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Interplay of Pathogenic TH1/TH17 Cells and Regulatory T Cells in Auto-immune Disease: A Tale of Yin and Yang

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TH17 Cells in Health and Disease

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Abstract

The propagation and regulation of an immune response is driven by effector and regulatory T cells in a network and fashion resembling the “yin” and “yang” concept in the traditional Chinese philosophy. The shift of the balance between “yin” and “yang” determines the direction of the response towards inflammation or its resolution. In auto-immune disease, the break of tolerance to self-antigens leads to differentiation and propagation of auto-reactive effector T cells and the restoration of the balance is a logical approach to effective treatments. In this review, we describe the characteristics and development of pathogenic TH1 and TH17 cells and Treg cells which regulate them in auto-immune disease. The emphasis is given to the crucial roles of cytokines in influencing lineage differentiation and function as well as interactions of these T cell subsets. We discuss current immuno-therapeutic strategies involving cytokine or cytokine receptor antibodies for the treatment of auto-immune diseases and the potential of traditional Chinese medicine in restoring the balance of “Yin” and “Yang” in a disease setting.

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References

  • Acosta-Rodriguez, E. V., G. Napolitani, et al. (2007a). “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 8(9): 942–9.

    PubMed  CAS  Google Scholar 

  • Acosta-Rodriguez, E. V., L. Rivino, et al. (2007b). “Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells.” Nat Immunol 8(6): 639–46.

    PubMed  CAS  Google Scholar 

  • Afzali, B., G. Lombardi, et al. (2007). “The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and auto-immune disease.” Clin Exp Immunol 148(1): 32–46.

    PubMed  CAS  Google Scholar 

  • Aggarwal, S., N. Ghilardi, et al. (2003). “Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17.” J Biol Chem 278(3): 1910–4.

    PubMed  CAS  Google Scholar 

  • Amadi-Obi, A., C. R. Yu, et al. (2007). “TH17 cells contribute to uveitis and scleritis and are expanded by IL-2 and inhibited by IL-27/STAT1.” Nat Med 13(6): 711–8.

    PubMed  CAS  Google Scholar 

  • Anderton, S. M. (2006). “Avoiding auto-immune disease--T cells know their limits.” Trends Immunol 27(5): 208–14.

    PubMed  CAS  Google Scholar 

  • Asseman, C., S. Mauze, et al. (1999). “An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation.” J Exp Med 190(7): 995–1004.

    PubMed  CAS  Google Scholar 

  • Bayer, A. L., J. Y. Lee, et al. (2008). “A function for IL-7R for CD4+CD25+Foxp3+ T regulatory cells.” J Immunol 181(1): 225–34.

    PubMed  CAS  Google Scholar 

  • Bayer, A. L., A. Yu, et al. (2005). “Essential role for interleukin-2 for CD4(+)CD25(+) T regulatory cell development during the neonatal period.” J Exp Med 201(5): 769–77.

    PubMed  CAS  Google Scholar 

  • Bennett, C. L., J. Christie, et al. (2001). “The immune dysregulation, polyendocrinopathy, entero-pathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3.” Nat Genet 27(1): 20–1.

    PubMed  CAS  Google Scholar 

  • Bensinger, S. J., A. Bandeira, et al. (2001). “Major histocompatibility complex class II-positive cortical epithelium mediates the selection of CD4(+)25(+) immuno-regulatory T cells.” J Exp Med 194(4): 427–38.

    PubMed  CAS  Google Scholar 

  • Benson, M. J., K. Pino-Lagos, et al. (2007). “All-trans retinoic acid mediates enhanced T reg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation.” J Exp Med 204(8): 1765–74.

    PubMed  CAS  Google Scholar 

  • Bettelli, E., Y. Carrier, et al. (2006). “Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells.” Nature 441(7090): 235–8.

    PubMed  CAS  Google Scholar 

  • Bielekova, B., B. Goodwin, et al. (2000). “Encephalitogenic potential of the myelin basic protein peptide (amino acids 83–99) in multiple sclerosis: results of a phase II clinical trial with an altered peptide ligand.” Nat Med 6(10): 1167–75.

    PubMed  CAS  Google Scholar 

  • Bielekova, B., T. Howard, et al. (2009). “Effect of anti-CD25 antibody daclizumab in the inhibition of inflammation and stabilization of disease progression in multiple sclerosis.” Arch Neurol 66(4): 483–9.

    PubMed  Google Scholar 

  • Bielekova, B., P. A. Muraro, et al. (1999). “Preferential expansion of auto-reactive T lymphocytes from the memory T-cell pool by IL-7.” J Neuroimmunol 100(1–2): 115–23.

    PubMed  CAS  Google Scholar 

  • Billiau, A., H. Heremans, et al. (1988). “Enhancement of experimental allergic encephalomyelitis in mice by antibodies against IFN-gamma.” J Immunol 140(5): 1506–10.

