Th17 Cells
2012; Elsevier BV; Volume: 181; Issue: 1 Linguagem: Inglês
10.1016/j.ajpath.2012.03.044
ISSN1525-2191
AutoresMohan S. Maddur, Pierre Miossec, Srini V. Kaveri, Jagadeesh Bayry,
Tópico(s)Whipple's Disease and Interleukins
ResumoTh17 cells that secrete the cytokines IL-17A and IL-17F and express lineage-specific transcription factor RORC (RORγt in mice) represent a distinct lineage of CD4+ T cells. Transforming growth factor-β and inflammatory cytokines, such as IL-6, IL-21, IL-1β, and IL-23, play central roles in the generation of Th17 cells. Th17 cells are critical for the clearance of extracellular pathogens, including Candida and Klebsiella. However, under certain conditions, these cells and their effector molecules, such as IL-17, IL-21, IL-22, GM-CSF, and CCL20, are associated with the pathogenesis of several autoimmune and inflammatory diseases, such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis, inflammatory bowel disease, and allergy and asthma. This review discusses these disease states and the various therapeutic strategies under investigation to target Th17 cells, which include blocking the differentiation and amplification of Th17 cells, inhibiting or neutralizing the cytokines of Th17 cells, and suppressing the transcription factors specific for Th17 cells. Th17 cells that secrete the cytokines IL-17A and IL-17F and express lineage-specific transcription factor RORC (RORγt in mice) represent a distinct lineage of CD4+ T cells. Transforming growth factor-β and inflammatory cytokines, such as IL-6, IL-21, IL-1β, and IL-23, play central roles in the generation of Th17 cells. Th17 cells are critical for the clearance of extracellular pathogens, including Candida and Klebsiella. However, under certain conditions, these cells and their effector molecules, such as IL-17, IL-21, IL-22, GM-CSF, and CCL20, are associated with the pathogenesis of several autoimmune and inflammatory diseases, such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis, inflammatory bowel disease, and allergy and asthma. This review discusses these disease states and the various therapeutic strategies under investigation to target Th17 cells, which include blocking the differentiation and amplification of Th17 cells, inhibiting or neutralizing the cytokines of Th17 cells, and suppressing the transcription factors specific for Th17 cells. CD4+ T cells are central in the process of immune response generation by coordinating with different immune cells. As effector cells, they are critical for the generation, sustenance, and regulation of immune responses against pathogens and self-antigens. CD4+ T cells are heterogeneous, and several subsets have been identified based on their distinct cytokine and transcription factor profiles. These subsets include Th1, Th2, and CD4+CD25+ regulatory T cells (Tregs). Although other T-cell subsets, such as transforming growth factor (TGF)-β-producing Th3 cells, IL-10-secreting T-regulatory type 1, IL-9-producing Th9 cells, and IL-22-producing Th22 cells, have been described, their lineage-specific transcription factors have not been identified. More recently, Th17 cells that secrete cytokines IL-17A and IL-17F and express surface IL-23 receptor (IL-23R) and lineage-specific transcription factor RORC (RORγt in mice) have been identified as a distinct lineage of CD4+ T cells.1Park H. Li Z. Yang X.O. Chang S.H. Nurieva R. Wang Y.H. Wang Y. Hood L. Zhu Z. Tian Q. Dong C. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17.Nat Immunol. 2005; 6: 1133-1141Crossref PubMed Google Scholar, 2Veldhoen M. Hocking R.J. Atkins C.J. Locksley R.M. Stockinger B. TGF-β in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells.Immunity. 2006; 24: 179-189Abstract Full Text Full Text PDF PubMed Google Scholar, 3Bettelli E. Carrier Y. Gao W. Korn T. Strom T.B. Oukka M. Weiner H.L. Kuchroo V.K. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells.Nature. 