Th17 and IL-17 play important roles in the clearance of extracellular bacterial and fungal infections. However, strong evidence also implicates the Th17 lineage in several autoimmune disorders including multiple sclerosis, psoriasis, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, and asthma. The Th17 subset has also been connected with type I diabetes, although whether it plays a role in the pathogenicity of or protection from the disease remains a controversial issue. In this review we have provided a comprehensive overview of Th17 pathogenicity and function, including novel evidence for a protective role of Th17 cells in conjunction with the microbiota gut flora in T1D onset and progression. 1. Introduction Antigen presenting cells activate na？ve T lymphocytes by presenting specific antigens, and by providing the necessary costimulatory signals and cytokine environment [1]. T lymphocytes bearing T cell receptor (TCR) specificity towards the presented antigen subsequently undergo clonal expansion and mediate effector functions largely dictated by the stimulatory and environmental clues provided [2]. In a past classical model, CD4+ effector T cells were assigned to either the Th1 or Th2 subset, each with its own distinct cytokines, transcription factors, and functions [3]. Th1 cells produce IFNγ and are regulated by IL-12 through the transcription factor Tbet, while Th2 cells produce the cytokines IL-4, IL-5, and IL-13 and are regulated by the transcription factor GATA3. Th1 cells are associated with protection against intracellular pathogens, and T lymphocytes bearing the Th2 phenotype regulate humoral immunity, and are involved in the protection against extracellular pathogens [4]. Having established a role for Th1 and Th2 cells within the context of immune defense against microorganisms, the Th1/Th2 paradigm was then utilized to garner insight into the onset and progression of autoimmune disorders. The goal of this review is to explicate how limitations of the Th1/Th2 paradigm in the context of autoimmunity led to the discovery of the Th17 phenotype, and to examine the implications of the Th17 phenotype within the context of several autoimmune disorders, including T1D. 2. A Shift in Focus to the Th17 Phenotype The experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS) provided the first clues to the possibility that other T cell effector functions, beyond those attributed to the Th1 and Th2 subsets, could be contributing to the onset and progression of autoimmune disorders. Under the
References
[1]
R. M. Steinman, D. Hawiger, K. Liu et al., “Dendritic cell function in vivo during the steady state: a role in peripheral tolerance,” Annals of the New York Academy of Sciences, vol. 987, pp. 15–25, 2003.
[2]
B. Stockinger, C. Bourgeois, and G. Kassiotis, “CD4+ memory T cells: functional differentiation and homeostasis,” Immunological Reviews, vol. 211, pp. 39–48, 2006.
[3]
T. R. Mosmann, H. Cherwinski, and M. W. Bond, “Two types of murine helper T cell clone. I: definition according to profiles of lymphokine activities and secreted proteins,” Journal of Immunology, vol. 136, no. 7, pp. 2348–2357, 1986.
[4]
J. Zhu, H. Yamane, and W. E. Paul, “Differentiation of effector CD4+ T cell populations,” Annual Review of Immunology, vol. 28, pp. 445–489, 2010.
[5]
C.-Q. Chu, S. Wittmer, and D. K. Dalton, “Failure to suppress the expansion of the activated CD4 T cell population in interferon γ-deficient mice leads to exacerbation of experimental autoimnaune encephalomyelitis,” Journal of Experimental Medicine, vol. 192, no. 1, pp. 123–128, 2000.
[6]
I. A. Ferber, S. Brocke, C. Taylor-Edwards et al., “Mice with a disrupted IFN-γ gene are susceptible to the induction of experimental autoimmune encephalomyelitis (EAE),” Journal of Immunology, vol. 156, no. 1, pp. 5–7, 1996.
[7]
D. O. Willenborg, S. Fordham, C. C. A. Bernard, W. B. Cowden, and I. A. Ramshaw, “IFN-γ plays a critical down-regulatory role in the induction and effector phase of myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis,” Journal of Immunology, vol. 157, no. 8, pp. 3223–3227, 1996.
[8]
G.-X. Zhang, B. Gran, S. Yu et al., “Induction of experimental autoimmune encephalomyelitis in IL-12 receptor-β2-deficient mice: IL-12 responsiveness is not required in the pathogenesis of inflammatory demyelination in the central nervous system,” Journal of Immunology, vol. 170, no. 4, pp. 2153–2160, 2003.
[9]
B. Becher, B. G. Durell, and R. J. Noelle, “Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12,” Journal of Clinical Investigation, vol. 110, no. 4, pp. 493–497, 2002.
[10]
B. Gran, G.-X. Zhang, S. Yu et al., “IL-12p35-deficient mice are susceptible to experimental autoimmune encephalomyelitis: evidence for redundancy in the IL-12 system in the induction of central nervous system autoimmune demyelination,” Journal of Immunology, vol. 169, no. 12, pp. 7104–7110, 2002.
[11]
D. J. Cua, J. Sherlock, Y. Chen et al., “Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain,” Nature, vol. 421, no. 6924, pp. 744–748, 2003.
[12]
B. Oppmann, R. Lesley, B. Blom 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, vol. 13, no. 5, pp. 715–725, 2000.
[13]
J. P. Leonard, K. E. Waldburger, S. J. Goldman, and H. W. Murray, “Prevention of experimental autoimmune encephalomyelitis by antibodies against interleukin 12,” Journal of Experimental Medicine, vol. 181, no. 1, pp. 381–386, 1995.
[14]
J. P. Leonard, K. E. Waldburger, and S. J. Goldman, “Regulation of experimental autoimmune encephalomyelitis by interleukin-12,” Annals of the New York Academy of Sciences, vol. 795, pp. 216–226, 1996.
[15]
C. S. Constantinescu, M. Wysocka, B. Hilliard et al., “Antibodies against IL-12 prevent superantigen-induced and spontaneous relapses of experimental autoimmune encephalomyelitis,” Journal of Immunology, vol. 161, no. 9, pp. 5097–5104, 1998.
[16]
B. M. Segal, B. K. Dwyer, and E. M. Shevach, “An interleukin (IL)-10/IL-12 immunoregulatory circuit controls susceptibility to autoimmune disease,” Journal of Experimental Medicine, vol. 187, no. 4, pp. 537–546, 1998.
[17]
H. P. M. Brok, M. Van Meurs, E. Blezer et al., “Prevention of experimental autoimmune encephalomyelitis in common marmosets using an anti-IL-12p40 monoclonal antibody,” Journal of Immunology, vol. 169, no. 11, pp. 6554–6563, 2002.
[18]
C. A. Murphy, C. L. Langrish, Y. Chen et al., “Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation,” Journal of Experimental Medicine, vol. 198, no. 12, pp. 1951–1957, 2003.
[19]
L. E. Harrington, R. D. Hatton, P. R. Mangan et al., “Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages,” Nature Immunology, vol. 6, no. 11, pp. 1123–1132, 2005.
[20]
C. L. Langrish, Y. Chen, W. M. Blumenschein et al., “IL-23 drives a pathogenic T cell population that induces autoimmune inflammation,” Journal of Experimental Medicine, vol. 201, no. 2, pp. 233–240, 2005.
[21]
H. Park, Z. Li, X. O. Yang et al., “A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17,” Nature Immunology, vol. 6, no. 11, pp. 1133–1141, 2005.
[22]
O. Kanagawa, G. Xu, A. Tevaarwerk, and B. A. Vaupel, “Protection of nonobese diabetic mice from diabetes by gene(s) closely linked to IFN-γ receptor loci,” Journal of Immunology, vol. 164, no. 7, pp. 3919–3923, 2000.
[23]
B. Wang, I. André, A. Gonzalez et al., “Interferon-γ impacts at multiple points during the progression of autoimmune diabetes,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 25, pp. 13844–13849, 1997.
[24]
M. Debray-Sachs, C. Carnaud, C. Boitard et al., “Prevention of diabetes in NOD mice treated with antibody to murine IFNγ,” Journal of Autoimmunity, vol. 4, no. 2, pp. 237–248, 1991.