    PubMed  CAS  Google Scholar 

  • Billich, A. (2007). “Drug evaluation: apilimod, an oral IL-12/IL-23 inhibitor for the treatment of auto-immune diseases and common variable immuno-deficiency.” IDrugs 10(1): 53–9.

    PubMed  CAS  Google Scholar 

  • Borsellino, G., M. Kleinewietfeld, et al. (2007). “Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression.” Blood 110(4): 1225–32.

    PubMed  CAS  Google Scholar 

  • Brunkow, M. E., E. W. Jeffery, et al. (2001). “Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse.” Nat Genet 27(1): 68–73.

    PubMed  CAS  Google Scholar 

  • Burchill, M. A., J. Yang, et al. (2007). “IL-2 receptor beta-dependent STAT5 activation is required for the development of Foxp3+ regulatory T cells.” J Immunol 178(1): 280–90.

    PubMed  CAS  Google Scholar 

  • Burkhart, C., G. Y. Liu, et al. (1999). “Peptide-induced T cell regulation of experimental auto-immune encephalomyelitis: a role for IL-10.” Int Immunol 11(10): 1625–34.

    PubMed  CAS  Google Scholar 

  • Burmester, G. R., X. Mariette, et al. (2007). “Adalimumab alone and in combination with disease-modifying anti-rheumatic drugs for the treatment of rheumatoid arthritis in clinical practice: the Research in Active Rheumatoid Arthritis (ReAct) trial.” Ann Rheum Dis 66(6): 732–9.

    PubMed  CAS  Google Scholar 

  • Cao, D., V. Malmstrom, et al. (2003). “Isolation and functional characterization of regulatory CD25brightCD4+ T cells from the target organ of patients with rheumatoid arthritis.” Eur J Immunol 33(1): 215–23.

    PubMed  CAS  Google Scholar 

  • Cao, D., R. van Vollenhoven, et al. (2004). “CD25brightCD4+ regulatory T cells are enriched in inflamed joints of patients with chronic rheumatic disease.” Arthritis Res Ther 6(4): R335–46.

    PubMed  CAS  Google Scholar 

  • Chabaud, M., J. M. Durand, et al. (1999). “Human interleukin-17: A T cell-derived pro-inflammatory cytokine produced by the rheumatoid synovium.” Arthritis Rheum 42(5): 963–70.

    PubMed  CAS  Google Scholar 

  • Chatila, T. A., F. Blaeser, et al. (2000). “JM2, encoding a fork head-related protein, is mutated in X-linked auto-immunity-allergic dysregulation syndrome.” J Clin Invest 106(12): R75–81.

    PubMed  CAS  Google Scholar 

  • Chen, W., W. Jin, et al. (2003). “Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3.” J Exp Med 198(12): 1875–86.

    PubMed  CAS  Google Scholar 

  • Chen, X., L. Fang, et al. (2009). “Thymic regulation of auto-immune disease by accelerated differentiation of Foxp3+ regulatory T cells through IL-7 signaling pathway.” J Immunol 183(10): 6135–44.

    PubMed  CAS  Google Scholar 

  • Chen, Y., C. L. Langrish, et al. (2006). “Anti-IL-23 therapy inhibits multiple inflammatory pathways and ameliorates auto-immune encephalomyelitis.” J Clin Invest 116(5): 1317–26.

    PubMed  CAS  Google Scholar 

  • Cho, M. L., J. W. Kang, et al. (2006). “STAT3 and NF-kappaB signal pathway is required for IL-23-mediated IL-17 production in spontaneous arthritis animal model IL-1 receptor antag-onist-deficient mice.” J Immunol 176(9): 5652–61.

    PubMed  CAS  Google Scholar 

  • Coffman, R. L. (2006). “Origins of the T(H)1-T(H)2 model: a personal perspective.” Nat Immunol 7(6): 539–41.

    PubMed  CAS  Google Scholar 

  • Collison, L. W., C. J. Workman, et al. (2007). “The inhibitory cytokine IL-35 contributes to regulatory T-cell function.” Nature 450(7169): 566–9.

    PubMed  CAS  Google Scholar 

  • Coombes, J. L., K. R. Siddiqui, et al. (2007). “A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism.” J Exp Med 204(8): 1757–64.

    PubMed  CAS  Google Scholar 

  • Corthay, A. (2009). “How do regulatory T cells work?” Scand J Immunol 70(4): 326–36.

    PubMed  CAS  Google Scholar 

  • Costantino, C. M., C. Baecher-Allan, et al. (2008). “Multiple sclerosis and regulatory T cells.” J Clin Immunol 28(6): 697–706.

    PubMed  Google Scholar 

  • Cua, D. J., J. Sherlock, et al. (2003). “Interleukin-23 rather than interleukin-12 is the critical cytokine for auto-immune inflammation of the brain.” Nature 421(6924): 744–8.

