Table of Contents Author Guidelines Submit a Manuscript
Clinical and Developmental Immunology
Volume 2012 (2012), Article ID 925135, 12 pages
http://dx.doi.org/10.1155/2012/925135
Review Article

CD4+T Cells: Differentiation and Functions

1Department of Gastroenterology, Zhongnan Hospital, Wuhan University School of Medicine, Wuhan 430071, China
2Center for Clinical Study of Intestinal Diseases, Zhongnan Hospital, Wuhan University School of Medicine, Wuhan 430071, China
3Key Laboratory of Allergy and Immune-Related Diseases, Wuhan University School of Medicine, Wuhan 430071, China
4Department of Paediatrics, Renmin Hospital, Wuhan University School of Medicine, Wuhan 430071, China
5Clinical Centre of Intestinal and Colorectal diseases, Hubei, Wuhan 430071, China

Received 14 October 2011; Revised 12 December 2011; Accepted 26 December 2011

Academic Editor: Niels Olsen Saraiva Camara

Copyright © 2012 Rishi Vishal Luckheeram et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. L. Klein, M. Hinterberger, G. Wirnsberger, and B. Kyewski, “Antigen presentation in the thymus for positive selection and central tolerance induction,” Nature Reviews Immunology, vol. 9, no. 12, pp. 833–844, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  2. J. Gill, M. Malin, J. Sutherland, D. Gray, G. Hollander, and R. Boyd, “Thymic generation and regeneration,” Immunological Reviews, vol. 195, pp. 28–50, 2003. View at Publisher · View at Google Scholar · View at Scopus
  3. Y. Takahama, “Journey through the thymus: stromal guides for T-cell development and selection,” Nature Reviews Immunology, vol. 6, no. 2, pp. 127–135, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  4. M. A. Daniels, E. Teixeiro, J. Gill et al., “Thymic selection threshold defined by compartmentalization of Ras/MAPK signalling,” Nature, vol. 444, no. 7120, pp. 724–729, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  5. M. G. Rudolph, R. L. Stanfield, and I. A. Wilson, “How TCRs bind MHCs, peptides, and coreceptors,” Annual Review of Immunology, vol. 24, pp. 419–466, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  6. T. K. Starr, S. C. Jameson, and K. A. Hogquist, “Positive and negative selection of T cells,” Annual Review of Immunology, vol. 21, pp. 139–176, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  7. J. P. Cabaniols, N. Fazilleau, A. Casrouge, P. Kourilsky, and J. M. Kanellopoulos, “Most α/β T cell receptor diversity is due to terminal deoxynucleotidyl transferase,” Journal of Experimental Medicine, vol. 194, no. 9, pp. 1385–1390, 2001. View at Publisher · View at Google Scholar · View at Scopus
  8. E. P. Rock, P. R. Sibbald, M. M. Davis, and Y. H. Chien, “CDR3 length in antigen-specific immune receptors,” Journal of Experimental Medicine, vol. 179, no. 1, pp. 323–328, 1994. View at Publisher · View at Google Scholar · View at Scopus
  9. E. Treiner and O. Lantz, “CD1d- and MR1-restricted invariant T cells: of mice and men,” Current Opinion in Immunology, vol. 18, no. 5, pp. 519–526, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  10. D. L. Drayton, S. Liao, R. H. Mounzer, and N. H. Ruddle, “Lymphoid organ development: from ontogeny to neogenesis,” Nature Immunology, vol. 7, no. 4, pp. 344–353, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  11. S. Ashkar, G. F. Weber, V. Panoutsakopoulou et al., “Eta-1 (osteopontin): an early component of type-1 (cell-mediated) immunity,” Science, vol. 287, no. 5454, pp. 860–864, 2000. View at Publisher · View at Google Scholar
  12. X. Tao, S. Constant, P. Jorritsma, and K. Bottomly, “Strength of TCR Signal Determines the Costimulatory Requirements for Th1 and Th2 CD4+ T Cell Differentiation,” Journal of Immunology, vol. 159, no. 12, pp. 5956–5963, 1997. View at Google Scholar · View at Scopus
  13. M. K. Jenkins, A. Khoruts, E. Ingulli et al., “In vivo activation of antigen-specific CD4 T cells,” Annual Review of Immunology, vol. 19, pp. 23–45, 2001. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  14. R. M. Steinman, D. Hawiger, and M. C. Nussenzweig, “Tolerogenic dendritic cells,” Annual Review of Immunology, vol. 21, pp. 685–711, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  15. A. Iwasaki and R. Medzhitov, “Toll-like receptor control of the adaptive immune responses,” Nature Immunology, vol. 5, no. 10, pp. 987–995, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  16. K. Kohu, H. Ohmori, W. F. Wong et al., “The Runx3 transcription factor augments Th1 and down-modulates Th2 Phenotypes by interacting with and attenuating GATA3,” Journal of Immunology, vol. 183, no. 12, pp. 7817–7824, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  17. R. J. Greenwald, G. J. Freeman, and A. H. Sharpe, “The B7 family revisited,” Annual Review of Immunology, vol. 23, pp. 515–548, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  18. M. Croft, “The role of TNF superfamily members in T-cell function and diseases,” Nature Reviews Immunology, vol. 9, no. 4, pp. 271–285, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  19. G. Trinchieri, S. Pflanz, and R. A. Kastelein, “The IL-12 family of heterodimeric cytokines: new players in the regulation of T cell responses,” Immunity, vol. 19, no. 5, pp. 641–644, 2003. View at Publisher · View at Google Scholar · View at Scopus
  20. G. Trinchieri and A. Sher, “Cooperation of Toll-like receptor signals in innate immune defence,” Nature Reviews Immunology, vol. 7, no. 3, pp. 179–190, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  21. M. Afkarian, J. R. Sedy, J. Yang et al., “T-bet is a STATI-induced regulator for IL-12R expression in naïve CD4+ T cells,” Nature Immunology, vol. 3, no. 6, pp. 549–557, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  22. G. Lugo-Villarino, R. Maldonado-López, R. Possemato, C. Peñaranda, and L. H. Glimcher, “T-bet is required for optimal production of IFN-γ and antigen-specific T cell activation by dendritic cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 13, pp. 7749–7754, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  23. V. Lazarevic, X. Chen, J. H. Shim et al., “T-bet represses TH 17 differentiation by preventing Runx1-mediated activation of the gene encoding RORγt,” Nature Immunology, vol. 12, no. 1, pp. 96–104, 2011. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  24. A. A. Lighvani, D. M. Frucht, D. Jankovic et al., “T-bet is rapidly induced by interferon-γ in lymphoid and myeloid cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 26, pp. 15137–15142, 2001. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  25. I. M. Djuretic, D. Levanon, V. Negreanu, Y. Groner, A. Rao, and K. M. Ansel, “Transcription factors T-bet and Runx3 cooperate to activate Ifng and silence Il4 in T helper type 1 cells,” Nature Immunology, vol. 8, no. 2, pp. 145–153, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  26. E. S. Hwang, S. J. Szabo, P. L. Schwartzberg, and L. H. Glimcher, “T helper cell fate specified by kinase-mediated interaction of T-bet with GATA-3,” Science, vol. 307, no. 5708, pp. 430–433, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  27. W. E. Thierfelder, J. M. Van Deursen, K. Yamamoto et al., “Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells,” Nature, vol. 382, no. 6587, pp. 171–174, 1996. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  28. T. M. Aune, P. L. Collins, and S. Chang, “Epigenetics and T helper 1 differentiation,” Immunology, vol. 126, no. 3, pp. 299–305, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  29. V. T. Thieu, Q. Yu, H. C. Chang et al., “Signal transducer and activator of transcription 4 is required for the transcription factor T-bet to promote T helper 1 cell-fate determination,” Immunity, vol. 29, no. 5, pp. 679–690, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  30. O. Komine, K. Hayashi, W. Natsume et al., “The Runx1 transcription factor inhibits the differentiation of naive CD4+ T cells into the Th2 lineage by repressing GATA3 expression,” Journal of Experimental Medicine, vol. 198, no. 1, pp. 51–61, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  31. K. J. Oestreich, A. C. Huang, and A. S. Weinmann, “The lineage-defining factors T-bet and Bcl-6 collaborate to regulate Th1 gene expression patterns,” Journal of Experimental Medicine, vol. 208, no. 5, pp. 1001–1013, 2011. View at Publisher · View at Google Scholar · View at PubMed
  32. K. Fujio, T. Okamura, and K. Yamamoto, “The family of IL-10-secreting CD4+ T cells,” Advances in Immunology, vol. 105, no. C, pp. 99–130, 2010. View at Publisher · View at Google Scholar · View at Scopus
  33. A. C. Mullen, A. S. Hutchins, F. A. High et al., “Hlx is induced by and genetically interacts with T-bet to promote heritable THI gene induction,” Nature Immunology, vol. 3, no. 7, pp. 652–658, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  34. M. H. Kaplan, U. Schindler, S. T. Smiley, and M. J. Grusby, “Stat6 is required for mediating responses to IL-4 and for the development of Th2 cells,” Immunity, vol. 4, no. 3, pp. 313–319, 1996. View at Publisher · View at Google Scholar · View at Scopus
