Th17 and regulatory T cell compartments, and the mechanisms by which these cells communicate and influence each other are just beginning to be understood. In this review, we highlight recent findings detailing the mechanisms driving Th17 andTREGplasticity and discuss the biologic consequences of their unique relationship.

scholarly journals CD4+ regulatory T cells require CTLA-4 for the maintenance of systemic tolerance

2009 ◽  
Vol 206 (2) ◽  
pp. 421-434 ◽  
Author(s):  
Randall H. Friedline ◽  
David S. Brown ◽  
Hai Nguyen ◽  
Hardy Kornfeld ◽  
JinHee Lee ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cell Function ◽  
Cytotoxic T Lymphocyte ◽  
Critical Role ◽  
Lymphoproliferative Disease ◽  
In Trans ◽  
And Function

Cytotoxic T lymphocyte antigen-4 (CTLA-4) plays a critical role in negatively regulating T cell responses and has also been implicated in the development and function of natural FOXP3+ regulatory T cells. CTLA-4–deficient mice develop fatal, early onset lymphoproliferative disease. However, chimeric mice containing both CTLA-4–deficient and –sufficient bone marrow (BM)–derived cells do not develop disease, indicating that CTLA-4 can act in trans to maintain T cell self-tolerance. Using genetically mixed blastocyst and BM chimaeras as well as in vivo T cell transfer systems, we demonstrate that in vivo regulation of Ctla4−/− T cells in trans by CTLA-4–sufficient T cells is a reversible process that requires the persistent presence of FOXP3+ regulatory T cells with a diverse TCR repertoire. Based on gene expression studies, the regulatory T cells do not appear to act directly on T cells, suggesting they may instead modulate the stimulatory activities of antigen-presenting cells. These results demonstrate that CTLA-4 is absolutely required for FOXP3+ regulatory T cell function in vivo.

Human CD25highFoxp3pos regulatory T cells differentiate into IL-17–producing cells

Blood ◽  
2008 ◽  
Vol 112 (6) ◽  
pp. 2340-2352 ◽  
Author(s):  
Hans J. P. M. Koenen ◽  
Ruben L. Smeets ◽  
Paul M. Vink ◽  
Esther van Rijssen ◽  
Annemieke M. H. Boots ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Epigenetic Modification ◽  
Trichostatin A ◽  
Cell Lineage ◽  
Microbial Infection ◽  
Negative Effect ◽  
Related Transcription Factor ◽  
Inflammatory Processes

Abstract The effector T-cell lineage shows great plasticity. Th17 cells are acknowledged to be instrumental in the response against microbial infection, but are also associated with autoimmune inflammatory processes. Here, we report that human regulatory T cells (CD4posCD25highFoxp3posCD127negCD27pos) can differentiate into IL-17–producing cells, when stimulated by allogeneic antigen-presenting cells, especially monocytes, in the presence of rhIL-2/rhIL-15. These regulatory T cell (Treg)–derived IL-17–producing cells showed high expression of the Th17-related transcription factor RORγt and were positively identified by CCR6 expression. This differentiation process was enhanced by exogenous IL-1β, IL-23, and IL-21, whereas IL-6 or TGFβ did not affect the emergence of IL-17–producing cells. The addition of IL-1 receptor antagonist (IL-1Ra), but not anti–IL-23 antibody, reduced IL-17–producing cell numbers. When an histone deacetylase (HDAC) inhibitor trichostatin A (TSA) was evaluated, we found a profound negative effect on the emergence of IL-17–producing cells from Tregs, implying that Treg differentiation into IL-17–producing cells depends on histone/protein deacetylase activity. Thus, the data suggest that epigenetic modification underlies the phenomenon of Treg plasticity here described.

scholarly journals Higher infiltration by Th17 cells compared with regulatory T cells is associated with severe acute T-cell-mediated graft rejection

2011 ◽  
Vol 43 (11) ◽  
pp. 630 ◽  
Author(s):  
Byung Ha Chung ◽  
Hye Jwa Oh ◽  
Shang Guo Piao ◽  
In O Sun ◽  
Seok Hui Kang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Graft Rejection ◽  
Th17 Cells

scholarly journals Targeting ion channel TRPM7 promotes thymic development of Regulatory T cells by increasing IL-2-dependent STAT5 activation

2018 ◽  
Author(s):  
Suresh K. Mendu ◽  
Michael S. Schappe ◽  
Emily K. Moser ◽  
Julia K. Krupa ◽  
Jason S. Rogers ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Ion Channel ◽  
Cell Lineage ◽  
Foxp3 Expression ◽  
List Type ◽  
Thymic Development ◽  
Genetic Deletion