    PubMed  CAS  Google Scholar 

  • Cui, G., X. Qin, et al. (2009). “Berberine differentially modulates the activities of ERK, p38 MAPK, and JNK to suppress Th17 and Th1 T cell differentiation in type 1 diabetic mice.” J Biol Chem 284(41): 28420–9.

    PubMed  CAS  Google Scholar 

  • Curotto de Lafaille, M. A. and J. J. Lafaille (2009). “Natural and adaptive foxp3+ regulatory T cells: more of the same or a division of labor?” Immunity 30(5): 626–35.

    PubMed  CAS  Google Scholar 

  • de Jong, B. A., T. W. Huizinga, et al. (2002). “Production of IL-1beta and IL-1Ra as risk factors for susceptibility and progression of relapse-onset multiple sclerosis.” J Neuroimmunol 126(1–2): 172–9.

    PubMed  Google Scholar 

  • Deaglio, S., K. M. Dwyer, et al. (2007). “Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression.” J Exp Med 204(6): 1257–65.

    PubMed  CAS  Google Scholar 

  • Dhillon, S., K. A. Lyseng-Williamson, et al. (2007). “Etanercept: a review of its use in the management of rheumatoid arthritis.” Drugs 67(8): 1211–41.

    PubMed  CAS  Google Scholar 

  • Ding, C., J. Xu, et al. (2008). “ABT-874, a fully human monoclonal anti-IL-12/IL-23 antibody for the potential treatment of auto-immune diseases.” Curr Opin Investig Drugs 9(5): 515–22.

    PubMed  CAS  Google Scholar 

  • Ehrenstein, M. R., J. G. Evans, et al. (2004). “Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNFalpha therapy.” J Exp Med 200(3): 277–85.

    PubMed  CAS  Google Scholar 

  • Elliott, M., J. Benson, et al. (2009). “Ustekinumab: lessons learned from targeting interleukin-12/23p40 in immune-mediated diseases.” Ann N Y Acad Sci 1182: 97–110.

    PubMed  CAS  Google Scholar 

  • Fantini, M. C., A. Rizzo, et al. (2007). “IL-21 regulates experimental colitis by modulating the balance between Treg and Th17 cells.” Eur J Immunol 37(11): 3155–63.

    PubMed  CAS  Google Scholar 

  • Fletcher, J. M., R. Lonergan, et al. (2009). “CD39+Foxp3+ regulatory T Cells suppress pathogenic Th17 cells and are impaired in multiple sclerosis.” J Immunol 183(11): 7602–10.

    PubMed  CAS  Google Scholar 

  • Fontenot, J. D., M. A. Gavin, et al. (2003). “Foxp3 programs the development and function of CD4+CD25+ regulatory T cells.” Nat Immunol 4(4): 330–6.

    PubMed  CAS  Google Scholar 

  • Fontenot, J. D., J. P. Rasmussen, et al. (2005a). “A function for interleukin 2 in Foxp3-expressing regulatory T cells.” Nat Immunol 6(11): 1142–51.

    PubMed  CAS  Google Scholar 

  • Fontenot, J. D., J. P. Rasmussen, et al. (2005b). “Regulatory T cell lineage specification by the forkhead transcription factor foxp3.” Immunity 22(3): 329–41.

    PubMed  CAS  Google Scholar 

  • Fromont, A., J. De Seze, et al. (2009). “Inflammatory demyelinating events following treatment with anti-tumor necrosis factor.” Cytokine 45(2): 55–7.

    PubMed  CAS  Google Scholar 

  • Garber, K. (2009). “Immunology’s quiet upheaval.” Nat Biotechnol 27(8): 687–9.

    PubMed  CAS  Google Scholar 

  • Garin, M. I., C. C. Chu, et al. (2007). “Galectin-1: a key effector of regulation mediated by CD4+CD25+ T cells.” Blood 109(5): 2058–65.

    PubMed  CAS  Google Scholar 

  • Gatto, B. (2008). “Atacicept, a homodimeric fusion protein for the potential treatment of diseases triggered by plasma cells.” Curr Opin Investig Drugs 9(11): 1216–27.

    PubMed  CAS  Google Scholar 

  • Germann, T., H. Hess, et al. (1996). “Characterization of the adjuvant effect of IL-12 and efficacy of IL-12 inhibitors in type II collagen-induced arthritis.” Ann N Y Acad Sci 795: 227–40.

    PubMed  CAS  Google Scholar 

  • Gondek, D. C., L. F. Lu, et al. (2005). “Cutting edge: contact-mediated suppression by CD4+CD25+ regulatory cells involves a granzyme B-dependent, perforin-independent mechanism.” J Immunol 174(4): 1783–6.

    PubMed  CAS  Google Scholar 

  • Green, E. A., L. Gorelik, et al. (2003). “CD4+CD25+ T regulatory cells control anti-islet CD8+ T cells through TGF-beta-TGF-beta receptor interactions in type 1 diabetes.” Proc Natl Acad Sci USA 100(19): 10878–83.

