IRF4 and its regulators: evolving insights into the pathogenesis of inflammatory arthritis?
Partha S. Biswas,
Govind Bhagat,
Alessandra B. Pernis,
Partha S. Biswas
Department of Medicine, Columbia University, New York, NY, USA.
Search for more papers by this authorGovind Bhagat
Department of Pathology, Columbia University, New York, NY, USA.
Search for more papers by this authorAlessandra B. Pernis
Department of Medicine, Columbia University, New York, NY, USA.
Search for more papers by this authorPartha S. Biswas,
Govind Bhagat,
Alessandra B. Pernis,
Partha S. Biswas
Department of Medicine, Columbia University, New York, NY, USA.
Search for more papers by this authorGovind Bhagat
Department of Pathology, Columbia University, New York, NY, USA.
Search for more papers by this authorAlessandra B. Pernis
Department of Medicine, Columbia University, New York, NY, USA.
Search for more papers by this authorAlessandra B. Pernis
Department of MedicineColumbia University630 West 168th StreetNew York, NY 10032, USATel.: +1 212 305 3763Fax: +1 212 305 4478e-mail: [email protected]
Abstract
Summary: Accumulating evidence from murine and human studies supports a key role for interleukin-17 (IL-17) and IL-21 in the pathogenesis of inflammatory arthritis. The pathways and molecular mechanisms that underlie the production of IL-17 and IL-21 are being rapidly elucidated. This review focuses on interferon regulatory factor 4 (IRF4), a member of the IRF family of transcription factors, which has emerged as a crucial controller of both IL-17 and IL-21 production. We first outline the complex role of IRF4 in the function of CD4+ T cells and then discuss recent studies from our laboratory that have revealed a surprising role for components of Rho GTPase-mediated pathways in controlling the activity of IRF4. A better understanding of these novel pathways will hopefully provide new insights into mechanisms responsible for the development of inflammatory arthritis and potentially guide the design of novel therapeutic approaches.
References
- 1 Goodnow CC, Sprent J, De St Groth BF, Vinuesa CG. Cellular and genetic mechanisms of self tolerance and autoimmunity. Nature 2005; 435: 590–597.
- 2 Lohr J, Knoechel B, Nagabhushanam V, Abbas AK. T-cell tolerance and autoimmunity to systemic and tissue-restricted self-antigens. Immunol Rev 2005; 204: 116–127.
- 3 Germain RN. Ligand-dependent regulation of T cell development and activation. Immunol Res 2003; 27: 277–286.
- 4 Love PE, Chan AC. Regulation of thymocyte development: only the meek survive. Curr Opin Immunol 2003; 15: 199–203.
- 5 Starr TK, Jameson SC, Hogquist KA. Positive and negative selection of T cells. Annu Rev Immunol 2003; 21: 139–176.
- 6 Smith-Garvin JE, Koretzky GA, Jordan MS. T cell activation. Annu Rev Immunol 2009; 27: 591–619.
- 7 Dustin ML. T-cell activation through immunological synapses and kinapses. Immunol Rev 2008; 221: 77–89.
- 8 McInnes IB, Schett G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol 2007; 7: 429–442.
- 9 Toh ML, Miossec P. The role of T cells in rheumatoid arthritis: new subsets and new targets. Curr Opin Rheumatol 2007; 19: 284–288.
- 10 Tesmer LA, Lundy SK, Sarkar S, Fox DA. Th17 cells in human disease. Immunol Rev 2008; 223: 87–113.
- 11 Gaffen SL. Structure and signalling in the IL-17 receptor family. Nat Rev Immunol 2009; 9: 556–567.
- 12 Ouyang W, Kolls JK, Zheng Y. The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity 2008; 28: 454–467.
- 13 Weaver CT, Hatton RD, Mangan PR, Harrington LE. IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu Rev Immunol 2007; 25: 821–852.
- 14 Ishigame H, et al. Differential roles of interleukin-17A and -17F in host defense against mucoepithelial bacterial infection and allergic responses. Immunity 2009; 30: 108–119.
- 15 Yang XO, et al. Regulation of inflammatory responses by IL-17F. J Exp Med 2008; 205: 1063–1075.