  35. L. H. Glimcher and K. M. Murphy, “Lineage commitment in the immune system: the T helper lymphocyte grows up,” Genes and Development, vol. 14, no. 14, pp. 1693–1711, 2000. View at Google Scholar · View at Scopus
  36. J. Zhu, L. Guo, C. J. Watson, J. Hu-Li, and W. E. Paul, “Stat6 is necessary and sufficient for IL-4's role in TH2 differentiation and cell expansion,” Journal of Immunology, vol. 166, no. 12, pp. 7276–7281, 2001. View at Google Scholar · View at Scopus
  37. J. Zhu, H. Yamane, J. Cote-Sierra, L. Guo, and W. E. Paul, “GATA-3 promotes Th2 responses through three different mechanisms: induction of Th2 cytokine production, selective growth of Th2 cells and inhibition of Th1 cell-specific factors,” Cell Research, vol. 16, no. 1, pp. 3–10, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  38. T. Usui, R. Nishikomori, A. Kitani, and W. Strober, “GATA-3 suppresses Th1 development by downregulation of Stat4 and not through effects on IL-12Rβ2 chain or T-bet,” Immunity, vol. 18, no. 3, pp. 415–428, 2003. View at Publisher · View at Google Scholar · View at Scopus
  39. J. Zhu, B. Min, J. Hu-Li et al., “Conditional deletion of Gata3 shows its essential function in TH1-TH2 responses,” Nature Immunology, vol. 5, no. 11, pp. 1157–1165, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  40. S. Y. Pai, M. L. Truitt, and I. C. Ho, “GATA-3 deficiency abrogates the development and maintenance of T helper type 2 cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 7, pp. 1993–1998, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  41. S. Horiuchi, A. Onodera, H. Hosokawa et al., “Genome-wide analysis reveals unique regulation of transcription of Th2-specific genes by GATA3,” Journal of Immunology, vol. 186, no. 11, pp. 6378–6389, 2011. View at Publisher · View at Google Scholar · View at PubMed
  42. U. Boehm, T. Klamp, M. Groot, and J. C. Howard, “Cellular responses to interferon-γ,” Annual Review of Immunology, vol. 15, pp. 749–795, 1997. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  43. S. K. Halonen, G. A. Taylor, and L. M. Weiss, “Gamma interferon-induced inhibition of Toxoplasma gondii in astrocytes is mediated by IGTP,” Infection and Immunity, vol. 69, no. 9, pp. 5573–5576, 2001. View at Publisher · View at Google Scholar · View at Scopus
  44. J. Cote-Sierra, G. Foucras, L. Guo et al., “Interleukin 2 plays a central role in Th2 differentiation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 11, pp. 3880–3885, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  45. J. Zhu, J. Cote-Sierra, L. Guo, and W. E. Paul, “Stat5 activation plays a critical role in Th2 differentiation,” Immunity, vol. 19, no. 5, pp. 739–748, 2003. View at Publisher · View at Google Scholar · View at Scopus
  46. J. I. Kim, I. C. Ho, M. J. Grusby, and L. H. Glimcher, “The transcription factor c-Maf controls the production of interleukin-4 but not other Th2 cytokines,” Immunity, vol. 10, no. 6, pp. 745–751, 1999. View at Publisher · View at Google Scholar · View at Scopus
  47. G. L. Stritesky, R. Muthukrishnan, S. Sehra et al., “The transcription factor STAT3 is required for T helper 2 cell development,” Immunity, vol. 34, no. 1, pp. 39–49, 2011. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  48. G. L. Stritesky and M. H. Kaplan, “Changing the STATus quo in T helper cells,” Transcription, vol. 2, no. 4, pp. 179–182, 2011. View at Publisher · View at Google Scholar · View at PubMed
  49. S. Diehl and M. Rincón, “The two faces of IL-6 on Th1/Th2 differentiation,” Molecular Immunology, vol. 39, no. 9, pp. 531–536, 2002. View at Publisher · View at Google Scholar · View at Scopus
  50. S. Diehl, J. Anguita, A. Hoffmeyer et al., “Inhibition of Th1 differentiation by IL-6 is mediated by SOCS1,” Immunity, vol. 13, no. 6, pp. 805–815, 2000. View at Publisher · View at Google Scholar · View at Scopus
  51. J. Zhu, D. Jankovic, A. Grinberg, L. Guo, and W. E. Paul, “Gfi-1 plays an important role in IL-2-mediated Th2 cell expansion,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 48, pp. 18214–18219, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  52. J. Zhu, L. Guo, B. Min et al., “Growth factor independent-1 induced by IL-4 regulates Th2 cell proliferation,” Immunity, vol. 16, no. 5, pp. 733–744, 2002. View at Publisher · View at Google Scholar · View at Scopus