    PubMed  CAS  Google Scholar 

  • Gregory, S. G., S. Schmidt, et al. (2007). “Interleukin 7 receptor alpha chain (IL7R) shows allelic and functional association with multiple sclerosis.” Nat Genet 39(9): 1083–91.

    PubMed  CAS  Google Scholar 

  • Grossman, W. J., J. W. Verbsky, et al. (2004). “Human T regulatory cells can use the perforin pathway to cause autologous target cell death.” Immunity 21(4): 589–601.

    PubMed  CAS  Google Scholar 

  • Hafler, D. A., A. Compston, et al. (2007). “Risk alleles for multiple sclerosis identified by a genome-wide study.” N Engl J Med 357(9): 851–62.

    PubMed  CAS  Google Scholar 

  • Harrington, L. E., R. D. Hatton, et al. (2005). “Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages.” Nat Immunol 6(11): 1123–32.

    PubMed  CAS  Google Scholar 

  • Hill, J. A., J. A. Hall, et al. (2008). “Retinoic acid enhances Foxp3 induction indirectly by relieving inhibition from CD4+CD44hi Cells.” Immunity 29(5): 758–70.

    PubMed  CAS  Google Scholar 

  • Hori, S., T. Nomura, et al. (2003). “Control of regulatory T cell development by the transcription factor Foxp3.” Science 299(5609): 1057–61.

    PubMed  CAS  Google Scholar 

  • Huter, E. N., G. A. Punkosdy, et al. (2008). “TGF-beta-induced Foxp3+ regulatory T cells rescue scurfy mice.” Eur J Immunol 38(7): 1814–21.

    PubMed  CAS  Google Scholar 

  • Hwang, S. Y., J. Y. Kim, et al. (2004). “IL-17 induces production of IL-6 and IL-8 in rheumatoid arthritis synovial fibroblasts via NF-kappaB- and PI3-kinase/Akt-dependent pathways.” Arthritis Res Ther 6(2): R120–8.

    PubMed  CAS  Google Scholar 

  • Issazadeh, S., M. Mustafa, et al. (1995). “Interferon gamma, interleukin 4 and transforming growth factor beta in experimental auto-immune encephalomyelitis in Lewis rats: dynamics of cellular mRNA expression in the central nervous system and lymphoid cells.” J Neurosci Res 40(5): 579–90.

    PubMed  CAS  Google Scholar 

  • Ivanov, II, B. S. McKenzie, et al. (2006). “The orphan nuclear receptor RORgammat directs the differentiation program of pro-inflammatory IL-17+ T helper cells.” Cell 126(6): 1121–33.

    Google Scholar 

  • Khattri, R., T. Cox, et al. (2003). “An essential role for Scurfin in CD4+CD25+ T regulatory cells.” Nat Immunol 4(4): 337–42.

    PubMed  CAS  Google Scholar 

  • Komiyama, Y., S. Nakae, et al. (2006). “IL-17 plays an important role in the development of experimental auto-immune encephalomyelitis.” J Immunol 177(1): 566–73.

    PubMed  CAS  Google Scholar 

  • Korn, T., E. Bettelli, et al. (2007a). “IL-21 initiates an alternative pathway to induce pro-inflammatory T(H)17 cells.” Nature 448(7152): 484–7.

    PubMed  CAS  Google Scholar 

  • Korn, T., E. Bettelli, et al. (2009). “IL-17 and Th17 Cells.” Annu Rev Immunol 27: 485–517.

    PubMed  CAS  Google Scholar 

  • Korn, T., M. Mitsdoerffer, et al. (2008). “IL-6 controls Th17 immunity in vivo by inhibiting the conversion of conventional T cells into Foxp3+ regulatory T cells.” Proc Natl Acad Sci USA 105(47): 18460–5.

    PubMed  CAS  Google Scholar 

  • Korn, T., J. Reddy, et al. (2007b). “Myelin-specific regulatory T cells accumulate in the CNS but fail to control auto-immune inflammation.” Nat Med 13(4): 423–31.

    PubMed  CAS  Google Scholar 

  • Kroenke, M. A., T. J. Carlson, et al. (2008). “IL-12- and IL-23-modulated T cells induce distinct types of EAE based on histology, CNS chemokine profile, and response to cytokine inhibition.” J Exp Med 205(7): 1535–41.

    PubMed  CAS  Google Scholar 

  • Kumar, M., N. Putzki, et al. (2006). “CD4+CD25+FoxP3+ T lymphocytes fail to suppress myelin basic protein-induced proliferation in patients with multiple sclerosis.” J Neuroimmunol 180(1–2): 178–84.

    PubMed  CAS  Google Scholar 

  • Langrish, C. L., Y. Chen, et al. (2005). “IL-23 drives a pathogenic T cell population that induces auto-immune inflammation.” J Exp Med 201(2): 233–40.

