The yin and yang of regulatory T cells and inflammation in RA

Rheumatoid arthritis (RA) is characterized by chronic inflammation leading to joint destruction. Regulatory T (TREG) cells are potent suppressors of autoimmunity, but are not capable of controlling every aspect of the inflammatory reaction. We have found that TREG-cell function is abnormal in patients with RA, and that a distinct population of TREG cells with potent suppressive properties is induced after therapy with inhibitors of tumor necrosis factor. In this Review, we discuss the mutual interactions between the opposing forces of TREG cells and inflammation in the context of RA. Therapeutic approaches that enhance TREG-cell function whilst controlling inflammation are likely to be the most effective strategies for restoring immune tolerance in patients with this disease.

[1]  C. Baecher-Allan,et al.  IL-17-producing human peripheral regulatory T cells retain suppressive function. , 2009, Blood.

[2]  T. Macdonald,et al.  IL-21 Counteracts the Regulatory T Cell-Mediated Suppression of Human CD4+ T Lymphocytes1 , 2007, The Journal of Immunology.

[3]  Chen Dong,et al.  Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. , 2008, Immunity.

[4]  N. Tubridy,et al.  CD39+Foxp3+ Regulatory T Cells Suppress Pathogenic Th17 Cells and Are Impaired in Multiple Sclerosis1 , 2009, The Journal of Immunology.

[5]  P. Schwarzenberger,et al.  Overexpression of IL-17 in the knee joint of collagen type II immunized mice promotes collagen arthritis and aggravates joint destruction , 2002, Inflammation Research.

[6]  L. Joosten,et al.  IL-17 derived from juxta-articular bone and synovium contributes to joint degradation in rheumatoid arthritis , 2001, Arthritis research.

[7]  Graham M Lord,et al.  In vivo activated monocytes from the site of inflammation in humans specifically promote Th17 responses , 2009, Proceedings of the National Academy of Sciences.

[8]  Kathleen M. Smith,et al.  Development, cytokine profile and function of human interleukin 17–producing helper T cells , 2007, Nature Immunology.

[9]  S. Alzabin,et al.  Blockade of tumor necrosis factor in collagen-induced arthritis reveals a novel immunoregulatory pathway for Th1 and Th17 cells , 2008, The Journal of experimental medicine.

[10]  T. Nomura,et al.  Control of Regulatory T Cell Development by the Transcription Factor Foxp3 , 2002 .

[11]  T. Yajima,et al.  IL‐15 exacerbates collagen‐induced arthritis with an enhanced CD4+ T cell response to produce IL‐17 , 2007, European journal of immunology.

[12]  Vincent C. Manganiello,et al.  Foxp3-dependent programme of regulatory T-cell differentiation , 2007, Nature.

[13]  J. Bijlsma,et al.  CD4(+)CD25(+) regulatory T cells in rheumatoid arthritis: differences in the presence, phenotype, and function between peripheral blood and synovial fluid. , 2004, Arthritis and rheumatism.

[14]  Richard O. Williams,et al.  ANTI-CD3 therapy expands the numbers of CD4+ and CD8+ Treg cells and induces sustained amelioration of collagen-induced arthritis. , 2010, Arthritis and rheumatism.

[15]  L. Cosmi,et al.  Phenotypic and functional features of human Th17 cells , 2007, The Journal of experimental medicine.

[16]  J. Bluestone,et al.  Central role of defective interleukin-2 production in the triggering of islet autoimmune destruction. , 2008, Immunity.

[17]  M. Ehrenstein,et al.  Anti–TNF-α therapy induces a distinct regulatory T cell population in patients with rheumatoid arthritis via TGF-β , 2007, The Journal of experimental medicine.

[18]  R. Lechler,et al.  The maintenance of human CD4+ CD25+ regulatory T cell function: IL-2, IL-4, IL-7 and IL-15 preserve optimal suppressive potency in vitro. , 2007, International immunology.

[19]  Danila Valmori,et al.  Human memory FOXP3+ Tregs secrete IL-17 ex vivo and constitutively express the TH17 lineage-specific transcription factor RORγt , 2009, Proceedings of the National Academy of Sciences.

[20]  G. Freeman,et al.  CD4+CD25high Regulatory Cells in Human Peripheral Blood1 , 2001, The Journal of Immunology.

[21]  L. Joosten,et al.  IL-17 Promotes Bone Erosion in Murine Collagen-Induced Arthritis Through Loss of the Receptor Activator of NF-κB Ligand/Osteoprotegerin Balance 1 , 2003, The Journal of Immunology.