[25]
M. J. Rapoport, A. Jaramillo, D. Zipris et al., “Interleukin 4 reverses T cell proliferative unresponsiveness and prevents the onset of diabetes in nonobese diabetic mice,” Journal of Experimental Medicine, vol. 178, no. 1, pp. 87–99, 1993.
[26]
B. Hultgren, X. Huang, N. Dybdal, and T. A. Stewart, “Genetic absence of γ-interferon delays but does not prevent diabetes in NOD mice,” Diabetes, vol. 45, no. 6, pp. 812–817, 1996.
[27]
D. V. Serreze, C. M. Post, H. D. Chapman, E. A. Johnson, B. Lu, and P. B. Rothman, “Interferon-γ receptor signaling is dispensable in the development of autoimmune type 1 diabetes in NOD mice,” Diabetes, vol. 49, no. 12, pp. 2007–2011, 2000.
[28]
R. Jain, D. M. Tartar, R. K. Gregg et al., “Innocuous IFNγ induced by adjuvant-free antigen restores normoglycemia in NOD mice through inhibition of IL-17 production,” Journal of Experimental Medicine, vol. 205, no. 1, pp. 207–218, 2008.
[29]
B. Wang, A. Gonzalez, P. H？glund, J. D. Katz, C. Benoist, and D. Mathis, “Interleukin-4 deficiency does not exacerbate disease in NOD mice,” Diabetes, vol. 47, no. 8, pp. 1207–1211, 1998.
[30]
E. M. Bradshaw, K. Raddassi, W. Elyaman et al., “Monocytes from patients with type 1 diabetes spontaneously secrete proinflammatory cytokines inducing Th17 cells,” Journal of Immunology, vol. 183, no. 7, pp. 4432–4439, 2009.
[31]
J. A. Emamaullee, J. Davis, S. Merani et al., “Inhibition of Th17 cells regulates autoimmune diabetes in NOD mice,” Diabetes, vol. 58, no. 6, pp. 1302–1311, 2009.
[32]
E. Nikoopour, J. A. Schwartz, K. Huszarik et al., “Th17 polarized cells from nonobese diabetic mice following mycobacterial adjuvant immunotherapy delay type 1 diabetes,” Journal of Immunology, vol. 184, no. 9, pp. 4779–4788, 2010.
[33]
G. Han, R. Wang, G. Chen et al., “Interleukin-17-producing γδ+ T cells protect NOD mice from type 1 diabetes through a mechanism involving transforming growth factor-β,” Immunology, vol. 129, no. 2, pp. 197–206, 2010.
[34]
A. Peters, Y. Lee, and V. K. Kuchroo, “The many faces of Th17 cells,” Current Opinion in Immunology, vol. 23, no. 6, pp. 702–706, 2011.
[35]
K. Hirota, J. H. Duarte, M. Veldhoen et al., “Fate mapping of IL-17-producing T cells in inflammatory responses,” Nature Immunology, vol. 12, no. 3, pp. 255–263, 2011.
[36]
D. Bending, H. de la Pe？a, M. Veldhoen et al., “Highly purified Th17 cells from BDC2.5NOD mice convert into Th1-like cells in NOD/SCID recipient mice,” Journal of Clinical Investigation, vol. 119, no. 3, pp. 565–572, 2009.
[37]
N. Martin-Orozco, Y. Chung, S. H. Chang, Y.-H. Wang, and C. Dong, “Th17 cells promote pancreatic inflammation but only induce diabetes efficiently in lymphopenic hosts after conversion into Th1 cells,” European Journal of Immunology, vol. 39, no. 1, pp. 216–224, 2009.
[38]
C. C. Picca, J. Larkin III, A. Boesteanu, M. A. Lerman, A. L. Rankin, and A. J. Caton, “Role of TCR specificity in CD4+CD25+ regulatory T-cell selection,” Immunological Reviews, vol. 212, pp. 74–85, 2006.
[39]
S. Sakaguchi, T. Yamaguchi, T. Nomura, and M. Ono, “Regulatory T cells and immune tolerance,” Cell, vol. 133, no. 5, pp. 775–787, 2008.
[40]
G. L. Cvetanovich and D. A. Hafler, “Human regulatory T cells in autoimmune diseases,” Current Opinion in Immunology, vol. 22, no. 6, pp. 753–760, 2010.
[41]
Y. K. Lee, R. Mukasa, R. D. Hatton, and C. T. Weaver, “Developmental plasticity of Th17 and Treg cells,” Current Opinion in Immunology, vol. 21, no. 3, pp. 274–280, 2009.
[42]
X. Zhou, S. L. Bailey-Bucktrout, L. T. Jeker et al., “Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo,” Nature Immunology, vol. 10, no. 9, pp. 1000–1007, 2009.
[43]
S. G. Zheng, “Regulatory T cells versus Th17: differentiation of Th17 versus Treg, are the mutually exclusive?” The American Journal of Clinical and Experimental Immunology, vol. 2, no. 1, pp. 94–106, 2013.
[44]
L. Li and V. A. Boussiotis, “The role of IL-17-producing Foxp3+ CD4+ T cells in inflammatory bowel disease and colon cancer,” Clinical Immunology, vol. 148, no. 2, pp. 246–253, 2013.
[45]
Z. Hovhannisyan, J. Treatman, D. R. Littman, and L. Mayer, “Characterization of interleukin-17-producing regulatory T cells in inflamed intestinal mucosa from patients with inflammatory bowel diseases,” Gastroenterology, vol. 140, no. 3, pp. 957–965, 2011.
[46]
E. Bettelli, Y. Carrier, W. Gao et al., “Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells,” Nature, vol. 441, no. 7090, pp. 235–238, 2006.
[47]
P. R. Mangan, L. E. Harrington, D. B. O'Quinn et al., “Transforming growth factor-β induces development of the T H17 lineage,” Nature, vol. 441, no. 7090, pp. 231–234, 2006.
[48]
M. Veldhoen, R. J. Hocking, C. J. Atkins, R. M. Locksley, and B. Stockinger, “TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells,” Immunity, vol. 24, no. 2, pp. 179–189, 2006.
[49]
M. Veldhoen, R. J. Hocking, R. A. Flavell, and B. Stockinger, “Signals mediated by transforming growth factor-β initiate autoimmune encephalomyelitis, but chronic inflammation is needed to sustain disease,” Nature Immunology, vol. 7, no. 11, pp. 1151–1156, 2006.
[50]
M. O. Li, S. Sanjabi, and R. Flavell, “Transforming growth factor-β controls development, homeostasis, and tolerance of T cells by regulatory T cell-dependent and -independent mechanisms,” Immunity, vol. 25, no. 3, pp. 455–471, 2006.
[51]
S. K. Bedoya, T. D. Wilson, E. L. Collins, K. Lau, and J. Larkin III, “Isolation and Differentiation of Th17 Naive CD4 T Lymphocytes,” Journal of Visualized Experiments, no. 79, Article ID e50765, 2013.
[52]
R. Nurieva, X. O. Yang, G. Martinez et al., “Essential autocrine regulation by IL-21 in the generation of inflammatory T cells,” Nature, vol. 448, no. 7152, pp. 480–483, 2007.
[53]
L. Zhou, I. I. Ivanov, R. Spolski et al., “IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways,” Nature Immunology, vol. 8, no. 9, pp. 967–974, 2007.
[54]
K. Ghoreschi, A. Laurence, X.-P. Yang et al., “Generation of pathogenic TH 17 cells in the absence of TGF-β 2 signalling,” Nature, vol. 467, no. 7318, pp. 967–971, 2010.
[55]
T. Korn, E. Bettelli, W. Gao et al., “IL-21 initiates an alternative pathway to induce proinflammatory T H17 cells,” Nature, vol. 448, no. 7152, pp. 484–487, 2007.
[56]
L. Guo, G. Wei, J. Zhu et al., “IL-1 family members and STAT activators induce cytokine production by Th2, Th17, and Th1 cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 32, pp. 13463–13468, 2009.