In BriefGenetic deletion of Trpm7 in T-cells or pharmacological inhibition of TRPM7 channel promotes the development of fully functional Treg cells by increasing IL-2Rα and STAT5-dependent FOXP3 expression in the developing thymocytes. The study identifies the ion channel TRPM7 as a putative drug target to increase Treg numbers in vivo and induce immunotolerance.HIGHLIGHTSIon channel TRPM7 controls Treg developmentThe deletion of Trpm7 in the T-cell lineage increases fully functional Treg cells in the peripheryTRPM7 negatively regulates Foxp3 expression by restraining IL-2-dependent STAT5 activationInhibition of TRPM7 channel by FTY720 promotes the development of functional Treg cellsSUMMARYThe thymic development of regulatory T cells (Treg), the crucial suppressors of the effector T cells (Teff), is governed by the transcription factor FOXP3. Despite the clinical significance of Treg cells, there is a dearth of druggable molecular targets capable of increasing Treg numbers in vivo. We report a surprising discovery that TRPM7 restrains Treg development by negatively regulating STAT5-dependent Foxp3 expression. The deletion of Trpm7 potentiates the thymic development of Treg cells, leads to a significantly higher frequency of functional Treg cells in the periphery and renders the mice highly resistant to T cell-dependent hepatitis. The deletion of Trpm7 or the inhibition of TRPM7 channel activity by the FDA-approved prodrug FTY720, increases IL-2 sensitivity through a feed forward positive feedback loop involving high IL-2Rα expression and STAT5 activation. Enhanced IL-2 signaling increases the expression of Foxp3 in thymocytes and promotes the development of Treg cells. Thus, TRPM7 emerges as the first ion channel that can be drugged to increase Treg numbers, revealing a novel pharmacological path toward the induction of immune tolerance.

scholarly journals Regulatory T-Cell Therapy in Liver Transplantation and Chronic Liver Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Angus Hann ◽  
Ye H. Oo ◽  
M. Thamara P. R. Perera
Keyword(s):  
T Cells ◽  
Liver Disease ◽  
T Cell ◽  
Cell Lineage ◽  
Solid Organ ◽  
T Helper 1 ◽  
T Cell Therapy ◽  
Immune Mediated ◽  
And Function ◽  
Type Of Injury

The constant exposure of the liver to gut derived foreign antigens has resulted in this organ attaining unique immunological characteristics, however it remains susceptible to immune mediated injury. Our understanding of this type of injury, in both the native and transplanted liver, has improved significantly in recent decades. This includes a greater awareness of the tolerance inducing CD4+ CD25+ CD127low T-cell lineage with the transcription factor FoxP3, known as regulatory T-Cells (Tregs). These cells comprise 5-10% of CD4+ T cells and are known to function as an immunological “braking” mechanism, thereby preventing immune mediated tissue damage. Therapies that aim to increase Treg frequency and function have proved beneficial in the setting of both autoimmune diseases and solid organ transplantations. The safety and efficacy of Treg therapy in liver disease is an area of intense research at present and has huge potential. Due to these cells possessing significant plasticity, and the potential for conversion towards a T-helper 1 (Th1) and 17 (Th17) subsets in the hepatic microenvironment, it is pre-requisite to modify the microenvironment to a Treg favourable atmosphere to maintain these cells’ function. In addition, implementation of therapies that effectively increase Treg functional activity in the liver may result in the suppression of immune responses and will hinder those that destroy tumour cells. Thus, fine adjustment is crucial to achieve this immunological balance. This review will describe the hepatic microenvironment with relevance to Treg function, and the role these cells have in both native diseased and transplanted livers.

scholarly journals Regulatory T cell expansion by a highly CD25-dependent IL-2 mutein arrests ongoing autoimmunity

2019 ◽  
Author(s):  
Liliane Khoryati ◽  
Minh Nguyet Pham ◽  
McKenna Sherve ◽  
Swarnima Kumari ◽  
Kevin Cook ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Dose Range ◽  
Interleukin 2 ◽  
Autoimmune Response ◽  
Wild Type ◽  
Effector Cells ◽  
Inflammatory Conditions ◽  
Receptor Component ◽  
And Function