- 16 Yamaguchi Y, et al. IL-17B and IL-17C are associated with TNF-alpha production and contribute to the exacerbation of inflammatory arthritis. J Immunol 2007; 179: 7128–7136.
- 17 Kuestner RE, et al. Identification of the IL-17 receptor related molecule IL-17RC as the receptor for IL-17F. J Immunol 2007; 179: 5462–5473.
- 18 Zrioual S, et al. IL-17RA and IL-17RC receptors are essential for IL-17A-induced ELR+ CXC chemokine expression in synoviocytes and are overexpressed in rheumatoid blood. J Immunol 2008; 180: 655–663.
- 19 Novatchkova M, Leibbrandt A, Werzowa J, Neubuser A, Eisenhaber F. The STIR-domain superfamily in signal transduction, development and immunity. Trends Biochem Sci 2003; 28: 226–229.
- 20 Yao Z, et al. Herpesvirus Saimiri encodes a new cytokine, IL-17, which binds to a novel cytokine receptor. Immunity 1995; 3: 811–821.
- 21 Ruddy MJ, et al. Functional cooperation between interleukin-17 and tumor necrosis factor-alpha is mediated by CCAAT/enhancer-binding protein family members. J Biol Chem 2004; 279: 2559–2567.
- 22 Shen F, Hu Z, Goswami J, Gaffen SL. Identification of common transcriptional regulatory elements in interleukin-17 target genes. J Biol Chem 2006; 281: 24138–24148.
- 23 Martel-Pelletier J, Mineau F, Jovanovic D, Di Battista JA, Pelletier JP. Mitogen-activated protein kinase and nuclear factor kappaB together regulate interleukin-17-induced nitric oxide production in human osteoarthritic chondrocytes: possible role of transactivating factor mitogen-activated protein kinase-activated proten kinase (MAPKAPK). Arthritis Rheum 1999; 42: 2399–2409.
- 24 Gaffen SL. Biology of recently discovered cytokines: interleukin-17--a unique inflammatory cytokine with roles in bone biology and arthritis. Arthritis Res Ther 2004; 6: 240–247.
- 25 Koenders MI, Joosten LA, Van Den Berg WB. Potential new targets in arthritis therapy: interleukin (IL)-17 and its relation to tumour necrosis factor and IL-1 in experimental arthritis. Ann Rheum Dis 2006; 65(Suppl): iii29–iii33.
- 26 Lubberts E. IL-17/Th17 targeting: on the road to prevent chronic destructive arthritis? Cytokine 2008; 41: 84–91.
- 27 Chabaud M, et al. Human interleukin-17: a T cell-derived proinflammatory cytokine produced by the rheumatoid synovium. Arthritis Rheum 1999; 42: 963–970.
- 28 Lubberts E, et al. IL-1-independent role of IL-17 in synovial inflammation and joint destruction during collagen-induced arthritis. J Immunol 2001; 167: 1004–1013.
- 29 Ziolkowska M, et al. High levels of IL-17 in rheumatoid arthritis patients: IL-15 triggers in vitro IL-17 production via cyclosporin A-sensitive mechanism. J Immunol 2000; 164: 2832–2838.
- 30 Kirkham BW, et al. Synovial membrane cytokine expression is predictive of joint damage progression in rheumatoid arthritis: a two-year prospective study (the DAMAGE study cohort). Arthritis Rheum 2006; 54: 1122–1131.
- 31 Bush KA, Farmer KM, Walker JS, Kirkham BW. Reduction of joint inflammation and bone erosion in rat adjuvant arthritis by treatment with interleukin-17 receptor IgG1 Fc fusion protein. Arthritis Rheum 2002; 46: 802–805.
- 32 Lubberts E, et al. Treatment with a neutralizing anti-murine interleukin-17 antibody after the onset of collagen-induced arthritis reduces joint inflammation, cartilage destruction, and bone erosion. Arthritis Rheum 2004; 50: 650–659.
- 33 Nakae S, Nambu A, Sudo K, Iwakura Y. Suppression of immune induction of collagen-induced arthritis in IL-17-deficient mice. J Immunol 2003; 171: 6173–6177.
- 34 Ettinger R, Kuchen S, Lipsky PE. The role of IL-21 in regulating B-cell function in health and disease. Immunol Rev 2008; 223: 60–86.