[57]
A. K. Marwaha, N. J. Leung, A. N. McMurchy, and M. K. Levings, “TH17 cells in autoimmunity and immunodeficiency: protective or pathogenic?” Frontiers in Immunology, vol. 3, article 129, 2012.
[58]
J. K. Kolls and A. Lindén, “Interleukin-17 family members and inflammation,” Immunity, vol. 21, no. 4, pp. 467–476, 2004.
[59]
S. C. Liang, A. J. Long, F. Bennett et al., “An IL-17F/A heterodimer protein is produced by mouse Th17 cells and induces airway neutrophil recruitment,” Journal of Immunology, vol. 179, no. 11, pp. 7791–7799, 2007.
[60]
J. F. Wright, Y. Guo, A. Quazi et al., “Identification of an interleukin 17F/17A heterodimer in activated human CD4+ T cells,” Journal of Biological Chemistry, vol. 282, no. 18, pp. 13447–13455, 2007.
[61]
G. Besin, S. Gaudreau, M. Menard, C. Guindi, G. Dupuis, and A. Amrani, “Thymic stromal lymphopoietin and thymic stromal lymphopoietin-conditioned dendritic cells induce regulatory T-cell differentiation and protection of NOD mice against diabetes,” Diabetes, vol. 57, no. 8, pp. 2107–2117, 2008.
[62]
S. Gaudreau, C. Guindi, M. Ménard, G. Besin, G. Dupuis, and A. Amrani, “Granulocyte-macrophage colony-stimulating factor prevents diabetes development in NOD mice by inducing tolerogenic dendritic cells that sustain the suppressive function of CD4+CD25+ regulatory T cells,” Journal of Immunology, vol. 179, no. 6, pp. 3638–3647, 2007.
[63]
K. M. Murphy and S. L. Reiner, “The lineage decisions of helper T cells,” Nature Reviews Immunology, vol. 2, no. 12, pp. 933–944, 2002.
[64]
I. I. Ivanov, B. S. McKenzie, L. Zhou et al., “The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells,” Cell, vol. 126, no. 6, pp. 1121–1133, 2006.
[65]
X. O. Yang, B. P. Pappu, R. Nurieva et al., “T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma,” Immunity, vol. 28, no. 1, pp. 29–39, 2008.
[66]
A. N. Mathur, H.-C. Chang, D. G. Zisoulis et al., “Stat3 and Stat4 direct development of IL-17-secreting Th cells,” Journal of Immunology, vol. 178, no. 8, pp. 4901–4907, 2007.
[67]
X. O. Yang, A. D. Panopoulos, R. Nurieva et al., “STAT3 regulates cytokine-mediated generation of inflammatory helper T cells,” Journal of Biological Chemistry, vol. 282, no. 13, pp. 9358–9363, 2007.
[68]
A. Brustle, S. Heink, M. Huber et al., “The development of inflammatory T(H)-17 cells requires interferon-regulatory factor 4,” Nature Immunology, vol. 8, no. 9, pp. 958–966, 2007.
[69]
M. Huber, A. Brüstle, K. Reinhard et al., “IRF4 is essential for IL-21-mediated induction, amplification, and stabilization of the Th17 phenotype,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 52, pp. 20846–20851, 2008.
[70]
M. Veldhoen, K. Hirota, A. M. Westendorf et al., “The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins,” Nature, vol. 453, no. 7191, pp. 106–109, 2008.
[71]
S. Keerthivasan, R. Suleiman, R. Lawlor et al., “Notch signaling regulates mouse and human Th17 differentiation,” Journal of Immunology, vol. 187, no. 2, pp. 692–701, 2011.
[72]
B. U. Schraml, K. Hildner, W. Ise et al., “The AP-1 transcription factor Batf controls T H 17 differentiation,” Nature, vol. 460, no. 7253, pp. 405–409, 2009.
[73]
R. Spolski, M. Kashyap, C. Robinson, Z. Yu, and W. J. Leonard, “IL-21 signaling is critical for the development of type I diabetes in the NOD mouse,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 37, pp. 14028–14033, 2008.
[74]
A. Kimura, T. Naka, K. Nohara, Y. Fujii-Kuriyama, and T. Kishimoto, “Aryl hydrocarbon receptor regulates Stat1 activation and participates in the development of Th17 cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 28, pp. 9721–9726, 2008.
[75]
N. T. Nguyen, T. Nakahama, and T. Kishimoto, “Aryl hydrocarbon receptor and experimental autoimmune arthritis,” Seminars in Immunopathology, vol. 35, no. 6, pp. 637–644, 2013.
[76]
T. Korn, E. Bettelli, M. Oukka, and V. K. Kuchroo, “IL-17 and Th17 cells,” Annual Review of Immunology, vol. 27, pp. 485–517, 2009.
[77]
M. Kleinewietfeld, A. Manzel, J. Titze et al., “Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells,” Nature, no. 7446, pp. 518–522, 2013.
[78]
C. Wu, N. Yosef, T. Thalhamer et al., “Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1,” Nature, vol. 496, no. 7446, pp. 513–517, 2013.
[79]
A. N. Mathur, H.-C. Chang, D. G. Zisoulis et al., “T-bet is a critical determinant in the instability of the IL-17-secreting T-helper phenotype,” Blood, vol. 108, no. 5, pp. 1595–1601, 2006.
[80]
M. M. Fort, J. Cheung, D. Yen et al., “IL-25 Induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo,” Immunity, vol. 15, no. 6, pp. 985–995, 2001.
[81]
A. M. Owyang, C. Zaph, E. H. Wilson et al., “Interleukin 25 regulates type 2 cytokine-dependent immunity and limits chronic inflammation in the gastrointestinal tract,” Journal of Experimental Medicine, vol. 203, no. 4, pp. 843–849, 2006.
[82]
S. A. Saenz, M. C. Siracusa, J. G. Perrigoue et al., “IL25 elicits a multipotent progenitor cell population that promotes T H 2 cytokine responses,” Nature, vol. 464, no. 7293, pp. 1362–1366, 2010.
[83]
J. Su, T. Chen, X. Y. Ji et al., “IL-25 downregulates Th1/Th17 immune response in an IL-10-dependent manner in inflammatory bowel disease,” Inflammatory Bowel Diseases, vol. 19, no. 4, pp. 720–728, 2013.
[84]
M. A. Kleinschek, A. M. Owyang, B. Joyce-Shaikh et al., “IL-25 regulates Th17 function in autoimmune inflammation,” Journal of Experimental Medicine, vol. 204, no. 1, pp. 161–170, 2007.
[85]
R. Caruso, C. Stolfi, M. Sarra et al., “Inhibition of monocyte-derived inflammatory cytokines by IL-25 occurs via p38 Map kinase-dependent induction of Socs-3,” Blood, vol. 113, no. 15, pp. 3512–3519, 2009.
[86]
K. S. Goudy, B. R. Burkhardt, C. Wasserfall et al., “Systemic overexpression of IL-10 induces CD4+CD25+ cell populations in vivo and ameliorates type 1 diabetes in nonobese diabetic mice in a dose-dependent fashion,” Journal of Immunology, vol. 171, no. 5, pp. 2270–2278, 2003.
[87]
S. You, C. Chen, W.-H. Lee, T. Brusko, M. Atkinson, and C.-P. Liu, “Presence of diabetes-inhibiting, glutamic acid decarboxylase-specific, IL-10-dependent, regulatory T cells in naive nonobese diabetic mice,” Journal of Immunology, vol. 173, no. 11, pp. 6777–6785, 2004.
[88]
Y. C. Zhang, A. Pileggi, A. Agarwal et al., “Adeno-associated virus-mediated IL-10 gene therapy inhibits diabetes recurrence in syngeneic islet cell transplantation of NOD mice,” Diabetes, vol. 52, no. 3, pp. 708–716, 2003.
[89]
R. A. Kastelein, C. A. Hunter, and D. J. Cua, “Discovery and biology of IL-23 and IL-27: related but functionally distinct regulators of inflammation,” Annual Review of Immunology, vol. 25, pp. 221–242, 2007.
