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• W2051615464 abstract "Production of cytokines is one of the major mechanisms employed by CD4+ T cells to coordinate immune responses. Although the molecular mechanisms controlling T cell cytokine production have been extensively studied, the factors that endow T cells with their ability to produce unique sets of cytokines have not been fully characterized. Interferon regulatory factor (IRF)-4 is a lymphoid-restricted member of the interferon regulatory factor family of transcriptional regulators, whose deficiency leads to a profound impairment in the ability of mature CD4+ T cells to produce cytokines. In these studies, we have investigated the mechanisms employed by IRF-4 to control cytokine synthesis. We demonstrate that stable expression of IRF-4 in Jurkat T cells not only leads to a strong enhancement in the synthesis of interleukin (IL)-2, but also enables these cells to start producing considerable amounts of IL-4, IL-10, and IL-13. Transient transfection assays indicate that IRF-4 can transactivate luciferase reporter constructs driven by either the human IL-2 or the human IL-4 promoter. A detailed analysis of the effects of IRF-4 on the IL-4 promoter reveals that IRF-4 binds to a site adjacent to a functionally important NFAT binding element and that IRF-4 cooperates with NFATc1. These studies thus support the notion that IRF-4 represents one of the lymphoid-specific components that control the ability of T lymphocytes to produce a distinctive array of cytokines. Production of cytokines is one of the major mechanisms employed by CD4+ T cells to coordinate immune responses. Although the molecular mechanisms controlling T cell cytokine production have been extensively studied, the factors that endow T cells with their ability to produce unique sets of cytokines have not been fully characterized. Interferon regulatory factor (IRF)-4 is a lymphoid-restricted member of the interferon regulatory factor family of transcriptional regulators, whose deficiency leads to a profound impairment in the ability of mature CD4+ T cells to produce cytokines. In these studies, we have investigated the mechanisms employed by IRF-4 to control cytokine synthesis. We demonstrate that stable expression of IRF-4 in Jurkat T cells not only leads to a strong enhancement in the synthesis of interleukin (IL)-2, but also enables these cells to start producing considerable amounts of IL-4, IL-10, and IL-13. Transient transfection assays indicate that IRF-4 can transactivate luciferase reporter constructs driven by either the human IL-2 or the human IL-4 promoter. A detailed analysis of the effects of IRF-4 on the IL-4 promoter reveals that IRF-4 binds to a site adjacent to a functionally important NFAT binding element and that IRF-4 cooperates with NFATc1. These studies thus support the notion that IRF-4 represents one of the lymphoid-specific components that control the ability of T lymphocytes to produce a distinctive array of cytokines. The coordination of an immune response is critically dependent on the ability of CD4+T cells to perform a unique set of effector functions. Crucial among these effector functions is the capacity of CD4+ T cells to secrete a distinctive array of cytokines including IL 1The abbreviations used are: IL, interleukin; IRF-4, interferon regulatory factor 4; NFAT, nuclear factor of activated T cell; EMSA, electrophoretic mobility shift assay; GAS, interferon-γ-activated site(s); IRF, interferon regulatory factor; ICSBP, interferon consensus sequence binding protein; ISRE, interferon-stimulated regulatory element; ELISA, enzyme-linked immunosorbent assay; PMA, phorbol 12-myristate 13-acetate; TH, T helper; STAT, signal transducers and