AbstractInterleukin-2 (IL-2) controls the homeostasis and function of regulatory T cells (Tregs) and defects in the IL-2 pathway contribute to multiple autoimmune diseases. Although recombinant IL-2 therapy has been efficacious in certain inflammatory conditions, the capacity for IL-2 to also activate inflammatory effector responses highlights the need for IL-2-based therapeutics with improved Treg-specificity. From a panel of rationally designed IL-2 variants, we identified IL-2 muteins with reduced potency and enhanced Treg-selectivity due to increased dependence on the IL-2-receptor component CD25. As an Fc-fused homodimer, the optimal Fc.IL-2 mutein induced selective Treg enrichment and reduced agonism of effector cells across a wide dose range. Furthermore, despite being a weaker agonist, overall Treg growth was greater and more sustained due to reduced receptor-mediated clearance of the Fc.IL-2 mutein compared to Fc-fused wild-type IL-2. Preferential Treg enrichment was also observed in the presence of activated pathogenic T cells in the autoimmune target organ, despite a loss of Treg-selectivity in an IL-2R-proximal response. These features allowed for extended resolution of spontaneous autoimmunity using infrequent dosing schedules. Thus, IL-2 muteins enable efficient, flexible, and targeted control of the autoimmune response.One Sentence SummaryA CD25-dependent IL-2 mutein selectively expands regulatory T cells and provides potent and targeted control of autoimmunity.

scholarly journals HuR Plays a Positive Role to Strengthen the Signaling Pathways of CD4+ T Cell Activation and Th17 Cell Differentiation

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Shiguang Yu ◽  
Morgan Tripod ◽  
Ulus Atasoy ◽  
Jing Chen
Keyword(s):  
T Cells ◽  
T Cell ◽  
Signaling Pathways ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Cell Activation ◽  
Cd4 T Cell ◽  
Th17 Cell Differentiation

After antigen and/or different cytokine stimulation, CD4+ T cells activated and differentiated into distinct T helper (Th) cells via differential T cell signaling pathways. Transcriptional regulation of the activation and differentiation of naïve CD4+ T cells into distinct lineage Th cells such as Th17 cells has been fully studied. However, the role of RNA-binding protein HuR in the signaling pathways of their activation and differentiation has not been well characterized. Here, we used HuR conditional knockout (HuR KO) CD4+ T cells to study mechanisms underlying HuR regulation of T cell activation and differentiation through distinct signaling pathways. Our work showed that, mechanistically, HuR positively promoted CD3g expression by binding its mRNA and enhanced the expression of downstream adaptor Zap70 and Malt1 in activated CD4+ T cells. Compared to WT Th0 cells, HuR KO Th0 cells with reduced Bcl-2 expression are much more susceptible to apoptosis than WT Th0 cells. We also found that HuR stabilized IL-6Rα mRNA and promoted IL-6Rα protein expression, thereby upregulating its downstream phosphorylation of Jak1 and Stat3 and increased level of phosphorylation of IκBα to facilitate Th17 cell differentiation. However, knockout of HuR increased IL-22 production in Th17 cells, which was due to HuR deficiency in reducing IL-22 transcription repressor c-Maf expression. These results highlight the importance of HuR in TCR signaling and IL-6/IL-6R axis driving naïve CD4+ T cell activation and differentiation into Th17 cells.

scholarly journals Control of T Cell Responses, Tolerance and Autoimmunity by Regulatory T Cells: Current Concepts

2003 ◽  
Vol 46 (4) ◽  
pp. 131-137 ◽  
Author(s):  
Pavel Chrobák
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Viral Infections ◽  
T Cell Responses ◽  
Cell Responses ◽  
Chronic Viral Infections ◽  
And Function ◽  
Special Circumstances ◽  
Immunosuppressive Cytokines

Regulatory T cells have emerged as an important mechanism of regulating tolerance and T cell responses. CD4+ regulatory T cells can be divided into two main groups, natural regulatory T cells, which express high levels of CD25 on their cell surface and phenotypically diverse adaptive (antigen induced) regulatory T cells. Natural regulatory T cells are made in the thymus, and require strong costimulatory signals for induction and maintenance, express a transcription factor called Foxp3, and function by a largely unknown mechanism. Adaptive (antigen induced) regulatory T cells are made by sub-optimal antigenic signals in the periphery, in the presence of immunosuppressive cytokines, often in special circumstances, such as chronic viral infections or after mucosal administration of antigen, and rely on cytokines such as IL-10 and TGF-β for suppression. Regulatory T cells offer a great potential for the treatment of autoimmune diseases and during transplantation.

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