[90]
E. Charles and J. L. Egwuagu III, “Therapeutic targeting of STAT pathways in CNS autoimmune diseases,” Landes Bioscience, vol. 2, no. 1, Article ID e24134, 2013.
[91]
A. Villarino, L. Hibbert, L. Lieberman et al., “The IL-27R (WSX-1) is required to suppress T cell hyperactivity during infection,” Immunity, vol. 19, no. 5, pp. 645–655, 2003.
[92]
M. Batten, J. Li, S. Yi et al., “Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleukin 17-producing T cells,” Nature Immunology, vol. 7, no. 9, pp. 929–936, 2006.
[93]
J. S. Stumhofer, A. Laurence, E. H. Wilson et al., “Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system,” Nature Immunology, vol. 7, no. 9, pp. 937–945, 2006.
[94]
D. C. Fitzgerald, B. Ciric, T. Touil et al., “Suppressive effect of IL-27 on encephalitogenic Th17 cells and the effector phase of experimental autoimmune encephalomyelitis,” Journal of Immunology, vol. 179, no. 5, pp. 3268–3275, 2007.
[95]
A. Amadi-Obi, C.-R. Yu, X. Liu et al., “TH17 cells contribute to uveitis and scleritis and are expanded by IL-2 and inhibited by IL-27/STAT1,” Nature Medicine, vol. 13, no. 6, pp. 711–718, 2007.
[96]
M. P. L. Reddy, H. Wang, S. Liu et al., “Association between type 1 diabetes and GWAS SNPs in the southeast US Caucasian population,” Genes and Immunity, vol. 12, no. 3, pp. 208–212, 2011.
[97]
R. Bergholdt, C. Brorsson, A. Palleja et al., “Identification of novel type 1 diabetes candidate genes by integrating genome-wide association data, protein-protein interactions, and human pancreatic islet gene expression,” Diabetes, vol. 61, no. 4, pp. 954–962, 2012.
[98]
A. Laurence, C. M. Tato, T. S. Davidson et al., “Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation,” Immunity, vol. 26, no. 3, pp. 371–381, 2007.
[99]
T. R. Malek, A. Yu, L. Zhu, T. Matsutani, D. Adeegbe, and A. L. Bayer, “IL-2 family of cytokines in T regulatory cell development and homeostasis,” Journal of Clinical Immunology, vol. 28, no. 6, pp. 635–639, 2008.
[100]
Z. Chen, A. Laurence, Y. Kanno et al., “Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 21, pp. 8137–8142, 2006.
[101]
L. D. Jager, R. Dabelic, L. W. Waiboci et al., “The kinase inhibitory region of SOCS-1 is sufficient to inhibit T-helper 17 and other immune functions in experimental allergic encephalomyelitis,” Journal of Neuroimmunology, vol. 232, no. 1-2, pp. 108–118, 2011.
[102]
A. V. Villarino, J. S. Stumhofer, C. J. M. Saris, R. A. Kastelein, F. J. De Sauvage, and C. A. Hunter, “IL-27 limits IL-2 production during Th1 differentiation,” Journal of Immunology, vol. 176, no. 1, pp. 237–247, 2006.
[103]
S. R. Paludan, “Interleukin-4 and interferon-γ: the quintessence of a mutual antagonistic relationship,” Scandinavian Journal of Immunology, vol. 48, no. 5, pp. 459–468, 1998.
[104]
S. H. Chang, Y. Chung, and C. Dong, “Vitamin D suppresses Th17 cytokine production by inducing C/EBP Homologous Protein (CHOP) expression,” Journal of Biological Chemistry, vol. 285, no. 50, pp. 38751–38755, 2010.
[105]
T. P. Staeva-Vieira and L. P. Freedman, “1,25-Dihydroxyvitamin D3 inhibits IFN-γ and IL-4 levels during in vitro polarization of primary murine CD4+ T cells,” Journal of Immunology, vol. 168, no. 3, pp. 1181–1189, 2002.
[106]
J. Tang, R. Zhou, D. Luger et al., “Calcitriol suppresses antiretinal autoimmunity through inhibitory effects on the Th17 effector response,” Journal of Immunology, vol. 182, no. 8, pp. 4624–4632, 2009.
[107]
J. A. Hall, J. R. Grainger, S. P. Spencer, and Y. Belkaid, “The role of retinoic acid in tolerance and immunity,” Immunity, vol. 35, no. 1, pp. 13–22, 2011.
[108]
L. Massacesi, A. L. Abbamondi, and C. Giorgi, “Suppression of experimental allergic encephalomyelitis by retinoic acid,” Journal of the Neurological Sciences, vol. 80, no. 1, pp. 55–64, 1987.
[109]
M. M. Escribese, E. Conde, A. Martín et al., “Therapeutic effect of all-trans-retinoic acid (at-RA) on an autoimmune nephritis experimental model: role of the VLA-4 integrin,” BMC Nephrology, vol. 8, article 3, 2007.
[110]
P. Konieczna, R. Ferstl, M. Ziegler et al., “Immunomodulation by Bifidobacterium infantis 35624 in the murine lamina propria requires retinoic acid-dependent and independent mechanisms,” PLoS ONE, vol. 8, no. 5, Article ID e62617, 2013.
[111]
J. Wu, Y. Zhang, Q. Liu, W. Zhong, and Z. Xia, “All-trans retinoic acid attenuates airway inflammation by inhibiting Th2 and Th17 response in experimental allergic asthma,” BMC Immunology, vol. 14, article 28, 2013.
[112]
K. M. Elias, A. Laurence, T. S. Davidson et al., “Retinoic acid inhibits Th17 polarization and enhances FoxP3 expression through a Stat-3/Stat-5 independent signaling pathway,” Blood, vol. 111, no. 3, pp. 1013–1020, 2008.
[113]
S. Xiao, H. Jin, T. Korn et al., “Retinoic acid increases Foxp3+ regulatory T cells and inhibits development of Th17 cells by enhancing TGF-β-driven Smad3 signaling and inhibiting IL-6 and IL-23 receptor expression,” Journal of Immunology, vol. 181, no. 4, pp. 2277–2284, 2008.
[114]
U. Ikeda, D. Wakita, T. Ohkuri et al., “1α,25-Dihydroxyvitamin D3 and all-trans retinoic acid synergistically inhibit the differentiation and expansion of Th17 cells,” Immunology Letters, vol. 134, no. 1, pp. 7–16, 2010.
[115]
E. V. Acosta-Rodriguez, G. Napolitani, A. Lanzavecchia, and F. Sallusto, “Interleukins 1β and 6 but not transforming growth factor-β are essential for the differentiation of interleukin 17-producing human T helper cells,” Nature Immunology, vol. 8, no. 9, pp. 942–949, 2007.
[116]
N. Manel, D. Unutmaz, and D. R. Littman, “The differentiation of human TH-17 cells requires transforming growth factor-β and induction of the nuclear receptor RORγt,” Nature Immunology, vol. 9, no. 6, pp. 641–649, 2008.
[117]
L. Yang, D. E. Anderson, C. Baecher-Allan et al., “IL-21 and TGF-β are required for differentiation of human T H17 cells,” Nature, vol. 454, no. 7202, pp. 350–352, 2008.
[118]
N. J. Wilson, K. Boniface, J. R. Chan, et al., “Development, cytokine profile and function of human interleukin 17-producing helper T cells,” Nature Immunology, vol. 8, no. 9, pp. 950–957, 2007.
[119]
N. Obermajer, J. L. Wong, R. P. Edwards, et al., “Induction and stability of human Th17 cells require endogenous NOS2 and cGMP-dependent NO signaling,” Journal of Experimental Medicine, vol. 210, no. 7, pp. 1433–1445, 2013.
[120]
E. V. Acosta-Rodriguez, L. Rivino, J. Geginat et al., “Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells,” Nature Immunology, vol. 8, no. 6, pp. 639–646, 2007.