activators of transcription1The abbreviations used are: IL, interleukin; IRF-4, interferon regulatory factor 4; NFAT, nuclear factor of activated T cell; EMSA, electrophoretic mobility shift assay; GAS, interferon-γ-activated site(s); IRF, interferon regulatory factor; ICSBP, interferon consensus sequence binding protein; ISRE, interferon-stimulated regulatory element; ELISA, enzyme-linked immunosorbent assay; PMA, phorbol 12-myristate 13-acetate; TH, T helper; STAT, signal transducers and activators of transcription-2, IL-4, and IFN-γ. Although most antigen-specific CD4+ T cells have the potential to secrete all of these cytokines, CD4+ T cells exposed to specific microenvironments can differentiate into two distinct subsets, termed T helper 1 (TH1) and T helper 2 (TH2) cells. These two subsets are restricted in the pattern of cytokines that they can produce. Thus TH1 cells secrete IL-2 and IFN-γ but not IL-4, while TH2 cells produce IL-4 (as well as IL-5, IL-6, IL-10, and IL-13) but not IL-2 or IFN-γ (1Murphy K.M. Ouyang W. Farrar J.D. Yang J. Ranganath S. Asnagli H. Afkarian M. Murphy T.L. Annu. Rev. Immunol. 2000; 18: 451-494Crossref PubMed Scopus (541) Google Scholar, 2Glimcher L.H. Murphy K.M. Genes Dev. 2000; 14: 1693-1711PubMed Google Scholar).One of the critical players responsible for transducing T cell activation signals into the acquisition of T cell effector functions is the NFAT family of transcriptional regulators (3Rao A. Luo C. Hogan P.G. Annu. Rev. Immunol. 1997; 15: 707-747Crossref PubMed Scopus (2203) Google Scholar, 4Crabtree G.R. Cell. 1999; 96: 611-614Abstract Full Text Full Text PDF PubMed Scopus (661) Google Scholar, 5Serfling E. Berberich-Siebelt F. Chuvpilo S. Jankevics E. Klein-Hessling S. Twardzik T. Avots A. Biochim. Biophys. Acta. 2000; 1498: 1-18Crossref PubMed Scopus (170) Google Scholar). This family is comprised of four calcium-regulated members, NFAT1 (NFATc2, NFATp), NFAT2 (NFATc1, NFATc), NFAT3 (NFATc4), and NFAT4 (NFATc3, NFATx). Upon activation of T cells, these proteins are rapidly dephosphorylated and translocate to the nucleus. This process is mediated by calcineurin, a calcium-regulated phosphatase, which is a well known target of the immunosuppressive drugs cyclosporin A and FK506 (6Kiani A. Rao A. Aramburu J. Immunity. 2000; 12: 359-372Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar). NFAT proteins have been shown to be involved in the regulation of several cytokine genes, including IL-2 and IL-4(3Rao A. Luo C. Hogan P.G. Annu. Rev. Immunol. 1997; 15: 707-747Crossref PubMed Scopus (2203) Google Scholar, 5Serfling E. Berberich-Siebelt F. Chuvpilo S. Jankevics E. Klein-Hessling S. Twardzik T. Avots A. Biochim. Biophys. Acta. 2000; 1498: 1-18Crossref PubMed Scopus (170) Google Scholar). The regulatory regions of cytokine genes usually contain multiple functionally important NFAT target sequences, for instance, the promoter of the IL-4 gene contains four (to five) distinct NFAT binding sites, termed P0 through P4 (7Szabo S.J. Glimcher L.H. Ho I.C. Curr. Opin. Immunol. 1997; 9: 776-781Crossref PubMed Scopus (70) Google Scholar). NFAT proteins bind DNA only weakly and optimal binding and NFAT-mediated transactivation requires their cooperation with additional transcription factors and the formation of “functional enhanceosomes” (8Macian F. Lopez-Rodriguez C. Rao A. Oncogene. 2001; 20: 2476-2489Crossref PubMed Scopus (610) Google Scholar). Genetic studies have revealed a complex role for NFAT proteins in the regulation of cytokine production and have highlighted the fact that members of this family can exert not only positive but also inhibitory effects on the production of specific cytokine profiles (9Xanthoudakis S. Viola J.P.B. Shaw K.T.Y. Luo C. Wallace J.D. Bozza P.T. Curran T. Rao A. Science. 