• 1
    Abbas, A. K., Murphy, K. M. and Sher, A., Functional diversity of helper T lymphocytes. Nature 1996. 383: 787793.
  • 2
    Glimcher, L. H. and Murphy, K. M., Lineage commitment in the immune system: the T helper lymphocyte grows up. Genes Dev. 2000. 14: 16931711.
  • 3
    Bettelli, E., Korn, T., Oukka, M. and Kuchroo, V. K., Induction and effector functions of T(H)17 cells. Nature 2008. 453: 10511057.
  • 4
    Dong, C., TH17 cells in development: an updated view of their molecular identity and genetic programming. Nat. Rev. Immunol. 2008. 8: 337348.
  • 5
    McGeachy, M. J. and Cua, D. J., Th17 cell differentiation: the long and winding road. Immunity 2008. 28: 445453.
  • 6
    Happel, K. I., Dubin, P. J., Zheng, M., Ghilardi, N., Lockhart, C., Quinton, L. J., Odden, A. R. et al., Divergent roles of IL-23 and IL-12 in host defense against Klebsiella pneumoniae. J. Exp. Med. 2005. 202: 761769.
  • 7
    Infante-Duarte, C., Horton, H. F., Byrne, M. C. and Kamradt, T., Microbial lipopeptides induce the production of IL-17 in Th cells. J. Immunol. 2000. 165: 61076115.
  • 8
    Weaver, C. T., Hatton, R. D., Mangan, P. R. and Harrington, L. E., IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu. Rev. Immunol. 2007. 25: 821852.
  • 9
    Fossiez, F., Djossou, O., Chomarat, P., Flores-Romo, L., Ait-Yahia, S., Maat, C., Pin, J. J. et al., T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines. J. Exp. Med. 1996. 183: 25932603.
  • 10
    Liang, S. C., Tan, X. Y., Luxenberg, D. P., Karim, R., Dunussi-Joannopoulos, K., Collins, M. and Fouser, L. A., Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J. Exp. Med. 2006. 203: 22712279.
  • 11
    Ouyang, W., Kolls, J. K. and Zheng, Y., The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity 2008. 28: 454467.
  • 12
    Chabaud, M., Durand, J. M., Buchs, N., Fossiez, F., Page, G., Frappart, L. and Miossec, P., Human interleukin-17: A T cell-derived proinflammatory cytokine produced by the rheumatoid synovium. Arthritis Rheum. 1999. 42: 963970.
  • 13
    Fujino, S., Andoh, A., Bamba, S., Ogawa, A., Hata, K., Araki, Y., Bamba, T. and Fujiyama, Y., Increased expression of interleukin 17 in inflammatory bowel disease. Gut 2003. 52: 6570.
  • 14
    Lock, C., Hermans, G., Pedotti, R., Brendolan, A., Schadt, E., Garren, H., Langer-Gould, A. et al., Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat. Med. 2002. 8: 500508.
  • 15
    Chung, Y., Yang, X., Chang, S. H., Ma, L., Tian, Q. and Dong, C., Expression and regulation of IL-22 in the IL-17-producing CD4+ T lymphocytes. Cell Res. 2006. 16: 902907.
  • 16
    Langrish, C. L., Chen, Y., Blumenschein, W. M., Mattson, J., Basham, B., Sedgwick, J. D., McClanahan, T. et al., IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 2005. 201: 233240.
  • 17
    Zheng, Y., Danilenko, D. M., Valdez, P., Kasman, I., Eastham-Anderson, J., Wu, J. and Ouyang, W., Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature 2007. 445: 648651.
  • 18
    Batten, M., Li, J., Yi, S., Kljavin, N. M., Danilenko, D. M., Lucas, S., Lee, J. et al., Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleukin 17-producing T cells. Nat. Immunol. 2006. 7: 929936.
  • 19
    Mangan, P. R., Harrington, L. E., O'Quinn, D. B., Helms, W. S., Bullard, D. C., Elson, C. O., Hatton, R. D. et al., Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 2006. 441: 231234.
  • 20
    Veldhoen, M., Hocking, R. J., Atkins, C. J., Locksley, R. M. and Stockinger, B., TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 2006. 24: 179189.
  • 21
    McGeachy, M. J., Bak-Jensen, K. S., Chen, Y., Tato, C. M., Blumenschein, W., McClanahan, T. and Cua, D. J., 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: 13901397.
  • 22
    Zhou, L., Ivanov, I. I., Spolski, R., Min, R., Shenderov, K., Egawa, T., Levy, D. E. 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: 967974.
  • 23
    Yang, X. O., Panopoulos, A. D., Nurieva, R., Chang, S. H., Wang, D., Watowich, S. S. and Dong, C., STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J. Biol. Chem. 2007. 282: 93589363.
  • 24
    Tangye, S. G., Cook, M. C. and Fulcher, D. A., Insights into the role of STAT3 in human lymphocyte differentiation as revealed by the hyper-IgE syndrome. J. Immunol. 2009. 182: 2128.