    PubMed  CAS  Google Scholar 

  • Laurence, A., C. M. Tato, et al. (2007). “Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation.” Immunity 26(3): 371–81.

    PubMed  CAS  Google Scholar 

  • Lee, S. K. and C. D. Surh (2005). “Role of interleukin-7 in bone and T-cell homeostasis.” Immunol Rev 208: 169–80.

    PubMed  CAS  Google Scholar 

  • Lindley, S., C. M. Dayan, et al. (2005). “Defective suppressor function in CD4(+)CD25(+) T-cells from patients with type 1 diabetes.” Diabetes 54(1): 92–9.

    PubMed  CAS  Google Scholar 

  • Lio, C. W. and C. S. Hsieh (2008). “A two-step process for thymic regulatory T cell development.” Immunity 28(1): 100–11.

    PubMed  CAS  Google Scholar 

  • Liu, X., Y. S. Lee, et al. (2008). “Loss of STAT3 in CD4+ T cells prevents development of experimental auto-immune diseases.” J Immunol 180(9): 6070–6.

    PubMed  CAS  Google Scholar 

  • Liu, X., S. Leung, et al. (2010). “Crucial role of interleukin-7 in T helper type 17 survival and expansion in auto-immune disease.” Nat Med 16(2): 191–7.

    Google Scholar 

  • Lock, C., G. Hermans, et al. (2002). “Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in auto-immune encephalomyelitis.” Nat Med 8(5): 500–8.

    PubMed  CAS  Google Scholar 

  • Lundmark, F., K. Duvefelt, et al. (2007). “Variation in interleukin 7 receptor alpha chain (IL7R) influences risk of multiple sclerosis.” Nat Genet 39(9): 1108–13.

    PubMed  CAS  Google Scholar 

  • Maini, R. N., F. C. Breedveld, et al. (2004). “Sustained improvement over two years in physical function, structural damage, and signs and symptoms among patients with rheumatoid arthritis treated with infliximab and methotrexate.” Arthritis Rheum 50(4): 1051–65.

    PubMed  CAS  Google Scholar 

  • Manel, N., D. Unutmaz, et al. (2008). “The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat.” Nat Immunol 9(6): 641–9.

    PubMed  CAS  Google Scholar 

  • Mangan, P. R., L. E. Harrington, et al. (2006). “Transforming growth factor-beta induces development of the T(H)17 lineage.” Nature 441(7090): 231–4.

    PubMed  CAS  Google Scholar 

  • Martin, R. (2008). “Humanized anti-CD25 antibody treatment with daclizumab in multiple sclerosis.” Neurodegener Dis 5(1): 23–6.

    PubMed  CAS  Google Scholar 

  • Matusevicius, D., P. Kivisakk, et al. (1999). “Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis.” Mult Scler 5(2): 101–4.

    PubMed  CAS  Google Scholar 

  • Mazzucchelli, R. and S. K. Durum (2007). “Interleukin-7 receptor expression: intelligent design.” Nat Rev Immunol 7(2): 144–54.

    PubMed  CAS  Google Scholar 

  • McFarland, H. F. and R. Martin (2007). “Multiple sclerosis: a complicated picture of autoimmunity.” Nat Immunol 8(9): 913–9.

    PubMed  CAS  Google Scholar 

  • McGeachy, M. J., K. S. Bak-Jensen, et al. (2007). “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 8(12): 1390–7.

    PubMed  CAS  Google Scholar 

  • McGeachy, M. J., Y. Chen, et al. (2009). “The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo.” Nat Immunol 10(3): 314–24.

    PubMed  CAS  Google Scholar 

  • Menter, A. (2009). “The status of biologic therapies in the treatment of moderate to severe psoriasis.” Cutis 84(4 Suppl): 14–24.

    PubMed  Google Scholar 

  • Mircic, M. and A. Kavanaugh (2009). “The clinical efficacy of tocilizumab in rheumatoid arthritis.” Drugs Today (Barc) 45(3): 189–97.

    Google Scholar 

  • Moreland, L. W. (2009). “Cytokines as targets for anti-inflammatory agents.” Ann N Y Acad Sci 1182: 88–96.

    PubMed  CAS  Google Scholar 

  • Mosmann, T. R., H. Cherwinski, et al. (1986). “Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins.” J Immunol 136(7): 2348–57.

    PubMed  CAS  Google Scholar 

  • Mosmann, T. R. and R. L. Coffman (1989). “TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties.” Annu Rev Immunol 7: 145–73.

    PubMed  CAS  Google Scholar 

  • Mottonen, M., J. Heikkinen, et al. (2005). “CD4+ CD25+ T cells with the phenotypic and functional characteristics of regulatory T cells are enriched in the synovial fluid of patients with rheumatoid arthritis.” Clin Exp Immunol 140(2): 360–7.