2006; 441: 235-238Crossref PubMed Google Scholar, 4Mangan P.R. Harrington L.E. O'Quinn D.B. Helms W.S. Bullard D.C. Elson C.O. Hatton R.D. Wahl S.M. Schoeb T.R. Weaver C.T. Transforming growth factor-beta induces development of the T(H)17 lineage.Nature. 2006; 441: 231-234Crossref PubMed Google Scholar Although Th17 cells share several surface markers with other CD4+ T cell subsets, recent results demonstrate that CCR6+CCR4+ or CCR2+CCR5− memory CD4+ T cells are bona fide Th17 cells, indicating that the Th17 population in the periphery is not homogeneous.5Acosta-Rodriguez E.V. Rivino L. Geginat J. Jarrossay D. Gattorno M. Lanzavecchia A. Sallusto F. Napolitani G. Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells.Nat Immunol. 2007; 8: 639-646Crossref PubMed Google Scholar, 6Annunziato F. Cosmi L. Santarlasci V. Maggi L. Liotta F. Mazzinghi B. Parente E. Fili L. Ferri S. Frosali F. Giudici F. Romagnani P. Parronchi P. Tonelli F. Maggi E. Romagnani S. Phenotypic and functional features of human Th17 cells.J Exp Med. 2007; 204: 1849-1861Crossref PubMed Google Scholar, 7Sato W. Aranami T. Yamamura T. Cutting edge: human Th17 cells are identified as bearing CCR2+CCR5- phenotype.J Immunol. 2007; 178: 7525-7529PubMed Google Scholar In addition, human Th17 cells specifically express lectin receptor CD161.6Annunziato F. Cosmi L. Santarlasci V. Maggi L. Liotta F. Mazzinghi B. Parente E. Fili L. Ferri S. Frosali F. Giudici F. Romagnani P. Parronchi P. Tonelli F. Maggi E. Romagnani S. Phenotypic and functional features of human Th17 cells.J Exp Med. 2007; 204: 1849-1861Crossref PubMed Google Scholar, 8Maggi L. Santarlasci V. Capone M. Peired A. Frosali F. Crome S.Q. Querci V. Fambrini M. Liotta F. Levings M.K. Maggi E. Cosmi L. Romagnani S. Annunziato F. CD161 is a marker of all human IL-17-producing T-cell subsets and is induced by RORC.Eur J Immunol. 2010; 40: 2174-2181Crossref PubMed Scopus (0) Google Scholar Th17 cells play critical roles in the clearance of extracellular pathogens, including Candida and Klebsiella. However, under certain conditions, these cells can also be associated with the pathogenesis of various autoimmune and inflammatory diseases. In the periphery, naïve CD4+ T cells on interaction with antigen-presenting cells can undergo differentiation into distinct lineages under the influence of specific cytokines. Extensive studies in recent years have contributed to an in-depth understanding of the generation and function of Th17 cells. Several groups convincingly showed that TGF-β and IL-6, two cytokines with opposing effects, synergize to induce orphan nuclear receptor RORγt, which orchestrates the expression of IL-17A and IL-17F in naïve T cells (Figure 1).2Veldhoen M. Hocking R.J. Atkins C.J. Locksley R.M. Stockinger B. TGF-β in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells.Immunity. 2006; 24: 179-189Abstract Full Text Full Text PDF PubMed Google Scholar, 3Bettelli E. Carrier Y. Gao W. Korn T. Strom T.B. Oukka M. Weiner H.L. Kuchroo V.K. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells.Nature. 2006; 441: 235-238Crossref PubMed Google Scholar, 4Mangan P.R. Harrington L.E. O'Quinn D.B. Helms W.S. Bullard D.C. Elson C.O. Hatton R.D. Wahl S.M. Schoeb T.R. Weaver C.T. Transforming growth factor-beta induces development of the T(H)17 lineage.Nature. 2006; 441: 231-234Crossref PubMed Google Scholar IL-6 is a proinflammatory and pleiotropic cytokine secreted in high amounts by the innate cells, B cells and subsets of activated T cells. In addition, tumor cells, fibroblasts, endothelial cells, and keratinocytes can contribute to IL-6. Although TGF-β is produced by multiple lineages of leukocytes and stromal cells, an autocrine or paracrine source of TGF-β is found to be important for Th17 differentiation in vivo.3Bettelli E. Carrier Y. Gao W. Korn T. Strom T.B. Oukka M. Weiner H.L. Kuchroo V.K. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells.Nature. 2006; 441: 235-238Crossref PubMed Google Scholar, 9Veldhoen M. Hocking R.J. Flavell R.A. Stockinger B. Signals mediated by transforming growth factor-beta initiate autoimmune encephalomyelitis, but chronic inflammation is needed to sustain disease.Nat Immunol. 2006; 7: 1151-1156Crossref PubMed Google Scholar, 10Gutcher I. Donkor M.K. Ma Q. Rudensky A.Y. Flavell R.A. Li M.O. Autocrine transforming growth factor-beta1 promotes in vivo Th17 cell differentiation.Immunity. 2011; 34: 396-408Abstract Full Text Full Text PDF PubMed Google Scholar Thus, Treg-derived TGF-β enables differentiation of Th17 cells when naïve T cells are co-cultured with activated dendritic cells (DCs). Th17 cells can also express high amounts of TGF-β, and this cytokine can act in an autocrine manner to maintain Th17 cells in vivo.10Gutcher I. Donkor M.K. Ma Q. Rudensky A.Y. Flavell R.A. Li M.O. Autocrine transforming growth factor-beta1 promotes in vivo Th17 cell differentiation.Immunity. 2011; 34: 396-408Abstract Full Text Full Text PDF PubMed Google Scholar Further, tumor necrosis factor (TNF)-α and IL-1β are found to enhance TGF-β-mediated and IL-6-mediated differentiation of Th17 cells.2Veldhoen M. Hocking R.J. Atkins C.J. Locksley R.M. Stockinger B. TGF-β in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells.Immunity. 2006; 24: 179-189Abstract Full Text Full Text PDF PubMed Google Scholar Because IL-6 knockout mice are found to be susceptible to experimental autoimmune encephalomyelitis (EAE) on depletion of Tregs, factors other than IL-6 are proposed to play roles in the induction of Th17 cells. TGF-β is found to synergize with IL-21 to induce RORγt and IL-17 in naïve T cells.11Korn T. Bettelli E. Gao W. Awasthi A. Jager A. Strom T.B. Oukka M. Kuchroo V.K. IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells.Nature. 2007; 448: 484-487Crossref PubMed Google Scholar, 12Nurieva R. Yang X.O. Martinez G. Zhang Y. Panopoulos A.D. Ma L. Schluns K. Tian Q. Watowich S.S. Jetten A.M. Dong C. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells.Nature. 2007; 448: 480-483Crossref PubMed Google Scholar Because Th17 cells are the major producers of IL-21, an autocrine amplification loop is established by IL-21 to enhance their differentiation.11Korn T. Bettelli E. Gao W. Awasthi A. Jager A. Strom T.B. Oukka M. Kuchroo V.K. IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells.Nature. 2007; 448: 484-487Crossref PubMed Google Scholar, 12Nurieva R. Yang X.O. Martinez G. Zhang Y. Panopoulos A.D. Ma L. Schluns K. Tian Q. Watowich S.S. Jetten A.M. Dong C. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells.Nature. 2007; 448: 480-483Crossref PubMed Google Scholar, 13Zhou L. Ivanov I.I. Spolski R. Min R. Shenderov K. Egawa T. Levy D.E. Leonard W.J. Littman D.R. IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways.Nat Immunol. 2007; 8: 967-974Crossref PubMed Google Scholar It is also believed that in the absence of inflammation, when IL-6 levels are low, IL-21 produced by Th17, NK, and NKT cells is important both to maintain and to amplify the pool of Th17 precursors.11Korn T. Bettelli E. Gao W. Awasthi A. Jager A. Strom T.B. Oukka M. Kuchroo V.K. IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells.Nature. 2007; 448: 484-487Crossref PubMed Google Scholar, 14Korn T. Bettelli E. Oukka M. Kuchroo V.K. IL-17 and Th17 cells.Annu Rev Immunol. 2009; 27: 485-517Crossref PubMed Google Scholar Thus, IL-21 has a major role in supporting Th17 cell differentiation and tissue inflammation. IL-23 is another inflammatory cytokine that contributes to Th17 generation. The combination of TGF-β and IL-6/IL-21 induces surface IL-23R on differentiating Th17 cells. Differentiating Th17 cells become responsive to activated myeloid cell–produced IL-23.4Mangan P.R. Harrington L.E. O'Quinn D.B. Helms W.S. Bullard D.C. Elson C.O. Hatton R.D. Wahl S.M. Schoeb T.R. Weaver C.T. Transforming growth factor-beta induces development of the T(H)17 lineage.Nature. 