1996; 272: 892-895Crossref PubMed Scopus (313) Google Scholar, 10Hodge M.R. Ranger A.M. de la Brousse F.C. Hoey T. Grusby M.J. Glimcher L.H. Immunity. 1996; 4: 397-405Abstract Full Text Full Text PDF PubMed Scopus (398) Google Scholar, 11Kiani A. Viola J.P.B. Lichtman A.H. Rao A. Immunity. 1997; 7: 849-860Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar, 12Schuh K. Kneitz B. Heyer J. Bommhardt U. Jannkevics E. Berberich-Siebelt F. Pfeffer K. Muller-Hermelink H.K. Schimpl A. Serfling E. Eur. J. Immunol. 1998; 28: 2456-2466Crossref PubMed Scopus (47) Google Scholar, 13Ranger A.M. Hodge M.R. Gravallese E.M. Oukka M. Davidson L. Alt F.W. de la Brousse F.C. Hoey T. Grusby M. Glimcher L.H. Immunity. 1998; 8: 125-134Abstract Full Text Full Text PDF PubMed Scopus (258) Google Scholar, 14Yoshida H. Nishina H. Takimoto H. Marengere L.E.M. Wakeham A.C. Bouchard D. Kong Y.-Y. Ohteki T. Shahinian A. Bachmann M. Ohashi P.S. Penninger J.M. Crabtree G.R. Mak T.W. Immunity. 1998; 8: 115-124Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar, 15Ranger A.M. Oukka M. Rengarajan J. Glimcher L.H. Immunity. 1998; 9: 627-635Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar, 16Peng S.L. Gerth A.J. Ranger A.M. Glimcher L.H. Immunity. 2001; 14: 13-20Abstract Full Text Full Text PDF PubMed Scopus (312) Google Scholar, 17Rengarajan J. Tang B. Glimcher L.H. Nature Immunol. 2002; 3: 48-54Crossref PubMed Scopus (129) Google Scholar). Despite the fact that NFAT proteins play a crucial role in the production of T cell cytokines, their expression can be detected in a wide variety of cells and deficiency of some NFAT proteins can lead to profound defects in the development of nonlymphoid cells (18Graef I.A. Cheng F. Crabtree G.R. Curr. Opin. Genet. Dev. 2001; 11: 505-512Crossref PubMed Scopus (178) Google Scholar). Many of the transcription factors, like AP-1, that have classically been shown to cooperate with NFAT proteins are also not restricted to lymphocytes. It is therefore unclear how lineage-specific expression of NFAT target genes is achieved.IRF-4 is a recently discovered member of the interferon regulatory factor (IRF) family of transcription factors whose expression is primarily restricted to lymphocytes (19Eisenbeis C. Singh H. Storb U. Genes Dev. 1995; 9: 1377-1387Crossref PubMed Scopus (413) Google Scholar, 20Matsuyama T. Grossman A. Mittrucker H. Siderovski D. Kiefer F. Kawakami T. Richardson C. Taniguchi T. Yoshinaga S. Mak T. Nucleic Acids Res. 1995; 23: 2127-2136Crossref PubMed Scopus (209) Google Scholar, 21Yamagata T. Nishida J. Tanaka T. Sakai R. Mitani K. Taniguchi T. Yazaki Y. Hirai H. Mol. Cell. Biol. 1996; 16: 1283-1294Crossref PubMed Scopus (186) Google Scholar, 22Iida S. Rao P. Butler M. Corradini P. Boccadoro M. Klein B. Chaganti R. Dalla-Favera R. Nat. Genet. 1997; 17: 226-230Crossref PubMed Scopus (303) Google Scholar). IRF-4 expression in B and T cells is up-regulated by pathways known to drive their activation (19Eisenbeis C. Singh H. Storb U. Genes Dev. 1995; 9: 1377-1387Crossref PubMed Scopus (413) Google Scholar, 21Yamagata T. Nishida J. Tanaka T. Sakai R. Mitani K. Taniguchi T. Yazaki Y. Hirai H. Mol. Cell. Biol. 1996; 16: 1283-1294Crossref PubMed Scopus (186) Google Scholar, 23Gupta S. Jiang M. Anthony A. Pernis A. J. Exp. Med. 1999; 190: 1837-1848Crossref PubMed Scopus (106) Google Scholar, 24Grossman A. Mittrucker H. Nicholl J. Suzuki A. Chung S. Antonio L. Suggs S. Sutherland G. Siderovski D. Mak T. Genomics. 1996; 37: 229-233Crossref PubMed Scopus (70) Google Scholar), and genetic studies have demonstrated that IRF-4 is a critical effector of mature lymphocyte function (25Mittrucker H. Matsuyama T. Grossman A. Kundig T. Potter J. Shahinian A. Wakeham A. Patterson B. Ohashi P. Mak T. Science. 