    PubMed  CAS  Google Scholar 

  • Mucida, D., Y. Park, et al. (2007). “Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid.” Science 317(5835): 256–60.

    PubMed  CAS  Google Scholar 

  • Murphy, C. A., C. L. Langrish, et al. (2003). “Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint auto-immune inflammation.” J Exp Med 198(12): 1951–7.

    PubMed  CAS  Google Scholar 

  • Nadkarni, S., C. Mauri, et al. (2007). “Anti-TNF-alpha therapy induces a distinct regulatory T cell population in patients with rheumatoid arthritis via TGF-beta.” J Exp Med 204(1): 33–9.

    PubMed  CAS  Google Scholar 

  • Nurieva, R., X. O. Yang, et al. (2007). “Essential autocrine regulation by IL-21 in the generation of inflammatory T cells.” Nature 448(7152): 480–3.

    PubMed  CAS  Google Scholar 

  • Oldfield, V., S. Dhillon, et al. (2009). “Tocilizumab: a review of its use in the management of rheumatoid arthritis.” Drugs 69(5): 609–32.

    PubMed  CAS  Google Scholar 

  • Palmer, M. J., V. S. Mahajan, et al. (2008). “Interleukin-7 receptor signaling network: an integrated systems perspective.” Cell Mol Immunol 5(2): 79–89.

    PubMed  CAS  Google Scholar 

  • Papp, K. A., R. G. Langley, et al. (2008). “Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2).” Lancet 371(9625): 1675–84.

    PubMed  CAS  Google Scholar 

  • Park, H., Z. Li, et al. (2005). “A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17.” Nat Immunol 6(11): 1133–41.

    PubMed  CAS  Google Scholar 

  • Peluso, I., M. C. Fantini, et al. (2007). “IL-21 counteracts the regulatory T cell-mediated suppression of human CD4+ T lymphocytes.” J Immunol 178(2): 732–9.

    PubMed  CAS  Google Scholar 

  • Pettinelli, C. B. and D. E. McFarlin (1981). “Adoptive transfer of experimental allergic encephalomyelitis in SJL/J mice after in vitro activation of lymph node cells by myelin basic protein: requirement for Lyt 1+ 2- T lymphocytes.” J Immunol 127(4): 1420–3.

    PubMed  CAS  Google Scholar 

  • Ren, Y., L. Lu, et al. (2008). “Novel immuno-modulatory properties of berbamine through selective down-regulation of STAT4 and action of IFN-gamma in experimental auto-immune encephalomyelitis.” J Immunol 181(2): 1491–8.

    PubMed  CAS  Google Scholar 

  • Rengarajan, J., S. J. Szabo, et al. (2000). “Transcriptional regulation of Th1/Th2 polarization.” Immunol Today 21(10): 479–83.

    PubMed  CAS  Google Scholar 

  • Renno, T., M. Krakowski, et al. (1995). “TNF-alpha expression by resident microglia and infiltrating leukocytes in the central nervous system of mice with experimental allergic encephalomyelitis. Regulation by Th1 cytokines.” J Immunol 154(2): 944–53.

    PubMed  CAS  Google Scholar 

  • Sakaguchi, S. (2004). “Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses.” Annu Rev Immunol 22: 531–62.

    PubMed  CAS  Google Scholar 

  • Sakaguchi, S., N. Sakaguchi, et al. (1995). “Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various auto-immune diseases.” J Immunol 155(3): 1151–64.

    PubMed  CAS  Google Scholar 

  • Salomon, B., D. J. Lenschow, et al. (2000). “B7/CD28 co-stimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control auto-immune diabetes.” Immunity 12(4): 431–40.

    PubMed  CAS  Google Scholar 

  • Sands, B. E., E. W. Jacobson, et al. (2009). “Randomized, double-blind, placebo-controlled trial of the oral interleukin-12/23 inhibitor apilimod mesylate for treatment of active Crohn’s disease.” Inflamm Bowel Dis.

    Google Scholar 

  • Sarkar, S. and D. A. Fox (2007). “Regulatory T cell defects in rheumatoid arthritis.” Arthritis Rheum 56(3): 710–3.

    PubMed  CAS  Google Scholar 

  • Serada, S., M. Fujimoto, et al. (2008). “IL-6 blockade inhibits the induction of myelin antigen-specific Th17 cells and Th1 cells in experimental auto-immune encephalomyelitis.” Proc Natl Acad Sci USA 105(26): 9041–6.

    PubMed  CAS  Google Scholar 

  • Skarica, M., T. Wang, et al. (2009). “Signal transduction inhibition of APCs diminishes th17 and Th1 responses in experimental auto-immune encephalomyelitis.” J Immunol 182(7): 4192–9.

    PubMed  CAS  Google Scholar 

  • Soper, D. M., D. J. Kasprowicz, et al. (2007). “IL-2Rbeta links IL-2R signaling with Foxp3 expression.” Eur J Immunol 37(7): 1817–26.