  • 25
    Ivanov, I. I., McKenzie, B. S., Zhou, L., Tadokoro, C. E., Lepelley, A., Lafaille, J. J., Cua, D. J. and Littman, D. R., The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 2006. 126: 11211133.
  • 26
    Manel, N., Unutmaz, D. and Littman, D. R., The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat. Nat. Immunol. 2008. 9: 641649.
  • 27
    Yang, X. O., Pappu, B. P., Nurieva, R., Akimzhanov, A., Kang, H. S., Chung, Y., Ma, L. et al., T Helper 17 Lineage Differentiation Is Programmed by Orphan Nuclear Receptors ROR[alpha] and ROR[gamma]. Immunity 2008. 28: 2939.
  • 28
    Zhang, F., Meng, G. and Strober, W., Interactions among the transcription factors Runx1, RORgammat and Foxp3 regulate the differentiation of interleukin 17-producing T cells. Nat. Immunol. 2008. 9: 12971306.
  • 29
    Brustle, A., Heink, S., Huber, M., Rosenplanter, C., Stadelmann, C., Yu, P., Arpaia, E. et al., The development of inflammatory T(H)-17 cells requires interferon-regulatory factor 4. Nat. Immunol. 2007. 8: 958966.
  • 30
    Acosta-Rodriguez, E. V., Rivino, L., Geginat, J., Jarrossay, D., Gattorno, M., Lanzavecchia, A., Sallusto, F. and Napolitani, G., Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nat. Immunol. 2007. 8: 639646.
  • 31
    Annunziato, F., Cosmi, L., Santarlasci, V., Maggi, L., Liotta, F., Mazzinghi, B., Parente, E. et al., Phenotypic and functional features of human Th17 cells. J. Exp. Med. 2007. 204: 18491861.
  • 32
    Wilson, N. J., Boniface, K., Chan, J. R., McKenzie, B. S., Blumenschein, W. M., Mattson, J. D., Basham, B. et al., Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nat. Immunol. 2007. 8: 950957.
  • 33
    Volpe, E., Servant, N., Zollinger, R., Bogiatzi, S. I., Hupe, P., Barillot, E. and Soumelis, V., 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: 650657.
  • 34
    Pene, J., Chevalier, S., Preisser, L., Venereau, E., Guilleux, M. H., Ghannam, S., Moles, J. P. et al., Chronically inflamed human tissues are infiltrated by highly differentiated th17 lymphocytes. J. Immunol. 2008. 180: 74237430.
  • 35
    Liu, H. and Rohowsky-Kochan, C., Regulation of IL-17 in human CCR6(+) effector memory T cells. J. Immunol. 2008. 180: 79487957.
  • 36
    Lim, H. W., Lee, J., Hillsamer, P. and Kim, C. H., Human Th17 cells share major trafficking receptors with both polarized effector T cells and FOXP3+ regulatory T cells. J. Immunol. 2008. 180: 122129.
  • 37
    Sato, W., Aranami, T. and Yamamura, T., Cutting edge: human Th17 cells are identified as bearing CCR2+CCR5 phenotype. J. Immunol. 2007. 178: 75257529.
  • 38
    Cosmi, L., De Palma, R., Santarlasci, V., Maggi, L., Capone, M., Frosali, F., Rodolico, G. et al., Human interleukin 17-producing cells originate from a CD161+CD4+ T cell precursor. J. Exp. Med. 2008. 205: 19031916.
  • 39
    Acosta-Rodriguez, E. V., Napolitani, G., Lanzavecchia, A. and Sallusto, F., Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. Nat. Immunol. 2007. 8: 942949.
  • 40
    Evans, H. G., Suddason, T., Jackson, I., Taams, L. S. and Lord, G. M., Optimal induction of T helper 17 cells in humans requires T cell receptor ligation in the context of Toll-like receptor-activated monocytes. Proc. Natl. Acad. Sci. USA 2007. 104: 1703417039.
  • 41
    Chen, Z., Tato, C. M., Muul, L., Laurence, A. and O'Shea, J. J., Distinct regulation of interleukin-17 in human T helper lymphocytes. Arthritis Rheum. 2007. 56: 29362946.
  • 42
    Yang, L., Anderson, D. E., Baecher-Allan, C., Hastings, W. D., Bettelli, E., Oukka, M., Kuchroo, V. K. and Hafler, D. A., IL-21 and TGF-beta are required for differentiation of human T(H)17 cells. Nature 2008. 454: 350352.
  • 43
    Santarlasci, V., Maggi, L., Capone, M., Frosali, F., Querci, V., De Palma, R., Liotta, F. et al., TGF-beta indirectly favors the development of human Th17 cells by inhibiting Th1 cells. Eur. J. Immunol. 2009. 39: 207215.
  • 44
    Yao, Z., Fanslow, W. C., Seldin, M. F., Rousseau, A. M., Painter, S. L., Comeau, M. R., Cohen, J. I. and Spriggs, M. K., Herpesvirus Saimiri encodes a new cytokine, IL-17, which binds to a novel cytokine receptor. Immunity 1995. 3: 811821.