- 35 Monteleone G, Pallone F, Macdonald TT. Interleukin-21 (IL-21)-mediated pathways in T cell-mediated disease. Cytokine Growth Factor Rev 2009; 20: 185–191.
- 36 Spolski R, Leonard WJ. Interleukin-21: basic biology and implications for cancer and autoimmunity. Annu Rev Immunol 2008; 26: 57–79.
- 37 Mehta DS, Wurster AL, Grusby MJ. Biology of IL-21 and the IL-21 receptor. Immunol Rev 2004; 202: 84–95.
- 38 Konforte D, Simard N, Paige CJ. IL-21: an executor of B cell fate. J Immunol 2009; 182: 1781–1787.
- 39 Imboden JB. The immunopathogenesis of rheumatoid arthritis. Annu Rev Pathol 2009; 4: 417–434.
- 40 Jang E, Cho SH, Park H, Paik DJ, Kim JM, Youn J. A positive feedback loop of IL-21 signaling provoked by homeostatic CD4+CD25- T cell expansion is essential for the development of arthritis in autoimmune K/BxN mice. J Immunol 2009; 182: 4649–4656.
- 41 Young DA, et al. Blockade of the interleukin-21/interleukin-21 receptor pathway ameliorates disease in animal models of rheumatoid arthritis. Arthritis Rheum 2007; 56: 1152–1163.
- 42 Hsu HC, et al. Interleukin 17-producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice. Nat Immunol 2008; 9: 166–175.
- 43 Doreau A, et al. Interleukin 17 acts in synergy with B cell-activating factor to influence B cell biology and the pathophysiology of systemic lupus erythematosus. Nat Immunol 2009; 10: 778–785.
- 44 Mosmann T, Coffman R. Th1 and Th2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol 1989; 7: 145–173.
- 45 Harrington LE, Mangan PR, Weaver CT. Expanding the effector CD4 T-cell repertoire: the Th17 lineage. Curr Opin Immunol 2006; 18: 349–356.
- 46 Takatori H, Kanno Y, Chen Z, O’Shea JJ. New complexities in helper T cell fate determination and the implications for autoimmune diseases. Mod Rheumatol 2008; 18: 533–541.
- 47 Harrington LE, et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 2005; 6: 1123–1132.
- 48 Park H, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 2005; 6: 1133–1141.
- 49 Langrish CL, et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 2005; 201: 233–240.
- 50 Bettelli E, Korn T, Oukka M, Kuchroo VK. Induction and effector functions of T(H)17 cells. Nature 2008; 453: 1051–1057.
- 51 Dong C. Th17 cells in development: an updated view of their molecular identity and genetic programming. Nat Rev Immunol 2008; 8: 337–348.
- 52 Zhou L, et al. TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature 2008; 453: 236–240.
- 53 Manel N, Unutmaz D, Littman DR. The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat. Nat Immunol 2008; 9: 641–649.
- 54 Volpe E, et al. A critical function for transforming growth factor-beta, interleukin 23 and proinflammatory cytokines in driving and modulating human T(H)-17 responses. Nat Immunol 2008; 9: 650–657.
- 55 Yang L, et al. IL-21 and TGF-beta are required for differentiation of human T(H)17 cells. Nature 2008; 454: 350–352.
- 56 Korn T, et al. IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature 2007; 448: 484–487.
- 57 Nurieva R, et al. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 2007; 448: 480–483.
- 58 Zhou L, et al. IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol 2007; 8: 967–974.
- 59 McGeachy MJ, et al. The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo. Nat Immunol 2009; 10: 314–324.
- 60 Stritesky GL, Yeh N, Kaplan MH. IL-23 promotes maintenance but not commitment to the Th17 lineage. J Immunol 2008; 181: 5948–5955.
- 61 Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 2006; 24: 179–189.
- 62 Chung Y, et al. Critical regulation of early Th17 cell differentiation by interleukin-1 signaling. Immunity 2009; 30: 576–587.
- 63 Ben-Sasson SZ, et al. IL-1 acts directly on CD4 T cells to enhance their antigen-driven expansion and differentiation. Proc Natl Acad Sci U S A 2009; 106: 7119–7124.