[121]
L. de Beaucoudrey, A. Puel, O. Filipe-Santos, et al., “Mutations in STAT3 and IL12RB1 impair the development of human IL-17-producing T cells,” Journal of Experimental Medicine, vol. 205, no. 7, pp. 1543–1550, 2008.
[122]
S. Tuomela, V. Salo, S. K. Tripathi, et al., “Identification of early gene expression changes during human Th17 cell differentiation,” Blood, vol. 119, no. 23, pp. e151–e160, 2012.
[123]
F. Zhang, G. Meng, and W. Strober, “Interactions among the transcription factors Runx1, RORγt and Foxp3 regulate the differentiation of interleukin 17-producing T cells,” Nature Immunology, vol. 9, no. 11, pp. 1297–1306, 2008.
[124]
L. Cosmi, R. de Palma, V. Santarlasci et al., “Human interleukin 17-producing cells originate from a CD161 +CD4+ T cell precursor,” Journal of Experimental Medicine, vol. 205, no. 8, pp. 1903–1916, 2008.
[125]
F. Annunziato, L. Cosmi, V. Santarlasci, et al., “Phenotypic and functional features of human Th17 cells,” Journal of Experimental Medicine, vol. 204, no. 8, pp. 1849–1861, 2007.
[126]
M. K. Spriggs, “Interleukin-17 and its receptor,” Journal of Clinical Immunology, vol. 17, no. 5, pp. 366–369, 1997.
[127]
D. V. Jovanovic, J. A. Di Battista, J. Martel-Pelletier et al., “IL-17 stimulates the production and expression of proinflammatory cytokines, IL-β and TNF-α, by human macrophages,” Journal of Immunology, vol. 160, no. 7, pp. 3513–3521, 1998.
[128]
Z. Yao, S. L. Painter, W. C. Fanslow et al., “Human IL-17: a novel cytokine derived from T cells,” Journal of Immunology, vol. 155, no. 12, pp. 5483–5486, 1995.
[129]
M. Laan, Z.-H. Cui, H. Hoshino et al., “Neutrophil recruitment by human IL-17 via C-X-C chemokine release in the airways,” Journal of Immunology, vol. 162, no. 4, pp. 2347–2352, 1999.
[130]
F. Fossiez, O. Djossou, P. Chomarat et al., “T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines,” Journal of Experimental Medicine, vol. 183, no. 6, pp. 2593–2603, 1996.
[131]
A. J. Fleetwood, A. D. Cook, and J. A. Hamilton, “Functions of granulocyte-macrophage colony-stimulating factor,” Critical Reviews in Immunology, vol. 25, no. 5, pp. 405–428, 2005.
[132]
E. Ricciotti and G. A. FitzGerald, “Prostaglandins and inflammation,” Arteriosclerosis, Thrombosis and Vascular Biologyl, vol. 31, no. 5, pp. 986–1000, 2011.
[133]
A. F. Sheibanie, I. Tadmori, H. Jing, E. Vassiliou, and D. Ganea, “Prostaglandin E2 induces IL-23 production in bone marrow-derived dendritic cells,” FASEB Journal, vol. 18, no. 11, pp. 1318–1320, 2004.
[134]
K. Boniface, K. S. Bak-Jensen, Y. Li et al., “Prostaglandin E2 regulates Th17 cell differentiation and function through cyclic AMP and EP2/EP4 receptor signaling,” Journal of Experimental Medicine, vol. 206, no. 3, pp. 535–548, 2009.
[135]
C. Chizzolini, R. Chicheportiche, M. Alvarez et al., “Prostaglandin E2 synergistically with interleukin-23 favors human Th17 expansion,” Blood, vol. 112, no. 9, pp. 3696–3703, 2008.
[136]
P. Schwarzenberger, V. la Russa, A. Miller et al., “IL-17 stimulates granulopoiesis in mice: use of an alternate, novel gene therapy-derived method for in vivo evaluation of cytokines,” Journal of Immunology, vol. 161, no. 11, pp. 6383–6389, 1998.
[137]
P. Ye, F. H. Rodriguez, S. Kanaly et al., “Requirement of interleukin 17 receptor signaling for lung CXC chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense,” Journal of Experimental Medicine, vol. 194, no. 4, pp. 519–527, 2001.
[138]
Q. Wu, R. J. Martin, J. G. Rino, R. Breed, R. M. Torres, and H. W. Chu, “IL-23-dependent IL-17 production is essential in neutrophil recruitment and activity in mouse lung defense against respiratory Mycoplasma pneumoniae infection,” Microbes and Infection, vol. 9, no. 1, pp. 78–86, 2007.
[139]
S. C. Higgins, A. G. Jarnicki, E. C. Lavelle, and K. H. G. Mills, “TLR4 mediates vaccine-induced protective cellular immunity to Bordetella pertussis: role of IL-17-producing T cells,” Journal of Immunology, vol. 177, no. 11, pp. 7980–7989, 2006.
[140]
W. Huang, L. Na, P. L. Fidel, and P. Schwarzenberger, “Requirement of interleukin-17A for systemic anti-Candida albicans host defense in mice,” Journal of Infectious Diseases, vol. 190, no. 3, pp. 624–631, 2004.
[141]
H. R. Conti, F. Shen, N. Nayyar et al., “Th17 cells and IL-17 receptor signaling are essential for mucosal host defense against oral candidiasis,” Journal of Experimental Medicine, vol. 206, no. 2, pp. 299–311, 2009.
[142]
A. Puel, S. Cypowyj, J. Bustamante et al., “Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity,” Science, vol. 332, no. 6025, pp. 65–68, 2011.
[143]
X. L. Rudner, K. I. Happel, E. A. Young, and J. E. Shellito, “Interleukin-23 (IL-23)-IL-17 cytokine axis in murine Pneumocystis carinii infection,” Infection and Immunity, vol. 75, no. 6, pp. 3055–3061, 2007.
[144]
Y. Lin, S. Ritchea, A. Logar et al., “Interleukin-17 is required for T helper 1 cell immunity and host resistance to the intracellular pathogen Francisella tularensis,” Immunity, vol. 31, no. 5, pp. 799–810, 2009.
[145]
J. S. Cho, E. M. Pietras, N. C. Garcia et al., “IL-17 is essential for host defense against cutaneous Staphylococcus aureus infection in mice,” Journal of Clinical Investigation, vol. 120, no. 5, pp. 1762–1773, 2010.
[146]
H. Ishigame, S. Kakuta, T. Nagai et al., “Differential roles of interleukin-17A and -17F in host defense against mucoepithelial bacterial infection and allergic responses,” Immunity, vol. 30, no. 1, pp. 108–119, 2009.
[147]
S. M. Schulz, G. K？hler, C. Holscher, Y. Iwakura, and G. Alber, “IL-17A is produced by Th17, γδ T cells and other CD4- lymphocytes during infection with Salmonella enterica serovar Enteritidis and has a mild effect in bacterial clearance,” International Immunology, vol. 20, no. 9, pp. 1129–1138, 2008.
[148]
S. M. Schulz, G. K？hler, N. Schütze et al., “Protective immunity to systemic infection with attenuated Salmonella enterica serovar enteritidis in the absence of IL-12 is associated with IL-23-dependent IL-22, but not IL-17,” Journal of Immunology, vol. 181, no. 11, pp. 7891–7901, 2008.
[149]
S. A. Khader, J. E. Pearl, K. Sakamoto et al., “IL-23 compensates for the absence of IL-12p70 and is essential for the IL-17 response during tuberculosis but is dispensable for protection and antigen-specific IFN-γ responses if IL-12p70 is available,” Journal of Immunology, vol. 175, no. 2, pp. 788–795, 2005.
[150]
M. Wüthrich, B. Gern, C. Y. Hung et al., “Vaccine-induced protection against 3 systemic mycoses endemic to North America requires Th17 cells in mice,” Journal of Clinical Investigation, vol. 121, no. 2, pp. 554–568, 2011.