2006; 441: 231-234Crossref PubMed Google Scholar, 12Nurieva R. Yang X.O. Martinez G. Zhang Y. Panopoulos A.D. Ma L. Schluns K. Tian Q. Watowich S.S. Jetten A.M. Dong C. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells.Nature. 2007; 448: 480-483Crossref PubMed Google Scholar, 13Zhou L. Ivanov I.I. Spolski R. Min R. Shenderov K. Egawa T. Levy D.E. Leonard W.J. Littman D.R. IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways.Nat Immunol. 2007; 8: 967-974Crossref PubMed Google Scholar IL-23 (p19) deficiency is associated with a reduced number of Th17 cells in vivo. IL-23 is also required for the maintenance of Th17 cells in vitro, for the induction of tissue inflammation by in vitro–generated Th17 cells, and for Th17-mediated chronic inflammation in vivo.9Veldhoen M. Hocking R.J. Flavell R.A. Stockinger B. Signals mediated by transforming growth factor-beta initiate autoimmune encephalomyelitis, but chronic inflammation is needed to sustain disease.Nat Immunol. 2006; 7: 1151-1156Crossref PubMed Google Scholar, 15McGeachy M.J. Chen Y. Tato C.M. Laurence A. Joyce-Shaikh B. Blumenschein W.M. McClanahan T.K. O'Shea J.J. Cua D.J. The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo.Nat Immunol. 2009; 10: 314-324Crossref PubMed Google Scholar IL-23 synergizes with IL-6 to enhance differentiation, survival, and stabilization of Th17 cells.13Zhou L. Ivanov I.I. Spolski R. Min R. Shenderov K. Egawa T. Levy D.E. Leonard W.J. Littman D.R. IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways.Nat Immunol. 2007; 8: 967-974Crossref PubMed Google Scholar, 15McGeachy M.J. Chen Y. Tato C.M. Laurence A. Joyce-Shaikh B. Blumenschein W.M. McClanahan T.K. O'Shea J.J. Cua D.J. The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo.Nat Immunol. 2009; 10: 314-324Crossref PubMed Google Scholar IL-23 can amplify Th17 cells by inducing proinflammatory cytokines, such as IL-1β, TNF-α, and IL-6, in innate immune cells.14Korn T. Bettelli E. Oukka M. Kuchroo V.K. IL-17 and Th17 cells.Annu Rev Immunol. 2009; 27: 485-517Crossref PubMed Google Scholar Thus, complete Th17 cell differentiation was proposed to comprise three different stages. The first stage is differentiation of Th17 cells triggered by the combined effect of TGF-β and IL-6/IL-21. The second stage is amplification of Th17 cells driven by IL-21 produced by Th17 cell themselves, probably with TGF-β. The third stage is stabilization of Th17 cells by IL-23.14Korn T. Bettelli E. Oukka M. Kuchroo V.K. IL-17 and Th17 cells.Annu Rev Immunol. 2009; 27: 485-517Crossref PubMed Google Scholar Despite these convincing findings regarding the requirement of cytokines (TGF-β, IL-6, IL-21, IL-23) for Th17 differentiation in mice, the absolute requirement of TGF-β has been questioned more recently. Th17 cells are present in the gut of TGF-β signaling–deficient mice.16Qin H. Wang L. Feng T. Elson C.O. Niyongere S.A. Lee S.J. Reynolds S.L. Weaver C.T. Roarty K. Serra R. Benveniste E.N. Cong Y. TGF-β promotes Th17 cell development through inhibition of SOCS3.J Immunol. 2009; 183: 97-105Crossref PubMed Scopus (0) Google Scholar, 17Ghoreschi K. Laurence A. Yang X.P. Tato C.M. McGeachy M.J. Konkel J.E. Ramos H.L. Wei L. Davidson T.S. Bouladoux N. Grainger J.R. Chen Q. Kanno Y. Watford W.T. Sun H.W. Eberl G. Shevach E.M. Belkaid Y. Cua D.J. Chen W. O'Shea J.J. Generation of pathogenic T(H)17 cells in the absence of TGF-β signalling.Nature. 