- 64 Koenders MI, et al. Interleukin-1 drives pathogenic Th17 cells during spontaneous arthritis in interleukin-1 receptor antagonist-deficient mice. Arthritis Rheum 2008; 58: 3461–3470.
- 65 Iezzi G, Sonderegger I, Ampenberger F, Schmitz N, Marsland BJ, Kopf M. CD40-CD40L cross-talk integrates strong antigenic signals and microbial stimuli to induce development of IL-17-producing CD4+ T cells. Proc Natl Acad Sci U S A 2009; 106: 876–881.
- 66 Saeki K, et al. A major lipid raft protein raftlin modulates T cell receptor signaling and enhances th17-mediated autoimmune responses. J Immunol 2009; 182: 5929–5937.
- 67 Laurence A, et al. Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity 2007; 26: 371–381.
- 68 Batten M, et al. Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleukin 17-producing T cells. Nat Immunol 2006; 7: 929–936.
- 69 Stumhofer JS, et al. Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system. Nat Immunol 2006; 7: 937–945.
- 70 Niedbala W, et al. Interleukin 27 attenuates collagen-induced arthritis. Ann Rheum Dis 2008; 67: 1474–1479.
- 71 Elias KM, et al. Retinoic acid inhibits Th17 polarization and enhances FoxP3 expression through a Stat-3/Stat-5 independent signaling pathway. Blood 2008; 111: 1013–1020.
- 72 Mucida D, et al. Reciprocal Th17 and regulatory T cell differentiation mediated by retinoic acid. Science 2007; 317: 256–260.
- 73 Schambach F, Schupp M, Lazar MA, Reiner SL. Activation of retinoic acid receptor-alpha favours regulatory T cell induction at the expense of IL-17-secreting T helper cell differentiation. Eur J Immunol 2007; 37: 2396–2399.
- 74 Xiao S, et al. Retinoic acid increases Foxp3+ regulatory T cells and inhibits development of Th17 cells by enhancing TGF-beta-driven Smad3 signaling and inhibiting IL-6 and IL-23 receptor expression. J Immunol 2008; 181: 2277–2284.
- 75 Nozaki Y, Yamagata T, Sugiyama M, Ikoma S, Kinoshita K, Funauchi M. Anti-inflammatory effect of all-trans-retinoic acid in inflammatory arthritis. Clin Immunol 2006; 119: 272–279.
- 76 McGeachy MJ, et al. TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology. Nat Immunol 2007; 8: 1390–1397.
- 77 Lee YK, et al. Late developmental plasticity in the T helper 17 lineage. Immunity 2009; 30: 92–107.
- 78 Nurieva R, Yang XO, Chung Y, Dong C. Cutting edge: in vitro generated Th17 cells maintain their cytokine expression program in normal but not lymphopenic hosts. J Immunol 2009; 182: 2565–2568.
- 79 Yang XO, et al. Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity 2008; 29: 44–56.
- 80 Voo KS, et al. Identification of IL-17-producing FOXP3+ regulatory T cells in humans. Proc Natl Acad Sci USA 2009; 106: 4793–4798.
- 81 King C, Tangye SG, Mackay CR. T follicular helper (TFH) cells in normal and dysregulated immune responses. Annu Rev Immunol 2008; 26: 741–766.
- 82 Bauquet AT, et al. The costimulatory molecule ICOS regulates the expression of c-Maf and IL-21 in the development of follicular T helper cells and Th-17 cells. Nat Immunol 2009; 10: 167–175.
- 83 Nurieva RI, et al. Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. Immunity 2008; 29: 138–149.
- 84 Vogelzang A, McGuire HM, Yu D, Sprent J, Mackay CR, King C. A fundamental role for interleukin-21 in the generation of T follicular helper cells. Immunity 2008; 29: 127–137.
- 85 Zhou L, Chong MM, Littman DR. Plasticity of CD4+ T cell lineage differentiation. Immunity 2009; 30: 646–655.
- 86 Schindler C, Strehlow I. Cytokines and STAT signaling. Adv Pharmacol 2000; 47: 113–174.
- 87 O’Shea JJ, Murray PJ. Cytokine signaling modules in inflammatory responses. Immunity 2008; 28: 477–487.