  53. I. C. Ho, D. Lo, and L. H. Glimcher, “c-maf Promotes T helper cell type 2 (Th2) and attenuates Th1 differentiation by both interleukin 4-dependent and -independent mechanisms,” Journal of Experimental Medicine, vol. 188, no. 10, pp. 1859–1866, 1998. View at Publisher · View at Google Scholar · View at Scopus
  54. J. Rengarajan, K. A. Mowen, K. D. McBride, E. D. Smith, H. Singh, and L. H. Glimcher, “Interferon regulatory factor 4 (IRF4) interacts with NFATc2 to modulate interleukin 4 gene expression,” Journal of Experimental Medicine, vol. 195, no. 8, pp. 1003–1012, 2002. View at Publisher · View at Google Scholar · View at Scopus
  55. M. Lohoff, H. W. Mittrücker, S. Prechtl et al., “Dysregulated T helper cell differentiation in the absence of interferon regulatory factor 4,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 18, pp. 11808–11812, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  56. M. Veldhoen, C. Uyttenhove, J. van Snick et al., “Transforming growth factor-β “reprograms” the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset,” Nature Immunology, vol. 9, no. 12, pp. 1341–1346, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  57. V. Staudt, E. Bothur, M. Klein et al., “Interferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells,” Immunity, vol. 33, no. 2, pp. 192–202, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  58. 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. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  59. 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. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  60. 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. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  61. 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. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  62. E. Volpe, N. Servant, R. Zollinger et al., “A critical function for transforming growth factor-β, interleukin 23 and proinflammatory cytokines in driving and modulating human TH-17 responses,” Nature Immunology, vol. 9, no. 6, pp. 650–657, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  63. W. Chen, W. Jin, N. Hardegen et al., “Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-β induction of transcription factor foxp3,” Journal of Experimental Medicine, vol. 198, no. 12, pp. 1875–1886, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  64. L. Zhou, J. E. Lopes, M. M. W. Chong et al., “TGF-β-induced Foxp3 inhibits TH17 cell differentiation by antagonizing RORγt function,” Nature, vol. 453, no. 7192, pp. 236–240, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  65. H. Qin, L. Wang, T. Feng et al., “TGF-β promotes Th17 cell development through inhibition of SOCS3,” Journal of Immunology, vol. 183, no. 1, pp. 97–105, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  66. 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. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  67. X. O. Yang, B. P. Pappu, R. Nurieva et al., “T Helper 17 lineage differentiation is programmed by orphan nuclear receptors RORα and RORγ,” Immunity, vol. 28, no. 1, pp. 29–39, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  68. 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. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  69. 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. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  70. 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. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  71. V. Lazarevic, X. Chen, J. H. Shim et al., “T-bet represses TH 17 differentiation by preventing Runx1-mediated activation of the gene encoding RORγt,” Nature Immunology, vol. 12, no. 1, pp. 96–104, 2011. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  72. 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. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  73. 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. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  74. 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. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  75. A. Brüstle, S. Heink, M. Huber et al., “The development of inflammatory TH-17 cells requires interferon-regulatory factor 4,” Nature Immunology, vol. 8, no. 9, pp. 958–966, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  76. Q. Chen, W. Yang, S. Gupta et al., “IRF-4-binding protein inhibits interleukin-17 and interleukin-21 production by controlling the activity of IRF-4 transcription factor,” Immunity, vol. 29, no. 6, pp. 899–911, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  77. T. Korn, E. Bettelli, W. Gao et al., “IL-21 initiates an alternative pathway to induce proinflammatory T (H)17 cells,” Nature, vol. 448, no. 7152, pp. 484–487, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  78. 