Phosphorylation of FOXP3 controls regulatory T cell function and is inhibited by TNF-α in rheumatoid arthritis
TL;DR: It is demonstrated that forkhead box P3 (FOXP3) transcriptional activity and Treg cell suppressive function are regulated by phosphorylation at Ser418 in the C-terminal DNA-binding domain through FOXP3 dephosphorylation.
Abstract: Regulatory T (Treg) cells suppress autoimmune disease, and impaired Treg cell function is associated with rheumatoid arthritis. Here we demonstrate that forkhead box P3 (FOXP3) transcriptional activity and, consequently, Treg cell suppressive function are regulated by phosphorylation at Ser418 in the C-terminal DNA-binding domain. In rheumatoid arthritis-derived Treg cells, the Ser418 site was specifically dephosphorylated by protein phosphatase 1 (PP1), whose expression and enzymatic activity were induced in the inflamed synovium by tumor necrosis factor α (TNF-α), leading to impaired Treg cell function. Moreover, TNF-α-induced Treg cell dysfunction correlated with increased numbers of interleukin-17 (IL-17)(+) and interferon-γ (IFN-γ)(+)CD4(+) T cells within the inflamed synovium in rheumatoid arthritis. Treatment with a TNF-α-specific antibody restored Treg cell function in subjects with rheumatoid arthritis, which was associated with decreased PP1 expression and increased FOXP3 phosphorylation in Treg cells. Thus, TNF-α controls the balance between Treg cells and pathogenic TH17 and TH1 cells in the synovium of individuals with rheumatoid arthritis through FOXP3 dephosphorylation.
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TL;DR: It is shown that TH17 cells originating from Foxp3+ T cells have a key role in the pathogenesis of autoimmune arthritis.
Abstract: Autoimmune diseases often result from an imbalance between regulatory T (Treg) cells and interleukin-17 (IL-17)-producing T helper (TH17) cells; the origin of the latter cells remains largely unknown. Foxp3 is indispensable for the suppressive function of Treg cells, but the stability of Foxp3 has been under debate. Here we show that TH17 cells originating from Foxp3(+) T cells have a key role in the pathogenesis of autoimmune arthritis. Under arthritic conditions, CD25(lo)Foxp3(+)CD4(+) T cells lose Foxp3 expression (herein called exFoxp3 cells) and undergo transdifferentiation into TH17 cells. Fate mapping analysis showed that IL-17-expressing exFoxp3 T (exFoxp3 TH17) cells accumulated in inflamed joints. The conversion of Foxp3(+)CD4(+) T cells to TH17 cells was mediated by synovial fibroblast-derived IL-6. These exFoxp3 TH17 cells were more potent osteoclastogenic T cells than were naive CD4(+) T cell-derived TH17 cells. Notably, exFoxp3 TH17 cells were characterized by the expression of Sox4, chemokine (C-C motif) receptor 6 (CCR6), chemokine (C-C motif) ligand 20 (CCL20), IL-23 receptor (IL-23R) and receptor activator of NF-κB ligand (RANKL, also called TNFSF11). Adoptive transfer of autoreactive, antigen-experienced CD25(lo)Foxp3(+)CD4(+) T cells into mice followed by secondary immunization with collagen accelerated the onset and increased the severity of arthritis and was associated with the loss of Foxp3 expression in the majority of transferred T cells. We observed IL-17(+)Foxp3(+) T cells in the synovium of subjects with active rheumatoid arthritis (RA), which suggests that plastic Foxp3(+) T cells contribute to the pathogenesis of RA. These findings establish the pathological importance of Foxp3 instability in the generation of pathogenic TH17 cells in autoimmunity.
880 citations
TL;DR: This review focuses on the biology of Th17 and regulatory T (Treg) cells and their role in inflammatory diseases, such as rheumatoid arthritis and suggests that the Th17/Treg balance plays a major role in the development and the disease outcomes of animal model and human autoimmune/inflammatory diseases.
707 citations
TL;DR: The therapeutic modulation of TNF now moves into the era of personalized medicine with society's challenging expectations of durable treatment success and of achieving long-term disease remission.
645 citations
Cites background from "Phosphorylation of FOXP3 controls r..."
...Moreover, phosphorylation of FOXP3 (a key transcription factor in Treg function) is downregulated by TNF [216]....
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...In addition, TNFR2 is highly expressed on Treg cells [215], and a recent report demonstrates that TNF antagonism restores normal function to dysregulated Treg cells in patients with RA, in a dose-dependent fashion [216]....
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TL;DR: Nature Reviews Immunology asks several experts for their views on the plasticity and stability of TReg cells.