    PubMed  CAS  Google Scholar 

  • Sospedra, M. and R. Martin (2005). “Immunology of multiple sclerosis.” Annu Rev Immunol 23: 683–747.

    PubMed  CAS  Google Scholar 

  • Sportes, C., F. T. Hakim, et al. (2008). “Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of naive T cell subsets.” J Exp Med 205(7): 1701–14.

    PubMed  CAS  Google Scholar 

  • Steinman, L. (2010). “Mixed results with modulation of TH-17 cells in human auto-immune diseases.” Nat Immunol 11(1): 41–4.

    Google Scholar 

  • Stritesky, G. L., N. Yeh, et al. (2008). “IL-23 promotes maintenance but not commitment to the Th17 lineage.” J Immunol 181(9): 5948–55.

    PubMed  CAS  Google Scholar 

  • Stromnes, I. M., L. M. Cerretti, et al. (2008). “Differential regulation of central nervous system auto-immunity by T(H)1 and T(H)17 cells.” Nat Med 14(3): 337–42.

    PubMed  CAS  Google Scholar 

  • Stubgen, J. P. (2008). “Tumor necrosis factor-alpha antagonists and neuropathy.” Muscle Nerve 37(3): 281–92.

    PubMed  CAS  Google Scholar 

  • Stummvoll, G. H., R. J. DiPaolo, et al. (2008). “Th1, Th2, and Th17 effector T cell-induced auto-immune gastritis differs in pathological pattern and in susceptibility to suppression by regulatory T cells.” J Immunol 181(3): 1908–16.

    PubMed  CAS  Google Scholar 

  • Sun, C. M., J. A. Hall, et al. (2007). “Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid.” J Exp Med 204(8): 1775–85.

    PubMed  CAS  Google Scholar 

  • Suri-Payer, E. and H. Cantor (2001). “Differential cytokine requirements for regulation of auto-immune gastritis and colitis by CD4(+)CD25(+) T cells.” J Auto-immun 16(2): 115–23.

    CAS  Google Scholar 

  • Sutton, C. E., S. J. Lalor, et al. (2009). “Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity.” Immunity 31(2): 331–41.

    PubMed  CAS  Google Scholar 

  • Szabo, S. J., S. T. Kim, et al. (2000). “A novel transcription factor, T-bet, directs Th1 lineage commitment.” Cell 100(6): 655–69.

    PubMed  CAS  Google Scholar 

  • Tai, X., M. Cowan, et al. (2005). “CD28 co-stimulation of developing thymocytes induces Foxp3 expression and regulatory T cell differentiation independently of interleukin 2.” Nat Immunol 6(2): 152–62.

    PubMed  CAS  Google Scholar 

  • Tao, R., E. F. de Zoeten, et al. (2007). “Deacetylase inhibition promotes the generation and function of regulatory T cells.” Nat Med 13(11): 1299–307.

    PubMed  CAS  Google Scholar 

  • Thornton, A. M. and E. M. Shevach (1998). “CD4+CD25+ immuno-regulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production.” J Exp Med 188(2): 287–96.

    PubMed  CAS  Google Scholar 

  • Traggiai, E., T. Biagioli, et al. (2001). “IL-7-enhanced T-cell response to myelin proteins in multiple sclerosis.” J Neuroimmunol 121(1–2): 111–9.

    PubMed  CAS  Google Scholar 

  • Tzartos, J. S., M. A. Friese, et al. (2008). “Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis.” Am J Pathol 172(1): 146–55.

    PubMed  CAS  Google Scholar 

  • Vaknin-Dembinsky, A., G. Murugaiyan, et al. (2008). “Increased IL-23 secretion and altered chemokine production by dendritic cells upon CD46 activation in patients with multiple sclerosis.” J Neuroimmunol 195(1–2): 140–5.

    PubMed  CAS  Google Scholar 

  • Valencia, X., G. Stephens, et al. (2006). “TNF downmodulates the function of human CD4+CD25hi T-regulatory cells.” Blood 108(1): 253–61.

    PubMed  CAS  Google Scholar 

  • van Amelsfort, J. M., K. M. Jacobs, et al. (2004). “CD4(+)CD25(+) regulatory T cells in rheumatoid arthritis: differences in the presence, phenotype, and function between peripheral blood and synovial fluid.” Arthritis Rheum 50(9): 2775–85.

    PubMed  Google Scholar 

  • van den Berg, W. B. and P. Miossec (2009). “IL-17 as a future therapeutic target for rheumatoid arthritis.” Nat Rev Rheumatol 5(10): 549–53.

    PubMed  Google Scholar 

  • Vang, K. B., J. Yang, et al. (2008). “IL-2, -7, and -15, but not thymic stromal lymphopoeitin, redundantly govern CD4+Foxp3+ regulatory T cell development.” J Immunol 181(5): 3285–90.