2010; 467: 967-971Crossref PubMed Google Scholar In T-bet-deficient and STAT6-deficient murine T cells, production of IL-17 could be induced by IL-6 alone in the absence of TGF-β.18Das J. Ren G. Zhang L. Roberts A.I. Zhao X. Bothwell A.L. Van Kaer L. Shi Y. Das G. Transforming growth factor β is dispensable for the molecular orchestration of Th17 cell differentiation.J Exp Med. 2009; 206: 2407-2416Crossref PubMed Scopus (0) Google Scholar IL-6 and IL-23 in combination with IL-1β were able to induce IL-17 production in the absence of TGF-β signaling,17Ghoreschi K. Laurence A. Yang X.P. Tato C.M. McGeachy M.J. Konkel J.E. Ramos H.L. Wei L. Davidson T.S. Bouladoux N. Grainger J.R. Chen Q. Kanno Y. Watford W.T. Sun H.W. Eberl G. Shevach E.M. Belkaid Y. Cua D.J. Chen W. O'Shea J.J. Generation of pathogenic T(H)17 cells in the absence of TGF-β signalling.Nature. 2010; 467: 967-971Crossref PubMed Google Scholar suggesting an alternative mode of Th17 cell differentiation. Th17 cells generated in the absence of TGF-β exhibit a phenotype of T-bet+RORγt+ and are pathogenic in vivo. However, this phenotype requires further validation because Th17 cells display profound instability as discussed later. Once the factors driving the differentiation of Th17 cells in mice were revealed convincingly, different cytokine combinations were examined to generate RORC-expressing human Th17 cells. Initially, it was argued that human Th17 differentiation is not dependent on TGF-β signaling, which is in contrast to murine Th17 cells. It was proposed that the combination of IL-1β and IL-6/IL-23 or IL-23 alone could differentiate human Th17 cells from naïve T cells.19Acosta-Rodriguez E.V. Napolitani G. Lanzavecchia A. Sallusto F. Interleukins 1β and 6 but not transforming growth factor-β are essential for the differentiation of interleukin 17-producing human T helper cells.Nat Immunol. 2007; 8: 942-949Crossref PubMed Google Scholar, 20Wilson N.J. Boniface K. Chan J.R. McKenzie B.S. Blumenschein W.M. Mattson J.D. Basham B. Smith K. Chen T. Morel F. Lecron J.C. Kastelein R.A. Cua D.J. McClanahan T.K. Bowman E.P. de Waal Malefyt R. Development, cytokine profile and function of human interleukin 17-producing helper T cells.Nat Immunol. 2007; 8: 950-957Crossref PubMed Google Scholar These results are biased because the differentiation of Th17 cells in these reports was performed using CD45RA+ Th cells purified from peripheral blood. Additionally, the endogenous source of TGF-β (eg, serum and platelets) was not carefully controlled in those reports. Subsequent studies done with serum-free medium and rigorously sorted naïve T cells resolved these issues, establishing that, similar to murine Th17 cells, TGF-β is indispensable for the differentiation of human Th17 cells from naïve T cells.21Yang L. Anderson D.E. Baecher-Allan C. Hastings W.D. Bettelli E. Oukka M. Kuchroo V.K. Hafler D.A. IL-21 and TGF-β are required for differentiation of human T(H)17 cells.Nature. 2008; 454: 350-352Crossref PubMed Google Scholar, 22Manel N. Unutmaz D. Littman D.R. The differentiation of human T(H)-17 cells requires transforming growth factor-β and induction of the nuclear receptor RORγt.Nat Immunol. 2008; 9: 641-649Crossref PubMed Google Scholar, 23Volpe E. Servant N. Zollinger R. Bogiatzi S.I. Hupe P. Barillot E. Soumelis V. A critical function for transforming growth factor-β, interleukin 23 and proinflammatory cytokines in driving and modulating human T(H)-17 responses.Nat Immunol. 2008; 9: 650-657Crossref PubMed Scopus (0) Google Scholar It is also believed that human Th17 cells can originate from a small subset of CD161+RORC+ precursors present in umbilical cord blood and thymus in response to a combination of IL-23 and IL-1β, even in the complete absence of TGF-β.24Cosmi L. De Palma R. Santarlasci V. Maggi L. Capone M. Frosali F. Rodolico G. Querci V. Abbate G. Angeli R. Berrino L. Fambrini M. Caproni M. Tonelli F. Lazzeri E. Parronchi P. Liotta F. Maggi E. Romagnani S. Annunziato F. Human interleukin 17-producing cells originate from a CD161+CD4+ T cell precursor.J Exp Med. 2008; 205: 1903-1916Crossref PubMed Google Scholar In our opinion as discussed subsequently, this setting mimics an expansion of a pre-existing Th17 population rather than the differentiation of de novo Th17 cells. TGF-β is essential for the induction of RORC in naïve T cells, although the expression and functions of RORC are inhibited at high concentrations of TGF-β.22Manel N. Unutmaz D. Littman D.R. The differentiation of human T(H)-17 cells requires transforming growth factor-β and induction of the nuclear receptor RORγt.Nat Immunol. 