1997; 275: 540-543Crossref PubMed Scopus (4) Google Scholar). Studies of the mechanisms employed by IRF-4 to modulate lymphocyte activation have so far primarily focused on its role in B cells. In these cells, IRF-4 is involved in the regulation of genes that display B cell-specific expression/regulation, and that are normally induced in response to B cell activation stimuli (26Pernis A.B. J. Interferon Cytokine Res. 2002; 22: 111-120Crossref PubMed Scopus (55) Google Scholar). The ability of IRF-4 to target these genes requires the presence of DNA-bound PU.1, an Ets protein expressed in macrophages and B cells but not in T cells (19Eisenbeis C. Singh H. Storb U. Genes Dev. 1995; 9: 1377-1387Crossref PubMed Scopus (413) Google Scholar, 27Pongubala J.M.R. Beveren C.V. Nagulapalli S. Klemsz M.J. McKercher S.R. Maki R.A. Atchinson M.L. Science. 1993; 259: 1622-1625Crossref PubMed Scopus (241) Google Scholar). The interaction of IRF-4 with PU.1 is believed to cause a conformational change in IRF-4 that unmasks its DNA binding domain thus allowing it to target DNA sites containing the core sequence for IRF binding (GAAA) (28Brass A. Kehrli E. Eisenbeis C. Storb U. Singh H. Genes Dev. 1996; 10: 2335-2347Crossref PubMed Scopus (209) Google Scholar, 29Brass A.L. Zhu A.Q. Singh H. EMBO J. 1999; 18: 977-991Crossref PubMed Scopus (148) Google Scholar). As demonstrated by studies on CD23b, a gene synergistically induced by CD40 and IL-4, IRF-4 may also function in the integration of B cell activation pathways as a result of its ability to participate in the formation of “enhanceosome-like” complexes (23Gupta S. Jiang M. Anthony A. Pernis A. J. Exp. Med. 1999; 190: 1837-1848Crossref PubMed Scopus (106) Google Scholar, 30Gupta S. Anthony A. Pernis A. J. Immunol. 2001; 166: 6104-6111Crossref PubMed Scopus (41) Google Scholar). Genetic studies have revealed that IRF-4 plays a fundamental role in the T cell compartment as well (25Mittrucker H. Matsuyama T. Grossman A. Kundig T. Potter J. Shahinian A. Wakeham A. Patterson B. Ohashi P. Mak T. Science. 1997; 275: 540-543Crossref PubMed Scopus (4) Google Scholar). T cells from IRF-4-deficient mice can undergo early activation events but are unable to complete their activation program and display a profound block in their ability to produce cytokines like IL-2, IL-4, and IFN-γ. The mechanisms by which IRF-4 controls the acquisition of T cell effector function have, however, not been fully elucidated.Here, we show that IRF-4 can modulate the expression of T cell cytokine genes by directly targeting their regulatory regions. Stable expression of IRF-4 in T cells lacking endogenous IRF-4 leads to a strong enhancement in the production of IL-2, IL-4, IL-10, and IL-13. Transient transfection assays employing reporter constructs driven by either the IL-2 or IL-4 promoters further demonstrate that the presence of IRF-4 leads to higher inducibility of these constructs. A detailed analysis of the human IL-4 promoter indicates that IRF-4 can bind to DNA elements situated next to well known NFAT binding sites. We furthermore show that IRF-4 can functionally cooperate with the NFATc1 (NFAT2) protein and that the effect of IRF-4 on cytokine production can be blocked by immunosuppressants known to interfere with NFAT activation. Taken together these data are consistent with the notion that IRF-4 can function as a lineage-specific partner for NFAT proteins. Thus, the induction of IRF-4 upon T cell activation is likely to represent one of the critical steps that can endow T cells with the ability to perform their unique set of biologic responses.DISCUSSIONThe synthesis of a distinctive array of cytokines is one of the most characteristic and critical functions of CD4+ T cells (43Noble A. Immunology. 