[22]  T. Schumacher,et al.  Adoptive therapy with redirected primary regulatory T cells results in antigen-specific suppression of arthritis , 2009, Proceedings of the National Academy of Sciences.

[23]  Edgar Schmitt,et al.  Epigenetic Control of the foxp3 Locus in Regulatory T Cells , 2007, PLoS biology.

[24]  CREB/ATF-dependent T cell receptor–induced FoxP3 gene expression: a role for DNA methylation , 2007, The Journal of Experimental Medicine.

[25]  J. Bluestone,et al.  Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo , 2009, Nature Immunology.

[26]  D. Zélénika,et al.  Induction of foxP3+ Regulatory T Cells in the Periphery of T Cell Receptor Transgenic Mice Tolerized to Transplants1 , 2004, The Journal of Immunology.

[27]  T. Nomura,et al.  CTLA-4 Control over Foxp3+ Regulatory T Cell Function , 2008, Science.

[28]  鬼頭 昭彦.  Indispensable role of the Runx1-Cbfβ transcription complex for in vivo-suppressive function of FoxP3[+] regulatory T cells , 2010 .

[29]  Graham M Lord,et al.  Optimal induction of T helper 17 cells in humans requires T cell receptor ligation in the context of Toll-like receptor-activated monocytes , 2007, Proceedings of the National Academy of Sciences.

[30]  D. Männel,et al.  Interaction of TNF with TNF Receptor Type 2 Promotes Expansion and Function of Mouse CD4+CD25+ T Regulatory Cells1 , 2007, The Journal of Immunology.

[31]  M. A. Curotto de Lafaille,et al.  Oral tolerance in the absence of naturally occurring Tregs. , 2005, The Journal of clinical investigation.

[32]  T. Naka,et al.  IL-6-dependent and -independent pathways in the development of interleukin 17-producing T helper cells , 2007, Proceedings of the National Academy of Sciences.

[33]  Shimon Sakaguchi,et al.  Regulatory T cells exert checks and balances on self tolerance and autoimmunity , 2010, Nature Immunology.

[34]  Sudha Kumari,et al.  Protein Kinase C-θ Mediates Negative Feedback on Regulatory T Cell Function , 2010, Science.

[35]  E. Assier,et al.  Shifting the imbalance from Th1/Th2 to Th17/treg: the changing rheumatoid arthritis paradigm. , 2008, Joint, bone, spine : revue du rhumatisme.

[36]  H. Weiner,et al.  Suppression of murine SLE by oral anti-CD3: inducible CD4+CD25-LAP+ regulatory T cells control the expansion of IL-17+ follicular helper T cells , 2009, Lupus.

[37]  S. Nakae,et al.  Suppression of Immune Induction of Collagen-Induced Arthritis in IL-17-Deficient Mice 1 , 2003, The Journal of Immunology.

[38]  M. Genovese,et al.  LY2439821, a humanized anti-interleukin-17 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: A phase I randomized, double-blind, placebo-controlled, proof-of-concept study. , 2010, Arthritis and rheumatism.

[39]  A. Peck,et al.  Precarious Balance: Th17 Cells in Host Defense , 2009, Infection and Immunity.

[40]  T. Gingeras,et al.  CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells , 2006, The Journal of experimental medicine.

[41]  Y. Koide,et al.  Reduced susceptibility to collagen-induced arthritis in mice deficient in IFN-gamma receptor. , 1998, Journal of immunology.

[42]  D. Laplaud,et al.  Patients with relapsing-remitting multiple sclerosis have normal Treg function when cells expressing IL-7 receptor alpha-chain are excluded from the analysis. , 2008, The Journal of clinical investigation.

[43]  H. Weiner,et al.  Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells , 2006, Nature.

[44]  P. Coulie,et al.  Membrane protein GARP is a receptor for latent TGF‐β on the surface of activated human Treg , 2009, European journal of immunology.

[45]  M. Genovese.  Treatment of Rheumatoid Arthritis , 2009 .

[46]  Ashley M. Miller,et al.  Mast cells express IL-17A in rheumatoid arthritis synovium. , 2010, Journal of immunology.

[47]  E. Olson,et al.  Deacetylase inhibition promotes the generation and function of regulatory T cells , 2007, Nature Medicine.

[48]  W. Hancock,et al.  Using histone deacetylase inhibitors to enhance Foxp3+ regulatory T‐cell function and induce allograft tolerance , 2009, Immunology and cell biology.

[49]  H. Lane,et al.  IL‐15 acts as a potent inducer of CD4+CD25hi cells expressing FOXP3 , 2008, European journal of immunology.