[151]
M. Wuthrich, V. LeBert, K. Galles et al., “Interleukin 1 enhances vaccine-induced antifungal T-helper 17 cells and resistance against Blastomyces dermatitidis infection,” Journal of Infectious Diseases, vol. 208, no. 7, pp. 1175–1182, 2013.
[152]
C. Lock, G. Hermans, R. Pedotti et al., “Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis,” Nature Medicine, vol. 8, no. 5, pp. 500–508, 2002.
[153]
H. Kebir, K. Kreymborg, I. Ifergan et al., “Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation,” Nature Medicine, vol. 13, no. 10, pp. 1173–1175, 2007.
[154]
J. S. Tzartos, M. A. Friese, M. J. Craner et al., “Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis,” The American Journal of Pathology, vol. 172, no. 1, pp. 146–155, 2008.
[155]
D. Matusevicius, P. Kivis？kk, B. He et al., “Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis,” Multiple Sclerosis, vol. 5, no. 2, pp. 101–104, 1999.
[156]
D. C. Fitzgerald, Z. Fonseca-Kelly, M. L. Cullimore et al., “Independent and interdependent immunoregulatory effects of IL-27, IFN-beta, and IL-10 in the suppression of human Th17 cells and murine experimental autoimmune encephalomyelitis,” Journal of Immunology, vol. 190, no. 7, pp. 3225–3234, 2013.
[157]
H. K. Kwon, G. C. Kim, Y. Kim et al., “Amelioration of experimental autoimmune encephalomyelitis by probiotic mixture is mediated by a shift in T helper cell immune response,” Clinical Immunology, vol. 146, no. 3, pp. 217–227, 2013.
[158]
K. Berer and G. Krishnamoorthy, “Commensal gut flora and brain autoimmunity: a love or hate affair?” Acta Neuropathologica, vol. 123, no. 5, pp. 639–651, 2012.
[159]
H. Yokote, S. Miyake, J. L. Croxford, S. Oki, H. Mizusawa, and T. Yamamura, “NKT cell-dependent amelioration of a mouse model of multiple sclerosis by altering gut flora,” The American Journal of Pathology, vol. 173, no. 6, pp. 1714–1723, 2008.
[160]
M. A. Lowes, A. M. Bowcock, and J. G. Krueger, “Pathogenesis and therapy of psoriasis,” Nature, vol. 445, no. 7130, pp. 866–873, 2007.
[161]
C. L. Kauffman, N. Aria, E. Toichi et al., “A phase I study evaluating the safety, pharmacokinetics, and clinical response of a human IL-12 p40 antibody in subjects with plaque psoriasis,” Journal of Investigative Dermatology, vol. 123, no. 6, pp. 1037–1044, 2004.
[162]
A. di Cesare, P. di Meglio, and F. O. Nestle, “The IL-23Th17 axis in the immunopathogenesis of psoriasis,” Journal of Investigative Dermatology, vol. 129, no. 6, pp. 1339–1350, 2009.
[163]
E. F. Wagner, H. B. Schonthaler, J. Guinea-Viniegra, and E. Tschachler, “Psoriasis: what we have learned from mouse models,” Nature Reviews Rheumatology, vol. 6, no. 12, pp. 704–714, 2010.
[164]
B. Homey, M. C. Dieu-Nosjean, A. Wiesenborn, et al., “Up-regulation of macrophage inflammatory protein-3 alpha/CCL20 and CC chemokine receptor 6 in psoriasis,” Journal of Immunology, vol. 164, no. 12, pp. 6621–6632, 2000.
[165]
B. J. Lewis, S. Rajpara, A. M. Haggart, H. M. Wilson, R. N. Barker, and A. D. Ormerod, “Predominance of activated, clonally expanded T helper type 17 cells within the CD4+ T cell population in psoriatic lesions,” Clinical and Experimental Immunology, vol. 173, no. 1, pp. 38–46, 2013.
[166]
I. B. McInnes and G. Schett, “The pathogenesis of rheumatoid arthritis,” The New England Journal of Medicine, vol. 365, no. 23, pp. 2205–2219, 2011.
[167]
S. Kotake, N. Udagawa, N. Takahashi et al., “IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis,” Journal of Clinical Investigation, vol. 103, no. 9, pp. 1345–1352, 1999.
[168]
J. Lee, J. Lee, M. K. Park, et al., “Interferon gamma suppresses collagen-induced arthritis by regulation of Th17 through the induction of indoleamine-2, 3-deoxygenase,” PLoS ONE, vol. 8, no. 4, Article ID e60900, 2013.
[169]
A. F. Sheibanie, T. Khayrullina, F. F. Safadi, and D. Ganea, “Prostaglandin E2 exacerbates collagen-induced arthritis in mice through the inflammatory interleukin-23/interleukin-17 axis,” Arthritis and Rheumatism, vol. 56, no. 8, pp. 2608–2619, 2007.
[170]
M. Chabaud, J. M. Durand, N. Buchs et al., “Human interleukin-17: a T cell-derived proinflammatory cytokine produced by the rheumatoid synovium,” Arthritis and Rheumatism, vol. 42, no. 5, pp. 963–970, 1999.
[171]
M. C. Honorati, R. Meliconi, L. Pulsatelli, S. Canè, L. Frizziero, and A. Facchini, “High in vivo expression of interleukin-17 receptor in synovial endothelial cells and chondrocytes from arthritis patients,” Rheumatology, vol. 40, no. 5, pp. 522–527, 2001.
[172]
M. G. Attur, R. N. Patel, S. B. Abramson, and A. R. Amin, “Interleukin-17 up-regulation of nitric oxide production in human osteoarthritis cartilage,” Arthritis and Rheumatism, vol. 40, no. 6, pp. 1050–1053, 1997.
[173]
M. F. van den Broek, M. C. J. van Bruggen, J. P. Koopman, M. P. Hazenberg, and W. B. van den Berg, “Gut flora induces and maintains resistance against streptococcal cell wall-induced arthritis in F344 rats,” Clinical and Experimental Immunology, vol. 88, no. 2, pp. 313–317, 1992.
[174]
H. C. Rath, H. H. Herfarth, J. S. Ikeda et al., “Normal luminal bacteria, especially bacteroides species, mediate chronic colitis, gastritis, and arthritis in HLA-B27/human β2 microglobulin transgenic rats,” Journal of Clinical Investigation, vol. 98, no. 4, pp. 945–953, 1996.
[175]
J. D. Taurog, J. A. Richardson, J. T. Croft et al., “The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats,” Journal of Experimental Medicine, vol. 180, no. 6, pp. 2359–2364, 1994.
[176]
H.-J. Wu, I. I. Ivanov, J. Darce et al., “Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells,” Immunity, vol. 32, no. 6, pp. 815–827, 2010.
[177]
D. K. Podolsky, “Inflammatory bowel disease,” The New England Journal of Medicine, vol. 347, no. 6, pp. 417–429, 2002.
[178]
P. J. Mannon, I. J. Fuss, L. Mayer et al., “Anti-interleukin-12 antibody for active Crohn's disease,” The New England Journal of Medicine, vol. 351, no. 20, pp. 2069–2079, 2004.
[179]
Z. Zhang, M. Zheng, J. Bindas, P. Schwarzenberger, and J. K. Kolls, “Critical role of IL-17 receptor signaling in acute TNBS-induced colitis,” Inflammatory Bowel Diseases, vol. 12, no. 5, pp. 382–388, 2006.
[180]
J. Mudter, J. Yu, C. Zufferey et al., “IRF4 regulates IL-17A promoter activity and controls RORγt-dependent Th17 colitis in vivo,” Inflammatory Bowel Diseases, vol. 17, no. 6, pp. 1343–1358, 2011.
[181]
D. Yen, J. Cheung, H. Scheerens et al., “IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6,” Journal of Clinical Investigation, vol. 116, no. 5, pp. 1310–1316, 2006.
[182]
A. F. Sheibanie, J.-H. Yen, T. Khayrullina et al., “The proinflammatory effect of prostaglandin E2 in experimental inflammatory bowel disease is mediated through the IL-23→IL-17 axis,” Journal of Immunology, vol. 178, no. 12, pp. 8138–8147, 2007.