2000; 101: 289-299Crossref PubMed Scopus (19) Google Scholar). Although the mechanisms involved in T cell cytokine production have been extensively studied (2Glimcher L.H. Murphy K.M. Genes Dev. 2000; 14: 1693-1711PubMed Google Scholar, 44Avni O. Rao A. Curr. Opin. Immunol. 2000; 12: 654-659Crossref PubMed Scopus (66) Google Scholar), the factors that are responsible for the ability of lymphocytes to selectively produce specific cytokines have not been fully elucidated. It has previously been reported that mice deficient in IRF-4, a lymphoid restricted member of the IRF family of transcription factors, display striking disturbances in T cell cytokine production (25Mittrucker H. Matsuyama T. Grossman A. Kundig T. Potter J. Shahinian A. Wakeham A. Patterson B. Ohashi P. Mak T. Science. 1997; 275: 540-543Crossref PubMed Scopus (4) Google Scholar). In these studies, therefore, we set out to investigate the mechanisms by which IRF-4 controls T cell cytokine synthesis. Our results indicate that stable expression of IRF-4 exerts profound effects on the ability of human T cells to produce multiple cytokines, including IL-2 and IL-4. We furthermore show that IRF-4 directly targets the promoters of these cytokines and that its effects require cooperation with NFATc1. Taken together with the information provided by the genetic studies, these data are thus consistent with the notion that IRF-4 represents one of the major lymphoid-restricted regulators of T cell cytokine synthesis.We have shown that stable expression of IRF-4 in human T cells can activate the expression of TH2-type cytokines (IL-4, IL-10, and IL-13). This is in agreement with two recent reports, which found that IRF-4-deficient T cells are impaired in their ability to differentiatein vitro toward a TH2 phenotype (45Rengarajan J. Mowen K.A. Mcbride K.D. Smith E.D. Singh H. Glimcher L.H. J. Exp. Med. 2002; 195: 1003-1012Crossref PubMed Scopus (261) Google Scholar, 46Lohoff M. Mittrucker H.-W. Prechtl S. Bischof S. Sommer F. Kock S. Ferrick D.A. Duncan G.S. Gessner A. Mak T.W. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 11808-11812Crossref PubMed Scopus (198) Google Scholar). This finding is furthermore supported by the fact that similarly to B cells (23Gupta S. Jiang M. Anthony A. Pernis A. J. Exp. Med. 1999; 190: 1837-1848Crossref PubMed Scopus (106) Google Scholar), expression of IRF-4 in T cells can be up-regulated upon exposure to IL-4, the most potent TH2 differentiating stimulus. 3S. Jang, unpublished observations., 4A. Dent, personal communication.Interestingly, no induction of IL-5 gene expression was noted in our system suggesting that additional factors may modulate the ability of IRF-4 to target different TH2-types cytokines.Our observations, however, indicate that IRF-4 does not simply function as a TH2-specific factor but it may also participate in the control of TH1-type cytokines because presence of IRF-4 markedly enhanced the induction of IL-2, a cytokine normally associated with the TH1 phenotype. The effect of IRF-4 on human IL-2 production is consistent with the phenotype of T cells from IRF-4 deficient mice, which display a marked impairment in the synthesis of IL-2 (25Mittrucker H. Matsuyama T. Grossman A. Kundig T. Potter J. Shahinian A. Wakeham A. Patterson B. Ohashi P. Mak T. Science. 1997; 275: 540-543Crossref PubMed Scopus (4) Google Scholar). Interestingly, if supplied with exogenous IL-2, IRF-4-deficient T cells are able to produce moderate levels of IL-2 upon restimulation (45Rengarajan J. Mowen K.A. Mcbride K.D. Smith E.D. Singh H. Glimcher L.H. J. Exp. Med. 2002; 195: 1003-1012Crossref PubMed Scopus (261) Google Scholar, 46Lohoff M. Mittrucker H.