- 88 Wei L, Laurence A, Elias KM, O’Shea JJ. IL-21 is produced by Th17 cells and drives IL-17 production in a STAT3-dependent manner. J Biol Chem 2007; 282: 34605–34610.
- 89 Yang XO, et al. STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J Biol Chem 2007; 282: 9358–9363.
- 90 Mathur AN, et al. Stat3 and Stat4 direct development of IL-17-secreting Th cells. J Immunol 2007; 178: 4901–4907.
- 91 Ansel KM, Djuretic I, Tanasa B, Rao A. Regulation of Th2 differentiation and Il4 locus accessibility. Annu Rev Immunol 2006; 24: 607–656.
- 92 Szabo SJ, Sullivan BM, Peng SL, Glimcher LH. Molecular mechanisms regulating Th1 immune responses. Annu Rev Immunol 2003; 21: 713–758.
- 93 Ivanov II, et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 2006; 126: 1121–1133.
- 94 Yang XO, et al. T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma. Immunity 2008; 28: 29–39.
- 95 Liu XK, Lin X, Gaffen SL. Crucial role for nuclear factor of activated T cells in T cell receptor-mediated regulation of human interleukin-17. J Biol Chem 2004; 279: 52762–52771.
- 96 Kim HP, Korn LL, Gamero AM, Leonard WJ. Calcium-dependent activation of interleukin-21 gene expression in T cells. J Biol Chem 2005; 280: 25291–25297.
- 97 Mehta DS, Wurster AL, Weinmann AS, Grusby MJ. NFATc2 and T-bet contribute to T-helper-cell-subset-specific regulation of IL-21 expression. Proc Natl Acad Sci USA 2005; 102: 2016–2021.
- 98 Schraml BU, et al. The AP-1 transcription factor Batf controls T(H)17 differentiation. Nature 2009; 460: 405–409.
- 99 Zhu J, et al. Down-regulation of Gfi-1 expression by TGF-beta is important for differentiation of Th17 and CD103+ inducible regulatory T cells. J Exp Med 2009; 206: 329–341.
- 100 Brustle A, et al. The development of inflammatory T(H)-17 cells requires interferon-regulatory factor 4. Nat Immunol 2007; 8: 958–966.
- 101 Huber M, et al. IRF4 is essential for IL-21-mediated induction, amplification, and stabilization of the Th17 phenotype. Proc Natl Acad Sci USA 2008; 105: 20846–20851.
- 102 Chen Q, et al. IRF-4 Binding Protein inhibits interleukin-17 and interleukin-21 production by controlling the activity of IRF-4 transcription factor. Immunity 2008; 299: 899–911.
- 103 Tamura T, Yanai H, Savitsky D, Taniguchi T. The IRF family transcription factors in immunity and oncogenesis. Annu Rev Immunol 2008; 26: 535–584.
- 104 Lohoff M, Mak TW. Roles of interferon-regulatory factors in T-helper-cell differentiation. Nat Rev Immunol 2005; 5: 125–135.
- 105 Chen W, et al. Insights into interferon regulatory factor activation from the crystal structure of dimeric IRF5. Nat Struct Mol Biol 2008; 15: 1213–1220.
- 106 Qin BY, et al. Crystal structure of IRF-3 reveals mechanism of autoinhibition and virus-induced phosphoactivation. Nat Struct Biol 2003; 10: 913–921.
- 107 Takahasi K, et al. X-ray crystal structure of IRF-3 and its functional implications. Nat Struct Biol 2003; 10: 922–927.
- 108 Eisenbeis C, Singh H, Storb U. Pip, a novel IRF family member, is a lymphoid-specific, PU.1-dependent transcriptional activator. Genes Dev 1995; 9: 1377–1387.
- 109 Brass AL, Zhu AQ, Singh H. Assembly requirements of PU.1-Pip (IRF-4) activator complexes: inhibiting function in vivo using fused dimers. EMBO J 1999; 18: 977–991.
- 110 Perkel JM, Atchison ML. A two-step mechanism for recruitment of Pip by PU.1. J Immunol 1998; 160: 241–252.
- 111 Gupta S, Jiang M, Anthony A, Pernis A. Lineage-specific modulation of IL-4 signaling by interferon regulatory factor 4. J Exp Med 1999; 190: 1837–1848.