[183]
R. Atreya, J. Mudter, S. Finotto et al., “Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: evidence in Crohn disease and experimental colitis in vivo,” Nature Medicine, vol. 6, pp. 583–588, 2010.
[184]
H. Ito, M. Takazoe, Y. Fukuda et al., “A pilot randomized trial of a human anti-interleukin-6 receptor monoclonal antibody in active Crohn's disease,” Gastroenterology, vol. 126, no. 4, pp. 989–996, 2004.
[185]
R. H. Duerr, K. D. Taylor, S. R. Brant et al., “A genome-wide association study identifies IL23R as an inflammatory bowel disease gene,” Science, vol. 314, no. 5804, pp. 1461–1463, 2006.
[186]
A. Y. Lee, R. Eri, A. B. Lyons, M. C. Grimm, and H. Korner, “CC chemokine ligand 20 and its cognate receptor CCR6 in mucosal T cell immunology and inflammatory bowel disease: odd couple or axis of evil?” Frontiers in Immunology, vol. 4, article 194, 2013.
[187]
S. Fujino, A. Andoh, S. Bamba et al., “Increased expression of interleukin 17 in inflammatory bowel disease,” Gut, vol. 52, no. 1, pp. 65–70, 2003.
[188]
V. Holtta, P. Klemetti, T. Sipponen, et al., “IL-23/IL-17 immunity as a hallmark of Crohn's disease,” Inflammatory Bowel Diseases, vol. 14, no. 9, pp. 1175–1184, 2008.
[189]
H. Rafa, H. Saoula, M. Belkhelfa et al., “IL-23/IL-17A axis correlates with the nitric oxide pathway in inflammatory bowel disease: immunomodulatory effect of retinoic acid,” Journal of Interferon and Cytokine Research, vol. 33, no. 7, pp. 355–368, 2013.
[190]
D. N. Frank, A. L. St. Amand, R. A. Feldman, E. C. Boedeker, N. Harpaz, and N. R. Pace, “Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 34, pp. 13780–13785, 2007.
[191]
J. Dicksved, J. Halfvarson, M. Rosenquist et al., “Molecular analysis of the gut microbiota of identical twins with Crohn's disease,” ISME Journal, vol. 2, no. 7, pp. 716–727, 2008.
[192]
B. Willing, J. Halfvarson, J. Dicksved et al., “Twin studies reveal specific imbalances in the mucosa-associated microbiota of patients with ileal Crohn's disease,” Inflammatory Bowel Diseases, vol. 15, no. 5, pp. 653–660, 2009.
[193]
D. N. Frank, C. E. Robertson, C. M. Hamm et al., “Disease phenotype and genotype are associated with shifts in intestinal-associated microbiota in inflammatory bowel diseases,” Inflammatory Bowel Diseases, vol. 17, no. 1, pp. 179–184, 2011.
[194]
K. Ohl and K. Tenbrock, “Inflammatory cytokines in systemic lupus erythematosus,” Journal of Biomedicine and Biotechnology, vol. 2011, Article ID 432595, 14 pages, 2011.
[195]
A. Alunno, E. Bartoloni, O. Bistoni, et al., “Balance between regulatory T and Th17 cells in systemic lupus erythematosus: the old and the new,” Clinical and Developmental Immunology, vol. 2012, Article ID 823085, 5 pages, 2012.
[196]
A. Nalbandian, J. C. Crispín, and G. C. Tsokos, “Interleukin-17 and systemic lupus erythematosus: current concepts,” Clinical and Experimental Immunology, vol. 157, no. 2, pp. 209–215, 2009.
[197]
H.-K. Kang, M. Liu, and S. K. Datta, “Low-dose peptide tolerance therapy of lupus generates plasmacytoid dendritic cells that cause expansion of autoantigen-specific regulatory T cells and contraction of inflammatory Th17 cells,” Journal of Immunology, vol. 178, no. 12, pp. 7849–7858, 2007.
[198]
N. Shinsuke and I. Hiroshi, “Overexpression of Epstein-Barr virus-induced gene 3 protein (EBI3) in MRL/lpr mice suppresses their lupus nephritis by activating regulatory T cells,” Autoimmunity, vol. 46, no. 7, pp. 446–454, 2013.
[199]
J. H. Fransen, J. V. D. Vlag, J. Ruben, G. J. Adema, J. H. Berden, and L. B. Hilbrands, “The role of dendritic cells in the pathogenesis of systemic lupus erythematosus,” Arthritis Research and Therapy, vol. 12, no. 2, article 207, 2010.
[200]
D. Y. Chen, Y. M. Chen, M. C. Wen, T. Y. Hsieh, W. T. Hung, and J. L. Lan, “The potential role of Th17 cells and Th17-related cytokines in the pathogenesis of nephritis,” Lupus, vol. 21, no. 13, pp. 1385–1396, 2012.
[201]
C. K. Wong, L. C. W. Lit, L. S. Tam, E. K. M. Li, P. T. Y. Wong, and C. W. K. Lam, “Hyperproduction of IL-23 and IL-17 in patients with systemic lupus erythematosus: implications for Th17-mediated inflammation in auto-immunity,” Clinical Immunology, vol. 127, no. 3, pp. 385–393, 2008.
[202]
W. Kleczynska, B. Jakiela, H. Plutecka, M. Milewski, M. Sanak, and J. Musial, “Imbalance between Th17 and regulatory T-cells in systemic lupus erythematosus,” Folia Histochemica et Cytobiologica, vol. 49, no. 4, pp. 646–653, 2011.
[203]
J. C. da Silva, H. A. Mariz, L. F. da Rocha Jr. et al., “Hydroxychloroquine decreases Th17-related cytokines in systemic lupus erythematosus and rheumatoid arthritis patients,” Clinics, vol. 68, no. 6, pp. 766–771, 2013.
[204]
L. Cosmi, F. Liotta, E. Maggi, S. Romagnani, and F. Annunziato, “Th17 cells: new players in asthma pathogenesis,” Allergy, vol. 66, no. 8, pp. 989–998, 2011.
[205]
H. Nakajima and K. Hirose, “Role of IL-23 and Th17 cells in airway inflammation in asthma,” Immune Network, vol. 10, no. 1, pp. 1–4, 2010.
[206]
P. W. Hellings, A. Kasran, Z. Liu et al., “Interleukin-17 orchestrates the granulocyte influx into airways after allergen inhalation in a mouse model of allergic asthma,” The American Journal of Respiratory Cell and Molecular Biology, vol. 28, no. 1, pp. 42–50, 2003.
[207]
N. Oda, P. B. Canelos, D. M. Essayan, B. A. Plunkett, A. C. Myers, and S.-K. Huang, “Interleukin-17F induces pulmonary neutrophilia and amplifies antigen-induced allergic response,” The American Journal of Respiratory and Critical Care Medicine, vol. 171, no. 1, pp. 12–18, 2005.
[208]
L. McKinley, J. F. Alcorn, A. Peterson et al., “TH17 cells mediate steroid-resistant airway inflammation and airway hyperresponsiveness in mice,” Journal of Immunology, vol. 181, no. 6, pp. 4089–4097, 2008.
[209]
T. Kobayashi, K. Iijima, J. L. Checkel, and H. Kita, “Interleukin-1-family cytokines drive T helper 2 and 17 cells to innocuous airborne antigens,” The American Journal of Respiratory Cell and Molecular Biology, vol. 49, no. 6, pp. 989–998, 2013.
[210]
C. Doe, M. Bafadhel, S. Siddiqui et al., “Expression of the T helper 17-associated cytokines IL-17A and IL-17F in asthma and COPD,” Chest, vol. 138, no. 5, pp. 1140–1147, 2010.
[211]
K. Li, Z. Wang, Y. Cao et al., “The study of the ratio and distribution of Th17 cells and Tc17 cells in asthmatic patients and the mouse model,” Asian Pacific Journal of Allergy and Immunology, vol. 31, no. 2, pp. 125–131, 2013.