[50]  V. Kuchroo,et al.  Myelin-specific regulatory T cells accumulate in the CNS but fail to control autoimmune inflammation , 2007, Nature Medicine.

[51]  N. L. Thangue,et al.  Drug Insight: histone deacetylase inhibitor-based therapies for cutaneous T-cell lymphomas , 2008, Nature Clinical Practice Oncology.

[52]  S. Huang,et al.  High susceptibility to collagen-induced arthritis in mice lacking IFN-gamma receptors. , 1997, Journal of immunology.

[53]  A. Rudensky,et al.  Dicer-dependent microRNA pathway safeguards regulatory T cell function , 2008, The Journal of experimental medicine.

[54]  S. Gaffen,et al.  Th17 cells at the crossroads of innate and adaptive immunity against infectious diseases at the mucosa , 2009, Mucosal Immunology.

[55]  Li Li,et al.  Conversion of Peripheral CD4+CD25− Naive T Cells to CD4+CD25+ Regulatory T Cells by TGF-β Induction of Transcription Factor Foxp3 , 2003, The Journal of experimental medicine.

[56]  P. Parren,et al.  Targeting interleukin-15 in patients with rheumatoid arthritis: a proof-of-concept study. , 2005, Arthritis and rheumatism.

[57]  L. Walker,et al.  Release from Regulatory T Cell-Mediated Suppression during the Onset of Tissue-Specific Autoimmunity Is Associated with Elevated IL-211 , 2008, The Journal of Immunology.

[58]  A. Rudensky,et al.  Single-cell analysis of normal and FOXP3-mutant human T cells: FOXP3 expression without regulatory T cell development. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[59]  P. Tak,et al.  MicroRNA-146A contributes to abnormal activation of the type I interferon pathway in human lupus by targeting the key signaling proteins. , 2009, Arthritis and rheumatism.

[60]  P. Petrow,et al.  The role of regulatory T cells in antigen-induced arthritis: aggravation of arthritis after depletion and amelioration after transfer of CD4+CD25+ T cells , 2005, Arthritis research & therapy.

[61]  Ruslan Medzhitov,et al.  Toll Pathway-Dependent Blockade of CD4+CD25+ T Cell-Mediated Suppression by Dendritic Cells , 2003, Science.

[62]  M. Feldmann,et al.  Anti-TNF biologic agents: still the therapy of choice for rheumatoid arthritis , 2009, Nature Reviews Rheumatology.

[63]  B. Malissen,et al.  Heterogeneity of natural Foxp3+ T cells: A committed regulatory T-cell lineage and an uncommitted minor population retaining plasticity , 2009, Proceedings of the National Academy of Sciences.

[64]  D. Isenberg,et al.  Compromised Function of Regulatory T Cells in Rheumatoid Arthritis and Reversal by Anti-TNFα Therapy , 2004, The Journal of experimental medicine.

[65]  F. Ramsdell,et al.  An essential role for Scurfin in CD4+CD25+ T regulatory cells , 2003, Nature Immunology.

[66]  G. Lal,et al.  Epigenetic mechanisms of regulation of Foxp3 expression. , 2009, Blood.

[67]  J. Bijlsma,et al.  Proinflammatory mediator-induced reversal of CD4+,CD25+ regulatory T cell-mediated suppression in rheumatoid arthritis. , 2007, Arthritis and rheumatism.

[68]  G. Schuler,et al.  Ex Vivo Isolation and Characterization of Cd4+Cd25+ T Cells with Regulatory Properties from Human Blood , 2001, The Journal of experimental medicine.

[69]  E. Shevach,et al.  Induction of FOXP3 expression in naive human CD4+FOXP3 T cells by T-cell receptor stimulation is transforming growth factor-beta dependent but does not confer a regulatory phenotype. , 2007, Blood.

[70]  P. Lipsky,et al.  TNF downmodulates the function of human CD4+CD25hi T-regulatory cells. , 2006, Blood.

[71]  A. Rudensky,et al.  Single-cell analysis of normal and FOXP 3-mutant human T cells : FOXP 3 expression without regulatory T cell development , 2006 .

[72]  M. Ehrenstein,et al.  Defects in CTLA-4 are associated with abnormal regulatory T cell function in rheumatoid arthritis , 2008, Proceedings of the National Academy of Sciences.

[73]  D. Levy,et al.  Epigenetic Regulation of Foxp3 Expression in Regulatory T Cells by DNA Methylation1 , 2009, The Journal of Immunology.