- 112 Brass A, Kehrli E, Eisenbeis C, Storb U, Singh H. Pip, a lymphoid-restricted IRF, contains a regulatory domain that is important for autoinhibition and ternary complex formation with the Ets factor PU.1. Genes Dev 1996; 10: 2335–2347.
- 113 Yamagata T, et al. A novel interferon regulatory factor family transcription factor, ICSAT/Pip/LSIRF, that negatively regulates the activity of interferon-regulated genes. Mol Cell Biol 1996; 16: 1283–1294.
- 114 Rosenbauer F, Waring JF, Foerster J, Wietstruk M, Philipp D, Horak I. Interferon consensus sequence binding protein and interferon regulatory factor-4/Pip form a complex that represses the expression of the interferon-stimulated gene-15 in macrophages. Blood 1999; 94: 4274–4281.
- 115 Saito M, et al. A signaling pathway mediating downregulation of BCL6 in germinal center B cells is blocked by BCL6 gene alterations in B cell lymphoma. Cancer Cell 2007; 12: 280–292.
- 116 Matsuyama T, et al. Molecular cloning of LSIRF, a lymphoid-specific member of the interferon regulatory factor family that binds the interferon-stimulated response element (ISRE). Nucl Acids Res 1995; 23: 2127–2136.
- 117 Grossman A, et al. Cloning of human lymphocyte-specific interferon regulatory factor (hLSIRF/hIRF4) and mapping of the gene to 6p23-25. Genomics 1996; 37: 229–233.
- 118 Grumont RJ, Gerondakis S. Rel induces interferon regulatory factor 4 (IRF-4) expression in lymphocytes: modulation of interferon-regulated gene expression by rel/nuclear factor kappaB. J Exp Med 2000; 191: 1281–1292.
- 119 Sharma S, et al. Activation and regulation of interferon regulatory factor 4 in HTLV type I-infected lymphocytes. AIDS Res Hum Retroviruses 2000; 16: 1613–1622.
- 120 Honma K, Kimura D, Tominaga N, Miyakoda M, Matsuyama T, Yui K. Interferon regulatory factor 4 differentially regulates the production of Th2 cytokines in naive vs. effector/memory CD4+ T cells. Proc Natl Acad Sci USA 2008; 105: 15890–15895.
- 121 Zheng Y, et al. Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses. Nature 2009; 458: 351–356.
- 122 Lehtonen A, et al. Differential expression of IFN regulatory factor 4 gene in human monocyte-derived dendritic cells and macrophages. J Immunol 2005; 175: 6570–6579.
- 123 Mittrucker H, et al. Requirement for the transcription factor LSIRF/IRF4 for mature B and T lymphocyte function. Science 1997; 275: 540–543.
- 124 Rengarajan J, Mowen KA, Mcbride KD, Smith ED, Singh H, Glimcher LH. Interferon regulatory factor 4 (IRF4) interacts with NFATc2 to modulate interleukin 4 gene expression. J Exp Med 2002; 195: 1003–1012.
- 125 Tominaga N, Ohkusu-Tsukada K, Udono H, Abe R, Matsuyama T, Yui K. Development of Th1 and not Th2 immune responses in mice lacking IFN-regulatory factor-4. Int Immunol 2003; 15: 1–10.
- 126 Falini B, et al. A monoclonal antibody (MUM1p) detects expression of the MUM1/IRF4 protein in a subset of germinal center B cells, plasma cells, and activated T cells. Blood 2000; 95: 2084–2092.
- 127 Lohoff M, et al. Dysregulated T helper cell differentiation in the absence of interferon regulatory factor 4. Proc Natl Acad Sci USA 2002; 99: 11808–11812.
- 128 Klein U, Dalla-Favera R. Germinal centres: role in B-cell physiology and malignancy. Nat Rev Immunol 2008; 8: 22–33.
- 129 Shaffer AL, Emre NC, Romesser PB, Staudt LM. IRF4: immunity. Malignancy! Therapy? Clin Cancer Res 2009; 15: 2954–2961.
- 130 Hu CM, Jang SY, Fanzo JC, Pernis AB. Modulation of T cell cytokine production by interferon regulatory factor-4. J Biol Chem 2002; 277: 49238–49246.