[212]
S. Molet, Q. Hamid, F. Davoine et al., “IL-17 is increased in asthmatic airways and induces human bronchial fibroblasts to produce cytokines,” Journal of Allergy and Clinical Immunology, vol. 108, no. 3, pp. 430–438, 2001.
[213]
E. B. Brandt, M. B. Kovacic, G. B. Lee et al., “Diesel exhaust particle induction of IL-17A contributes to severe asthma,” Journal of Allergy and Clinical Immunology, vol. 132, no. 5, pp. 1194.e2–1204.e2, 2013.
[214]
S. L. Russell, M. J. Gold, M. Hartmann et al., “Early life antibiotic-driven changes in microbiota enhance susceptibility to allergic asthma,” EMBO Reports, vol. 13, no. 5, pp. 440–447, 2012.
[215]
“Type 1 Diabetes Fact Sheet,” Juvenile Diabetes Research Foundation International, 2013, http://jdrf.org/about-jdrf/fact-sheets/type-1-diabetes-facts/.
[216]
S. Shao, F. He, Y. Yang, G. Yuan, M. Zhang, and X. Yu, “Th17 cells in type 1 diabetes,” Cellular Immunology, vol. 280, no. 1, pp. 16–21, 2012.
[217]
B. L. Wajchenberg, “β-cell failure in diabetes and preservation by clinical treatment,” Endocrine Reviews, vol. 28, no. 2, pp. 187–218, 2007.
[218]
J. E. Smith-Garvin, G. A. Koretzky, and M. S. Jordan, “T cell activation,” Annual Review of Immunology, vol. 27, pp. 591–619, 2009.
[219]
E. Sebzda, V. A. Wallace, J. Mayer, R. S. M. Yeung, T. W. Mak, and P. S. Ohashi, “Positive and negative thymocyte selection induced by different concentrations of a single peptide,” Science, vol. 263, no. 5153, pp. 1615–1618, 1994.
[220]
P. H？glund, J. Mintern, C. Waltzinger, W. Heath, C. Benoist, and D. Mathis, “Initiation of autoimmune diabetes by developmentally regulated presentation of islet cell antigens in the pancreatic lymph nodes,” Journal of Experimental Medicine, vol. 189, no. 2, pp. 331–339, 1999.
[221]
Y. Zhang, B. O'Brien, J. Trudeau, R. Tan, P. Santamaria, and J. P. Dutz, “In situ β cell death promotes priming of diabetogenic CD8 T lymphocytes,” Journal of Immunology, vol. 168, no. 3, pp. 1466–1472, 2002.
[222]
M.-C. Gagnerault, J. J. Luan, C. Lotton, and F. Lepault, “Pancreatic lymph nodes are required for priming of β cell reactive T cells in NOD mice,” Journal of Experimental Medicine, vol. 196, no. 3, pp. 369–377, 2002.
[223]
D. Zipris, “Epidemiology of type 1 diabetes and what animal models teach us about the role of viruses in disease mechanisms,” Clinical Immunology, vol. 131, no. 1, pp. 11–23, 2009.
[224]
K. A. Metcalfe, G. A. Hitman, R. E. Rowe et al., “Concordance for Type 1 diabetes in identical twins is affected by insulin genotype,” Diabetes Care, vol. 24, no. 5, pp. 838–842, 2001.
[225]
M. J. Redondo, L. Yu, M. Hawa et al., “Heterogeneity of Type I diabetes: analysis of monozygotic twins in Great Britain and the United States,” Diabetologia, vol. 44, no. 3, pp. 354–362, 2001.
[226]
V. Hyttinen, J. Kaprio, L. Kinnunen, M. Koskenvuo, and J. Tuomilehto, “Genetic liability of type 1 diabetes and the onset age among 22, 650 young Finnish twin pairs: a nationwide follow-up study,” Diabetes, vol. 52, no. 4, pp. 1052–1055, 2003.
[227]
R. E. Ley, D. A. Peterson, and J. I. Gordon, “Ecological and evolutionary forces shaping microbial diversity in the human intestine,” Cell, vol. 124, no. 4, pp. 837–848, 2006.
[228]
J. Chow and S. K. Mazmanian, “Getting the bugs out of the immune system: do bacterial microbiota “Fix” intestinal T cell responses?” Cell Host and Microbe, vol. 5, no. 1, pp. 8–12, 2009.
[229]
O. Vaarala, M. A. Atkinson, and J. Neu, “The “perfect storm” for type 1 diabetes: the complex interplay between intestinal microbiota, gut permeability, and mucosal immunity,” Diabetes, vol. 57, no. 10, pp. 2555–2562, 2008.
[230]
C. Alam, E. Bittoun, D. Bhagwat et al., “Effects of a germ-free environment on gut immune regulation and diabetes progression in non-obese diabetic (NOD) mice,” Diabetologia, vol. 54, no. 6, pp. 1398–1406, 2011.
[231]
S. Brugman, F. A. Klatter, J. T. J. Visser et al., “Antibiotic treatment partially protects against type 1 diabetes in the Bio-Breeding diabetes-prone rat: is the gut flora involved in the development of type 1 diabetes?” Diabetologia, vol. 49, no. 9, pp. 2105–2108, 2006.
[232]
C. T. Brown, A. G. Davis-Richardson, A. Giongo et al., “Gut microbiome metagenomics analysis suggests a functional model for the development of autoimmunity for type 1 diabetes,” PLoS ONE, vol. 6, no. 10, Article ID e25792, 2011.
[233]
M. C. de Goffau, K. Luopajarvi, M. Knip, et al., “Fecal microbiota composition differs between children with beta-cell autoimmunity and those without,” Diabetes, vol. 62, no. 4, pp. 1238–1244, 2013.
[234]
E. Badami, C. Sorini, M. Coccia et al., “Defective differentiation of regulatory FoxP3+ T cells by small-intestinal dendritic cells in patients with type 1 diabetes,” Diabetes, vol. 60, no. 8, pp. 2120–2124, 2011.
[235]
K. I. Happel, P. J. Dubin, M. Zheng et al., “Divergent roles of IL-23 and IL-12 in host defense against Klebsiella pneumoniae,” Journal of Experimental Medicine, vol. 202, no. 6, pp. 761–769, 2005.
[236]
J. G. Markle, D. N. Frank, S. Mortin-Toth, et al., “Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity,” Science, vol. 339, no. 6123, pp. 1084–1088, 2013.
[237]
L. F. Roesch, G. L. Lorca, G. Casella et al., “Culture-independent identification of gut bacteria correlated with the onset of diabetes in a rat model,” ISME Journal, vol. 3, no. 5, pp. 536–548, 2009.
[238]
R. Valladares, D. Sankar, N. Li et al., “Lactobacillus johnsonii N6.2 mitigates the development of type 1 diabetes in BB-DP rats,” PLoS ONE, vol. 5, no. 5, Article ID e10507, 2010.
[239]
K. Lau, P. Benitez, A. Ardissone et al., “Inhibition of type 1 diabetes correlated to a Lactobacillus johnsonii N6.2-mediated Th17 bias,” Journal of Immunology, vol. 186, no. 6, pp. 3538–3546, 2011.
[240]
M. A. Kriegel, E. Sefik, J. A. Hill, H.-J. Wu, C. Benoist, and D. Mathis, “Naturally transmitted segmented filamentous bacteria segregate with diabetes protection in nonobese diabetic mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 28, pp. 11548–11553, 2011.
[241]
I. I. Ivanov, R. D. L. Frutos, N. Manel et al., “Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine,” Cell Host and Microbe, vol. 4, no. 4, pp. 337–349, 2008.
[242]
S. L. Russell, M. J. Gold, B. P. Willing, L. Thorson, K. M. McNagny, and B. B. Finlay, “Perinatal antibiotic treatment affects murine microbiota, immune responses and allergic asthma,” Gut Microbes, vol. 4, no. 2, pp. 158–164, 2013.