  • 45
    Allan, S. E., Alstad, A. N., Merindol, N., Crellin, N. K., Amendola, M., Bacchetta, R., Naldini, L. et al., Generation of potent and stable human CD4+ T regulatory cells by activation-independent expression of FOXP3. Mol. Ther. 2008. 16: 194202.
  • 46
    Amendola, M., Venneri, M. A., Biffi, A., Vigna, E. and Naldini, L., Coordinate dual-gene transgenesis by lentiviral vectors carrying synthetic bidirectional promoters. Nat. Biotechnol. 2005. 23: 108116.
  • 47
    Singh, S. P., Zhang, H. H., Foley, J. F., Hedrick, M. N. and Farber, J. M., Human T cells that are able to produce IL-17 express the chemokine receptor CCR6. J. Immunol. 2008. 180: 214221.
  • 48
    Kebir, H., Kreymborg, K., Ifergan, I., Dodelet-Devillers, A., Cayrol, R., Bernard, M., Giuliani, F. et al., Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation. Nat. Med. 2007. 13: 11731175.
  • 49
    Stritesky, G. L., Yeh, N. and Kaplan, M. H., IL-23 promotes maintenance but not commitment to the Th17 lineage. J. Immunol. 2008. 181: 59485955.
  • 50
    Huter, E. N., Stummvoll, G. H., DiPaolo, R. J., Glass, D. D. and Shevach, E. M., Cutting Edge: antigen-specific TGFbeta-induced regulatory T cells suppress Th17-mediated autoimmune disease. J. Immunol. 2008. 181: 82098213.
  • 51
    Stummvoll, G. H., DiPaolo, R. J., Huter, E. N., Davidson, T. S., Glass, D., Ward, J. M. and Shevach, E. M., Th1, Th2, and Th17 effector T cell-induced autoimmune gastritis differs in pathological pattern and in susceptibility to suppression by regulatory T cells. J. Immunol. 2008. 181: 19081916.
  • 52
    Koenen, H. J., Smeets, R. L., Vink, P. M., van Rijssen, E., Boots, A. M. and Joosten, I., Human CD25highFoxp3pos regulatory T-cells differentiate into IL-17 producing cells. Blood 2008. 112: 23402352.
  • 53
    Radhakrishnan, S., Cabrera, R., Schenk, E. L., Nava-Parada, P., Bell, M. P., Van,Keulen, V. P., Marler, R. J. et al., Reprogrammed FoxP3+ T regulatory cells become IL-17+ antigen-specific autoimmune effectors in vitro and in vivo. J. Immunol. 2008. 181: 31373147.
  • 54
    Xu, L., Kitani, A., Fuss, I. and Strober, W., Cutting edge: regulatory T cells induce CD4+CD25Foxp3 T cells or are self-induced to become Th17 cells in the absence of exogenous TGF-beta. J. Immunol. 2007. 178: 67256729.
  • 55
    Yang, X. O., Nurieva, R., Martinez, G. J., Kang, H. S., Chung, Y., Pappu, B. P., Shah, B. et al., Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity 2008. 29: 4456.
  • 56
    Zheng, S. G., Wang, J. and Horwitz, D. A., Cutting edge: Foxp3+CD4+CD25+ regulatory T cells induced by IL-2 and TGF-beta are resistant to Th17 conversion by IL-6. J. Immunol. 2008. 180: 71127116.
  • 57
    Annunziato, F., Cosmi, L., Liotta, F., Maggi, E. and Romagnani, S., The phenotype of human Th17 cells and their precursors, the cytokines that mediate their differentiation and the role of Th17 cells in inflammation. Int. Immunol. 2008. 20: 13611368.
  • 58
    Oppmann, B., Lesley, R., Blom, B., Timans, J. C., Xu, Y., Hunte, B., Vega, F. et al., Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 2000. 13: 715725.
  • 59
    Amadi-Obi, A., Yu, C. R., Liu, X., Mahdi, R. M., Clarke, G. L., Nussenblatt, R. B., Gery, I. et al., TH17 cells contribute to uveitis and scleritis and are expanded by IL-2 and inhibited by IL-27/STAT1. Nat. Med. 2007. 13: 711718.
  • 60
    Laurence, A., Tato, C. M., Davidson, T. S., Kanno, Y., Chen, Z., Yao, Z., Blank, R. B. et al., Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity 2007. 26: 371381.
  • 61
    Thornton, A. M., Donovan, E. E., Piccirillo, C. A. and Shevach, E. M., Cutting edge: IL-2 is critically required for the in vitro activation of CD4+CD25+ T cell suppressor function. J. Immunol. 2004. 172: 65196523.
  • 62
    Pasare, C. and Medzhitov, R., Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 2003. 299: 10331036.
  • 63
    Lohr, J., Knoechel, B., Wang, J. J., Villarino, A. V. and Abbas, A. K., Role of IL-17 and regulatory T lymphocytes in a systemic autoimmune disease. J. Exp. Med. 2006. 203: 27852791.
  • 64
    Gaffen, S. L., Biology of recently discovered cytokines: interleukin-17--a unique inflammatory cytokine with roles in bone biology and arthritis. Arthritis Res. Ther. 2004. 6: 240247.