- 131 Lee CG, et al. A distal cis-regulatory element, CNS-9, controls NFAT1 and IRF4-mediated IL-10 gene activation in T helper cells. Mol Immunol 2009; 46: 613–621.
- 132 Cao S, Liu J, Song L, Ma X. The protooncogene c-Maf is an essential transcription factor for IL-10 gene expression in macrophages. J Immunol 2005; 174: 3484–3492.
- 133 Xu J, et al. c-Maf regulates IL-10 expression during Th17 polarization. J Immunol 2009; 182: 6226–6236.
- 134 Ahyi AN, Chang HC, Dent AL, Nutt SL, Kaplan MH. IFN regulatory factor 4 regulates the expression of a subset of Th2 cytokines. J Immunol 2009; 183: 1598–1606.
- 135 Pernis AB. The role of IRF-4 in B and T cell activation and differentiation. J Interf Cytok Res 2002; 22: 111–120.
- 136 Bustelo XR, Sauzeau V, Berenjeno IM. GTP-binding proteins of the Rho/Rac family: regulation, effectors and functions in vivo. BioEssays 2007; 29: 356–370.
- 137 Heasman SJ, Ridley AJ. Mammalian Rho GTPases: new insights into their functions from in vivo studies. Nat Rev Mol Cell Biol 2008; 9: 690–701.
- 138 Tybulewicz VL, Henderson RB. Rho family GTPases and their regulators in lymphocytes. Nat Rev Immunol 2009; 9: 630–644.
- 139 Schmidt A, Hall A. Guanine nucleotide exchange factors for Rho GTPases: turning on the switch. Genes Dev 2002; 16: 1587–1609.
- 140 Angkachatchai V, Finkel Th. ADP-ribosylation of rho by C3 ribosyltransferase inhibits IL-2 production and sustained calcium influx in activated T cells. J Immunol 1999; 163: 3819–3825.
- 141 Sanui T, et al. DOCK2 is essential for antigen-induced translocation of TCR and lipid rafts, but not PKC-theta and LFA-1, in T cells. Immunity 2003; 19: 119–129.
- 142 Genot EM, Arrieumerlou C, Ku G, Burgering BM, Weiss A, Kramer IM. The T-cell receptor regulates Akt (protein kinase B) via a pathway involving Rac1 and phosphatidylinositide 3-kinase. Mol Cell Biol 2000; 20: 5469–5478.
- 143 Tskvitaria-Fuller I, Seth A, Mistry N, Gu H, Rosen MK, Wulfing C. Specific patterns of Cdc42 activity are related to distinct elements of T cell polarization. J Immunol 2006; 177: 1708–1720.
- 144 Tharaux PL, et al. Rho kinase promotes alloimmune responses by regulating the proliferation and structure of T cells. J Immunol 2003; 171: 96–105.
- 145 Bustelo XR. Understanding Rho/Rac biology in T-cells using animal models. BioEssays 2002; 24: 602–612.
- 146 Cantrell DA. GTPases and T cell activation. Immunol Rev 2003; 192: 122–130.
- 147 Vicente-Manzanares M, Sanchez-Madrid F. Role of the cytoskeleton during leukocyte responses. Nat Rev Immunol 2004; 4: 110–122.
- 148 Burkhardt JK, Carrizosa E, Shaffer MH. The actin cytoskeleton in T cell activation. Annu Rev Immunol 2008; 26: 233–259.
- 149 Li B, et al. Role of the guanosine triphosphatase Rac2 in T helper 1 cell differentiation. Science 2000; 288: 2219–2222.
- 150 Yu H, Leitenberg D, Li B, Flavell RA. Deficiency of small GTPase Rac2 affects T cell activation. J Exp Med 2001; 194: 915–926.
- 151 Cannon JL, et al. Wasp recruitment to the T cell:APC contact site occurs independently of Cdc42 activation. Immunity 2001; 15: 249–259.
- 152 Cantrell D. Vav-1 and T cells. Eur J Immunol 2003; 33: 1070–1072.
- 153 Tybulewicz VL. Vav-family proteins in T-cell signalling. Curr Opin Immunol 2005; 17: 267–274.