Abstract: Regulatory T (TReg) cells are crucial for the prevention of fatal autoimmunity in mice and humans. Forkhead box P3 (FOXP3)(+) TReg cells are produced in the thymus and are also generated from conventional CD4(+) T cells in peripheral sites. It has been suggested that FOXP3(+) TReg cells might become unstable under certain inflammatory conditions and might adopt a phenotype that is more characteristic of effector CD4(+) T cells. These suggestions have caused considerable debate in the field and have important implications for the therapeutic use of TReg cells. In this article, Nature Reviews Immunology asks several experts for their views on the plasticity and stability of TReg cells.
451 citations
TL;DR: How the instability and plasticity of Treg cells can contribute to the breakdown of tolerance and lead to autoimmune disease is described.
Abstract: In recent years, the understanding of regulatory T cell (Treg cell) biology has expanded considerably. Key observations have challenged the traditional definition of Treg cells and have provided insight into the underlying mechanisms responsible for the development of autoimmune diseases, with new therapeutic strategies that improve disease outcome. This Review summarizes the newer concepts of Treg cell instability, Treg cell plasticity and tissue-specific Treg cells, and their relationship to autoimmunity. Those three main concepts have changed the understanding of Treg cell biology: how they interact with other immune and non-immune cells; their functions in specific tissues; and the implications of this for the pathogenesis of autoimmune diseases.
415 citations
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TL;DR: The in vitro model systems that have been developed to define the mechanisms used by Treg cells to suppress a large number of distinct target cell types are reviewed.
1,675 citations
TL;DR: Clonal deletion of autoreactive T cells in the thymus is not the sole mechanism for the induction of tolerance to self-antigens since partial depletion of peripheral CD4(+) T cells from neonatal and adult animals results in the development of organ-specific autoimmunity.
Abstract: Clonal deletion of autoreactive T cells in the thymus is not the sole mechanism for the induction of tolerance to self-antigens since partial depletion of peripheral CD4 ' T cells from neonatal and adult animals results in the development of organ-specific autoimmunity. Reconstitution of these immunodeficient animals with populations of regulatory CD4 ' T cells prevents the development of autoimmunity. The lineage of regulatory CD4 ' T cells is generated in the thymus and can be dis- tinguished from effector cells by the expression of unique membrane antigens. The target antigens for these suppressor populations and their mechanisms of action remain poorly defined. Depletion of regulatory T cells may be useful in the induction of immunity to weak antigens, such as tumor-specific antigens. Conversely, enhancement of regulatory T cell function may be a useful adjunct to the therapy of autoimmune diseases and for prevention of allograft rejection.
1,299 citations
TL;DR: These data are the first to demonstrate that regulatory T cells are functionally compromised in RA, and indicate that modulation of Regulatory T cells by anti-TNFα therapy may be a further mechanism by which this disease is ameliorated.
Abstract: Regulatory T cells have been clearly implicated in the control of disease in murine models of autoimmunity. The paucity of data regarding the role of these lymphocytes in human autoimmune disease has prompted us to examine their function in patients with rheumatoid arthritis (RA). Regulatory (CD4+CD25+) T cells isolated from patients with active RA displayed an anergic phenotype upon stimulation with anti-CD3 and anti-CD28 antibodies, and suppressed the proliferation of effector T cells in vitro. However, they were unable to suppress proinflammatory cytokine secretion from activated T cells and monocytes, or to convey a suppressive phenotype to effector CD4+CD25− T cells. Treatment with antitumor necrosis factor α (TNFα; Infliximab) restored the capacity of regulatory T cells to inhibit cytokine production and to convey a suppressive phenotype to “conventional” T cells. Furthermore, anti-TNFα treatment led to a significant rise in the number of peripheral blood regulatory T cells in RA patients responding to this treatment, which correlated with a reduction in C reactive protein. These data are the first to demonstrate that regulatory T cells are functionally compromised in RA, and indicate that modulation of regulatory T cells by anti-TNFα therapy may be a further mechanism by which this disease is ameliorated.
1,257 citations
TL;DR: By switching transcriptional partners, NFAT converts the acute T cell activation program into the suppressor program of Tregs, and this work shows that regulatory T cell (Treg) function is mediated by an analogous cooperative complex of NFAT with the forkhead transcription factor FOXP3, a lineage specification factor for Treg
1,138 citations
TL;DR: This Review discusses the biologic contribution and therapeutic potential of the major cytokine families to RA pathology, focusing on molecules contained within the TNF-alpha, IL-1,IL-6, Il-23, and IL-2 families.
Abstract: A large number of cytokines are active in the joints of patients with rheumatoid arthritis (RA). It is now clear that these cytokines play a fundamental role in the processes that cause inflammation, articular destruction, and the comorbidities associated with RA. Following the success of TNF-α blockade as a treatment for RA, other cytokines now offer alternative targets for therapeutic intervention or might be useful as predictive biomarkers of disease. In this Review, we discuss the biologic contribution and therapeutic potential of the major cytokine families to RA pathology, focusing on molecules contained within the TNF-α, IL-1, IL-6, IL-23, and IL-2 families.
948 citations