    PubMed  CAS  Google Scholar 

  • Viglietta, V., C. Baecher-Allan, et al. (2004). “Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis.” J Exp Med 199(7): 971–9.

    PubMed  CAS  Google Scholar 

  • Vudattu, N. K., S. Kuhlmann-Berenzon, et al. (2009). “Increased numbers of IL-7 receptor molecules on CD4+CD25-CD107a+T-cells in patients with auto-immune diseases affecting the central nervous system.” PLoS One 4(8): e6534.

    PubMed  Google Scholar 

  • Wan, Y. Y. and R. A. Flavell (2005). “Identifying Foxp3-expressing suppressor T cells with a bicistronic reporter.” Proc Natl Acad Sci USA 102(14): 5126–31.

    PubMed  CAS  Google Scholar 

  • Wang, Z., J. Qiu, et al. (2007). “Anti-inflammatory properties and regulatory mechanism of a novel derivative of artemisinin in experimental auto-immune encephalomyelitis.” J Immunol 179(9): 5958–65.

    PubMed  CAS  Google Scholar 

  • Waugh, J. and C. M. Perry (2005). “Anakinra: a review of its use in the management of rheumatoid arthritis.” BioDrugs 19(3): 189–202.

    PubMed  CAS  Google Scholar 

  • Weaver, C. T., R. D. Hatton, et al. (2007). “IL-17 family cytokines and the expanding diversity of effector T cell lineages.” Annu Rev Immunol 25: 821–52.

    PubMed  CAS  Google Scholar 

  • Wildin, R. S., F. Ramsdell, et al. (2001). “X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy.” Nat Genet 27(1): 18–20.

    PubMed  CAS  Google Scholar 

  • Wilson, N. J., K. Boniface, et al. (2007). “Development, cytokine profile and function of human interleukin 17-producing helper T cells.” Nat Immunol 8(9): 950–7.

    PubMed  CAS  Google Scholar 

  • Wing, K., Y. Onishi, et al. (2008). “CTLA-4 control over Foxp3+ regulatory T cell function.” Science 322(5899): 271–5.

    PubMed  CAS  Google Scholar 

  • Yang, L., D. E. Anderson, et al. (2008a). “IL-21 and TGF-beta are required for differentiation of human T(H)17 cells.” Nature 454(7202): 350–2.

    PubMed  CAS  Google Scholar 

  • Yang, X. O., R. Nurieva, et al. (2008b). “Molecular antagonism and plasticity of regulatory and inflammatory T cell programs.” Immunity 29(1): 44–56.

    PubMed  CAS  Google Scholar 

  • Yang, X. O., A. D. Panopoulos, et al. (2007). “STAT3 regulates cytokine-mediated generation of inflammatory helper T cells.” J Biol Chem 282(13): 9358–63.

    PubMed  CAS  Google Scholar 

  • Yao, Z., Y. Kanno, et al. (2007). “Non-redundant roles for Stat5a/b in directly regulating Foxp3.” Blood 109(10): 4368–75.

    PubMed  CAS  Google Scholar 

  • Zhang, X., D. N. Koldzic, et al. (2004). “IL-10 is involved in the suppression of experimental auto-immune encephalomyelitis by CD25+CD4+ regulatory T cells.” Int Immunol 16(2): 249–56.

    PubMed  CAS  Google Scholar 

  • Zheng, W. and R. A. Flavell (1997). “The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells.” Cell 89(4): 587–96.

    PubMed  CAS  Google Scholar 

  • Zhou, L., M. M. Chong, et al. (2009). “Plasticity of CD4+ T cell lineage differentiation.” Immunity 30(5): 646–55.

    PubMed  CAS  Google Scholar 

  • Zhou, L., Ivanov, II, et al. (2007). “IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways.” Nat Immunol 8(9): 967–74.

    PubMed  CAS  Google Scholar 

  • Zhou, L., J. E. Lopes, et al. (2008). “TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function.” Nature 453(7192): 236–40.

    PubMed  CAS  Google Scholar 

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  1. Department of Neuroimmunology, GlaxoSmithKline Research and Development Center, 898 Halei Road, Building 3, Zhangjiang Pudong, Shanghai, 201203, China

    Jingwu Zhang

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  1. Xuebin Liu
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  2. Stewart Leung
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  3. Lei Fang
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  4. Xi Chen
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  1. King's College London, Department of Nephrology and Transplanta, Guy's Hospital, London, WC2R 2LS, United Kingdom

    Shuiping Jiang

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Liu, X., Leung, S., Fang, L., Chen, X., Guo, T., Zhang, J. (2011). Interplay of Pathogenic TH1/TH17 Cells and Regulatory T Cells in Auto-immune Disease: A Tale of Yin and Yang. In: Jiang, S. (eds) TH17 Cells in Health and Disease. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-9371-7_19

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