-W. Prechtl S. Bischof S. Sommer F. Kock S. Ferrick D.A. Duncan G.S. Gessner A. Mak T.W. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 11808-11812Crossref PubMed Scopus (198) Google Scholar). One possible scenario reconciling these findings is that the requirements for IRF-4 in the production of individual cytokines may be dynamically regulated as a T cell proceeds along a specific differentiation pathway. For instance, naive T cells may rely more heavily on the presence of IRF-4 for their initial “burst” of IL-2 production whereas differentiated TH1 cells may have evolved additional redundant mechanisms that render the IRF-4 requirement for IL-2 production less stringent. A role for IRF-4 in the control of TH1 cytokine production is further supported by the fact that recent studies have revealed that IRF-4-deficient T cells differentiated in vitro under TH1 conditions display moderate to severe defects in the ability to synthesize IFN-γ, another TH1-type cytokine (45Rengarajan J. Mowen K.A. Mcbride K.D. Smith E.D. Singh H. Glimcher L.H. J. Exp. Med. 2002; 195: 1003-1012Crossref PubMed Scopus (261) Google Scholar, 46Lohoff M. Mittrucker H.-W. Prechtl S. Bischof S. Sommer F. Kock S. Ferrick D.A. Duncan G.S. Gessner A. Mak T.W. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 11808-11812Crossref PubMed Scopus (198) Google Scholar). Interestingly, preliminary results indicate that the up-regulation of IRF-4 is differentially controlled in the two TH subsets. Induction of IRF-4 expression in established TH1 cells can occur in response to TCR-mediated signals, but, consistent with the known extinction of IL-4 signaling in these cells (47Huang H. Paul W.E. J. Exp. Med. 1998; 187: 1305-1313Crossref PubMed Scopus (92) Google Scholar), the IL-4-mediated up-regulation of IRF-4 is no longer detectable. Thus, although IRF-4 can be expressed in both TH1 and TH2 cells, its induction occurs in very distinct molecular milieus, and this, in turn, is likely to profoundly affect its functional capabilities.Our studies indicate that IRF-4 can functionally interact with NFATc1, a member of a well known family of transcription factors known to play a key role in T cell cytokine production (3Rao A. Luo C. Hogan P.G. Annu. Rev. Immunol. 1997; 15: 707-747Crossref PubMed Scopus (2203) Google Scholar, 5Serfling E. Berberich-Siebelt F. Chuvpilo S. Jankevics E. Klein-Hessling S. Twardzik T. Avots A. Biochim. Biophys. Acta. 2000; 1498: 1-18Crossref PubMed Scopus (170) Google Scholar). Although NFATc1 was originally identified as a critical regulator of IL-2 gene expression in activated T cells (48Northrop J.P. Ho S.N. Chen L. Thomas D.J. Timmerman L.A. Nolan G.P. Admon A. Crabtree G.R. Nature. 1994; 369: 497-502Crossref PubMed Scopus (522) Google Scholar), subsequent studies have uncovered a much broader biological role for this protein as demonstrated by the fact that lack of NFATc1 results not only in impaired T cell function but also in profound defects in the development of cardiac valves (49de la Pompa J.L. Timmerman L.A. Takimoto H. Yoshida H. Elia A.J. Samper E. Potter J. Wakeham A. Marengere L. Langille B.L. Crabtree G.R. Mak T.W. Nature. 1998; 392: 182-186Crossref PubMed Scopus (542) Google Scholar, 50Ranger A.M. Grusby M.J. Hodge M.R. Gravallese E.M. de la Brousse F.C. Hoey T. Mickanin C. Baldwin H.S. Glimcher L.H. Nature. 