- 154 Hotfilder M, Baxendale S, Cross MA, Sablitzky F. Def-2, -3, -6, -8, novel mouse genes differentially expressed in the hematopoietic system. Br J Haematol 1999; 106: 335–344.
- 155 Gupta S, et al. Molecular cloning of IBP, a SWAP-70 homologous GEF, which is highly expressed in the immune system. Human Immunol 2003; 64: 389–401.
- 156 Tanaka Y, et al. SWAP-70-like adapter of T cells, an adapter protein that regulates early TCR-initiated signaling in Th2 lineage cells. Immunity 2003; 18: 403–414.
- 157 Shinohara M, et al. SWAP-70 is a guanine-nucleotide-exchange factor that mediates signalling of membrane ruffling. Nature 2002; 416: 759–763.
- 158
Borggrefe T,
Masat L,
Wabl M,
Riwar B,
Cattoretti G,
Jessberger R.
Cellular, intracellular, and developmental expression patterns of murine SWAP-70.
Eur J Immunol
1999; 29: 1812–1822.
10.1002/(SICI)1521-4141(199906)29:06<1812::AID-IMMU1812>3.0.CO;2-J CAS PubMed Web of Science® Google Scholar
- 159 Becart S, Balancio AJ, Charvet C, Feau S, Sedwick CE, Altman A. Tyrosine-phosphorylation-dependent translocation of the SLAT protein to the immunological synapse is required for NFAT transcription factor activation. Immunity 2008; 29: 704–719.
- 160 Gupta S, et al. T cell receptor engagement leads to the recruitment of IBP, a novel guanine nucleotide exchange factor, to the immunological synapse. J Biol Chem 2003; 278: 43451–43459.
- 161 Mavrakis KJ, McKinlay KJ, Jones P, Sablitzky F. DEF6, a novel PH-DH-like domain protein, is an upstream activator of the Rho GTPases Rac1, Cdc42, and RhoA. Exp Cell Res 2004; 294: 335–344.
- 162 Oka T, Ihara S, Fukui Y. Cooperation of DEF6 with activated Rac in regulating cell morphology. J Biol Chem 2007; 282: 2011–2018.
- 163 Masat L, et al. Association of SWAP-70 with the B cell antigen receptor complex. Proc Natl Acad Sci U S A 2000; 97: 2180–2184.
- 164 Fanzo JC, et al. Loss of IRF-4-binding protein leads to the spontaneous development of systemic autoimmunity. J Clin Invest 2006; 116: 703–714.
- 165 Becart S, et al. SLAT regulates Th1 and Th2 inflammatory responses by controlling Ca2+/NFAT signaling. J Clin Invest 2007; 117: 2164–2175.
- 166 Murphy KM, Heimberger AB, Loh DY. Induction by antigen of intrathymic apoptosis of CD4+CD8+TCRlo thymocytes in vivo. Science 1990; 250: 1720–1723.
- 167 Baccala R, Theofilopoulos AN. The new paradigm of T-cell homeostatic proliferation-induced autoimmunity. Trends Immunol 2005; 26: 5–8.
- 168 Hickman SP, Turka LA. Homeostatic T cell proliferation as a barrier to T cell tolerance. Philos Trans R Soc Lond B Biol Sci 2005; 360: 1713–1721.
- 169 Jameson SC. T cell homeostasis: keeping useful T cells alive and live T cells useful. Semin Immunol 2005; 17: 231–237.
- 170 Krupica T Jr, Fry TJ, Mackall CL. Autoimmunity during lymphopenia: a two-hit model. Clin Immunol 2006; 120: 121–128.
- 171 Marleau AM, Sarvetnick N. T cell homeostasis in tolerance and immunity. J Leukoc Biol 2005; 78: 575–584.
- 172 Huppa JBGM, Sumen C, Davis MM. Continuous T cell receptor signaling required for synapse maintenance and full effector potential. Nat Immunol 2003; 4: 749–755.
- 173 Tskvitaria-Fuller I, Rozelle AL, Yin HL, Wulfing C. Regulation of sustained actin dynamics by the TCR and costimulation as a mechanism of receptor localization. J Immunol 2003; 171: 2287–2295.
Citing Literature