2008; 9: 641-649Crossref PubMed Google Scholar However, inflammatory cytokines, such as IL-21, IL-1β, IL-6, and IL-23, relieve the inhibition of RORC in CD4+ T cells and trigger the expression of IL-17 (Figure 1).21Yang L. Anderson D.E. Baecher-Allan C. Hastings W.D. Bettelli E. Oukka M. Kuchroo V.K. Hafler D.A. IL-21 and TGF-β are required for differentiation of human T(H)17 cells.Nature. 2008; 454: 350-352Crossref PubMed Google Scholar, 22Manel N. Unutmaz D. Littman D.R. The differentiation of human T(H)-17 cells requires transforming growth factor-β and induction of the nuclear receptor RORγt.Nat Immunol. 2008; 9: 641-649Crossref PubMed Google Scholar, 23Volpe E. Servant N. Zollinger R. Bogiatzi S.I. Hupe P. Barillot E. Soumelis V. A critical function for transforming growth factor-β, interleukin 23 and proinflammatory cytokines in driving and modulating human T(H)-17 responses.Nat Immunol. 2008; 9: 650-657Crossref PubMed Scopus (0) Google Scholar Essentially, naïve T cells do not express IL-1R and IL-23R. However, these receptors are induced after exposure to TGF-β and IL-6/IL-21, making the cells receptive to IL-1β and IL-23.21Yang L. Anderson D.E. Baecher-Allan C. Hastings W.D. Bettelli E. Oukka M. Kuchroo V.K. Hafler D.A. IL-21 and TGF-β are required for differentiation of human T(H)17 cells.Nature. 2008; 454: 350-352Crossref PubMed Google Scholar, 25Lee W.W. Kang S.W. Choi J. Lee S.H. Shah K. Eynon E.E. Flavell R.A. Kang I. Regulating human Th17 cells via differential expression of IL-1 receptor.Blood. 2010; 115: 530-540Crossref PubMed Scopus (0) Google Scholar It has been shown that the combination of TGF-β and IL-21 is sufficient to induce the differentiation of human Th17 cells from naïve T cells, and IL-1β and IL-6 are important for enhancing the expansion of differentiated and memory Th17 cells.21Yang L. Anderson D.E. Baecher-Allan C. Hastings W.D. Bettelli E. Oukka M. Kuchroo V.K. Hafler D.A. IL-21 and TGF-β are required for differentiation of human T(H)17 cells.Nature. 2008; 454: 350-352Crossref PubMed Google Scholar TGF-β also favors human Th17 differentiation indirectly because of its suppressive activity on T-bet expression and the generation of Th1 cells.26Santarlasci V. Maggi L. Capone M. Frosali F. Querci V. De Palma R. Liotta F. Cosmi L. Maggi E. Romagnani S. Annunziato F. TGF-β indirectly favors the development of human Th17 cells by inhibiting Th1 cells.Eur J Immunol. 2009; 39: 207-215Crossref PubMed Google Scholar Thus, cytokine requirements for driving the differentiation of Th17 cells are similar in both humans and mice. Differentiation of Th17 cells requires the cooperative interaction of downstream molecules of TGF-β and IL-6 receptor–mediated signaling pathways (Figure 1). Basically, naïve T cells are receptive to IL-6 because these cells express functional IL-6 receptor. IL-6 receptor consists of the inducible subunit IL-6Rα and the constitutively expressed signaling subunit gp130. Although T-cell receptor stimulation and IL-6 signaling down-regulate IL-6Rα expression on naïve T cells, TGF-β can maintain the receptiveness of T cells to IL-6 by inducing the expression of IL-6α. Binding of IL-6 to its receptor activates STAT3 but is transient owing to the induction of suppressor of cytokine signaling 3 (SOCS3). STAT3 activation is necessary but not sufficient for RORγt expression. TGF-β signaling through its receptor (ie, the TGFβRI-TGFβRII complex) activates the Smad2 pathway, leading to the expression of both Foxp3 and RORγt.27Martinez G.J. Zhang Z. Reynolds J.M. Tanaka S. Chung Y. Liu T. Robertson E. Lin X. Feng X.H. Dong C. Smad2 positively regulates the generation of Th17 cells.J Biol Chem. 2010; 285: 29039-29043Crossref PubMed Scopus (0) Google Scholar TGF-β signaling through Smad2/3 inhibits IL-6-induced and IL-21-induced SOCS3 expression, enhancing and prolonging STAT3 activation in naïve T cells.16Qin H. Wang L. Feng T. Elson C.O. Niyongere S.A. Lee S.J. Reynolds S.L. Weaver C.T. Roarty K. Serra R. Benveniste E.N. Cong Y. TGF-β promotes Th17 cell development through inhibition of SOCS3.J Immunol. 