1998; 392: 186-190Crossref PubMed Scopus (508) Google Scholar). Given that NFATc1 expression is not solely confined to lymphocytes, the pairing of a lymphoid-restricted factor like IRF-4 with NFATc1 may thus enable NFATc1 to acquire the ability to exert its actions in a T cell-specific manner. Interestingly, T cell cytokine production is controlled not simply by NFATc1 but by a complex interplay among the different NFAT family members. This is evidenced by in vivo studies showing that lack of different combinations of NFAT proteins can result in either profound deficiencies or marked hyperactivation of T cell effector functions (15Ranger A.M. Oukka M. Rengarajan J. Glimcher L.H. Immunity. 1998; 9: 627-635Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar, 16Peng S.L. Gerth A.J. Ranger A.M. Glimcher L.H. Immunity. 2001; 14: 13-20Abstract Full Text Full Text PDF PubMed Scopus (312) Google Scholar, 17Rengarajan J. Tang B. Glimcher L.H. Nature Immunol. 2002; 3: 48-54Crossref PubMed Scopus (129) Google Scholar). Interestingly, during the course of these studies another group reported that murine IRF-4 can interact with a different NFAT family member, NFATc2 (45Rengarajan J. Mowen K.A. Mcbride K.D. Smith E.D. Singh H. Glimcher L.H. J. Exp. Med. 2002; 195: 1003-1012Crossref PubMed Scopus (261) Google Scholar). It will thus be important to determine in in vivo settings whether distinct NFAT proteins can differentially modulate the ability of IRF-4 to drive cytokine production. An intricate association of IRF-4 with distinct members of the NFAT family may underlie the complex defects in TH differentiation observed in IRF-4-deficient mice (46Lohoff M. Mittrucker H.-W. Prechtl S. Bischof S. Sommer F. Kock S. Ferrick D.A. Duncan G.S. Gessner A. Mak T.W. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 11808-11812Crossref PubMed Scopus (198) Google Scholar).Cooperation of IRF-4 and NFATc1 in IL-4 production is linked to the ability of IRF-4 to target the promoter of this gene at a site adjacent to a well characterized NFAT binding site, P1 (5Serfling E. Berberich-Siebelt F. Chuvpilo S. Jankevics E. Klein-Hessling S. Twardzik T. Avots A. Biochim. Biophys. Acta. 2000; 1498: 1-18Crossref PubMed Scopus (170) Google Scholar, 7Szabo S.J. Glimcher L.H. Ho I.C. Curr. Opin. Immunol. 1997; 9: 776-781Crossref PubMed Scopus (70) Google Scholar). Competition experiments furthermore suggest that IRF-4 complexes can similarly target additional NFAT binding sites present in the IL-4 promoter like P4. Interestingly, both P1 and P4 have been shown to be critical regulatory elements for IL-4 gene expression in response to T cell stimulation and TH2 differentiation (33Li-Weber M. Salgame P. Hu C. Davydov I.V. Laur O. Klevenz S. Krammer P.H. J. Immunol. 1998; 161: 1380-1389PubMed Google Scholar, 51Wenner C.A. Szabo S.J. Murphy K.M. J. Immunol. 1997; 158: 765-773PubMed Google Scholar, 52Li-Weber M. Salgame P. Hu C. Davydov I.V. Krammer P.H. J. Immunol. 1997; 158: 1194-1200PubMed Google Scholar), further supporting a physiologic role for IRF-4 in the control of this cytokine. Given that both IRF-4 and NFATc1 have been reported to possess only weak DNA binding activity (3Rao A. Luo C. Hogan P.G. Annu. Rev. Immunol. 1997; 15: 707-747Crossref PubMed Scopus (2203) Google Scholar, 28Brass A. Kehrli E. Eisenbeis C. Storb U. Singh H. Genes Dev. 1996; 10: 2335-2347Crossref PubMed Scopus (209) Google Scholar), a likely scenario for their cooperation is that the interaction of NFAT with IRF-4 may facilitate IRF-4 binding to its DNA element and vice versa. This is indeed supported by our EMSA experiments, which demonstrate that addition of the anti-IRF-4 antibody can also affect DNA binding by NFAT (Fig. 5 B) and that lack of IRF-4 blocks the appearance of all P1-IRF inducible complexes (Fig. 5 D). We have furthermore found by glutathione S-transferase pull-down experiments that IRF-4 and NFATc1 can physically interact. 5C. Hu, unpublished observations. However, in contrast to what has been reported for the association between murine IRF-4 and NFATc2 (45Rengarajan J. Mowen K.A. Mcbride K.D. Smith E.D. Singh H. Glimcher L.H. J. Exp. Med. 2002; 195: 1003-1012Crossref PubMed Scopus (261) Google Scholar), we have been unable to coimmunoprecipitate the endogenous proteins suggesting that ternary complex formation with DNA may be necessary to stabilize the IRF-4/NFATc1 interaction. Interestingly, the regions encompassing the P1 and P4 regulatory elements can be targeted by additional transcription factors like AP-1 and NF-κB/Rel proteins (40Szabo S.J. Gold J.S. Murphy T.L. Murphy K.M. Mol. Cell. Biol. 1993; 13: 4793-4805Crossref PubMed Scopus (234) Google Scholar, 41Rooney J.W. Hoey T. Glimcher L.H. Immunity. 1995; 2: 473-483Abstract Full Text PDF PubMed Scopus (237) Google Scholar, 42Li-Weber M. Giasi M. Krammer P.H. J. Biol. Chem. 1998; 273: 32460-32466Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar). It will thus be important to determine whether IRF-4 may interact with these additional factors as well. We furthermore suspect that, like the case of NFAT proteins (53Agarwal S. Avni O. Rao A. Immunity. 2000; 12: 643-652Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar,54Solymar D.C. Agarwal S. Bassing C.H. Alt F.W. Rao A. Immunity. 2002; 17: 41-50Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar), IRF-4 may not simply target cytokine promoters but also additional enhancer elements that are critical for optimal and cell type-specific cytokine expression. The fact that deficiency of IRF-4 was also recently reported to be associated with defects in the up-regulation of GATA3 in TH2 cells (46Lohoff M. Mittrucker H.-W. Prechtl S. Bischof S. Sommer F. Kock S. Ferrick D.A. Duncan G.S. Gessner A. Mak T.W. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 11808-11812Crossref PubMed Scopus (198) Google Scholar) suggests that the mechanism employed by IRF-4 to modulate T cell cytokine production is likely to be multifaceted.The ability of IRF-4 to cooperate with NFAT proteins may have important clinical implications. Indeed, addition of cyclosporin A and FK506, two well known NFAT inhibitors (6Kiani A. Rao A. Aramburu J. Immunity. 2000; 12: 359-372Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar), completely blocked the ability of IRF-4 to drive cytokine synthesis. These findings suggest that in addition to exerting a direct inhibitory effect on NFAT proteins, these immunosuppressive drugs can also profoundly interfere with the function of tissue-restricted NFAT partners like IRF-4. Given that many of the side effects of cyclosporin A and FK506 have been attributed to inhibition of NFAT proteins in nonlymphoid tissues (6Kiani A. Rao A. Aramburu J. Immunity. 2000; 12: 359-372Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar), targeting of the IRF-4/NFAT interaction may thus allow for the development of more selective immunosuppressants and minimize potentially deleterious side effects. The NFAT/IRF-4 interaction might also be a target for HTLVI, an oncogenic retrovirus known to usurp the activation program of T cells (55Copeland K.F. Heeney J.L. Microbiol. Rev. 1996; 60: 722-742Crossref PubMed Google Scholar). The hallmark of HTLVI-mediated T cell transformation is the up-regulation of T cell cytokine production, and most notably of IL-2. Tax, the major HTLVI gene product involved in this effect has been shown to up-regulate the expression of IRF-4 in T cells via a pathway involving NF-κB and NFAT (56Mamane Y. Sharma S. Graandvaux N. Hernandez E. Hiscott J. J. Interferon Cytokine Res. 2002; 22: 135-143Crossref PubMed Scopus (26) Google Scholar) as well as to induce the binding of NFAT-containing complexes to cytokine promoters (57Good L. Maggirwar S.B. Sun S.-C" @default.
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