2009; 183: 97-105Crossref PubMed Scopus (0) Google Scholar, 27Martinez G.J. Zhang Z. Reynolds J.M. Tanaka S. Chung Y. Liu T. Robertson E. Lin X. Feng X.H. Dong C. Smad2 positively regulates the generation of Th17 cells.J Biol Chem. 2010; 285: 29039-29043Crossref PubMed Scopus (0) Google Scholar Sustained activation of STAT3 in the presence of IL-6 and TGF-β relieves Foxp3-mediated suppression of RORγt, enhances RORγt expression, and facilitates the Th17 transcriptional program. Smad-independent induction of Th17 cells by TGF-β has also been described. TGF-β can induce RORγt expression and Th17 cell differentiation by signaling through the JNK-c-Jun pathway and by suppressing Eomesodermin, a negative regulator of Th17 cells.28Ichiyama K. Sekiya T. Inoue N. Tamiya T. Kashiwagi I. Kimura A. Morita R. Muto G. Shichita T. Takahashi R. Yoshimura A. Transcription factor Smad-independent T helper 17 cell induction by transforming-growth factor-β is mediated by suppression of eomesodermin.Immunity. 2011; 34: 741-754Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar TGF-β-induced and IL-6-induced STAT3 activation also induces the expression of another related nuclear receptor, RORα, which synergizes with RORγt in Th17 cell differentiation. In cooperation with STAT3, both RORγt and RORα bind to the IL-17 promoter region, leading to competent induction of IL-17A, IL-17F, and IL-21.29Wei L. Laurence A. Elias K.M. O'Shea J.J. IL-21 is produced by Th17 cells and drives IL-17 production in a STAT3-dependent manner.J Biol Chem. 2007; 282: 34605-34610Crossref PubMed Google Scholar, 30Chen Z. Laurence A. Kanno Y. Pacher-Zavisin M. Zhu B.M. Tato C. Yoshimura A. Hennighausen L. O'Shea J.J. Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells.Proc Natl Acad Sci U S A. 2006; 103: 8137-8142Crossref PubMed Scopus (0) Google Scholar In view of the similar and redundant role to that of RORγt, RORα is believed to be a minor player in Th17 cell differentiation. IL-23 signaling through IL-23R (induced by TGF-β and IL-6/IL-21) further enhances the activation of STAT3, which is coordinated with RORγt to stabilize Th17 cells and their function.30Chen Z. Laurence A. Kanno Y. Pacher-Zavisin M. Zhu B.M. Tato C. Yoshimura A. Hennighausen L. O'Shea J.J. Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells.Proc Natl Acad Sci U S A. 2006; 103: 8137-8142Crossref PubMed Scopus (0) Google Scholar IL-6 signaling enhances the expression of IL-1R on differentiating Th17 cells. IL-1β acts in synergy with IL-6 and IL-23 for the polarization of Th17 cells by regulating the expression of interferon regulatory factor 4 (IRF4), which favors the functional expression of RORγt.31Chung Y. Chang S.H. Martinez G.J. Yang X.O. Nurieva R. Kang H.S. Ma L. Watowich S.S. Jetten A.M. Tian Q. Dong C. Critical regulation of early Th17 cell differentiation by interleukin-1 signaling.Immunity. 2009; 30: 576-587Abstract Full Text Full Text PDF PubMed Google Scholar, 32Brustle A. Heink S. Huber M. Rosenplanter C. Stadelmann C. Yu P. Arpaia E. Mak T.W. Kamradt T. Lohoff M. The development of inflammatory T(H)-17 cells requires interferon-regulatory factor 4.Nat Immunol. 2007; 8: 958-966Crossref PubMed Google Scholar Therefore, based on the activation state of T cells that are differentially receptive to various cytokine signals, the cytokines required for Th17 lineage commitment vary. 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