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. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  79. 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. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  80. L. Zhou, I. I. Ivanov, R. Spolski et al., “IL-6 programs TH-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. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  81. 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. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  82. W. Chen, W. Jin, N. Hardegen et al., “Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-β induction of transcription factor Foxp3,” Journal of Experimental Medicine, vol. 198, no. 12, pp. 1875–1886, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  83. M. O. Li, Y. Y. Wan, and R. A. Flavell, “T Cell-Produced Transforming Growth Factor-β1 Controls T Cell Tolerance and Regulates Th1- and Th17-Cell Differentiation,” Immunity, vol. 26, no. 5, pp. 579–591, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  84. M. A. Kriegel, M. O. Li, S. Sanjabi, Y. Y. Wan, and R. A. Flavell, “Transforming growth factor-β: recent advances on its role in immune tolerance,” Current Rheumatology Reports, vol. 8, no. 2, pp. 138–144, 2006. View at Publisher · View at Google Scholar · View at Scopus
  85. A. Yoshimura and G. Muto, “TGF-β function in immune suppression,” Current Topics in Microbiology and Immunology, vol. 350, pp. 127–147, 2011. View at Publisher · View at Google Scholar · View at PubMed
  86. J. D. Fontenot, M. A. Gavin, and A. Y. Rudensky, “Foxp3 programs the development and function of CD4+CD25+ regulatory T cells,” Nature Immunology, vol. 4, no. 4, pp. 330–336, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  87. H. Yagi, T. Nomura, K. Nakamura et al., “Crucial role of FOXP3 in the development and function of human CD25+CD4+ regulatory T cells,” International Immunology, vol. 16, no. 11, pp. 1643–1656, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  88. T. Takimoto, Y. Wakabayashi, T. Sekiya, and N. Inoue, “Smad2 and Smad3 are redundantly essential for the TGF-β-mediated regulation of regulatory T plasticity and Th1 development,” Journal of Immunology, vol. 185, no. 2, pp. 842–855, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  89. Y. Tone, K. Furuuchi, Y. Kojima, M. L. Tykocinski, M. I. Greene, and M. Tone, “Smad3 and NFAT cooperate to induce Foxp3 expression through its enhancer,” Nature Immunology, vol. 9, no. 2, pp. 194–202, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  90. G. J. Martinez, Z. Zhang, Y. Chung et al., “Smad3 differentially regulates the induction of regulatory and inflammatory T cell differentiation,” Journal of Biological Chemistry, vol. 284, no. 51, pp. 35283–35286, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  91. 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. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  92. T. S. Davidson, R. J. DiPaolo, J. Andersson, and E. M. Shevach, “Cutting edge: IL-2 is essential for TGF-β-mediated induction of Foxp3+ T regulatory cells,” Journal of Immunology, vol. 178, no. 7, pp. 4022–4026, 2007. View at Google Scholar · View at Scopus
  93. M. A. Burchill, J. Yang, C. Vogtenhuber, B. R. Blazar, and M. A. Farrar, “IL-2 receptor β-dependent STAT5 activation is required for the development of Foxp3+ regulatory T cells,” Journal of Immunology, vol. 178, no. 1, pp. 280–290, 2007. View at Google Scholar · View at Scopus
  94. S. Brandenburg, T. Takahashi, M. de la Rosa et al., “IL-2 induces in vivo suppression by CD4+CD25+Foxp3+ regulatory T cells,” European Journal of Immunology, vol. 38, no. 6, pp. 1643–1653, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  95. M. H. Kaplan, N. L. Glosson, G. L. Stritesky et al., “STAT3-dependent IL-21 production from T helper cells regulates hematopoietic progenitor cell homeostasis,” Blood, vol. 117, no. 23, pp. 6198–6201, 2011. View at Publisher · View at Google Scholar · View at PubMed
  96. Y. Wu, M. Borde, V. Heissmeyer et al., “FOXP3 controls regulatory T cell function through cooperation with NFAT,” Cell, vol. 126, no. 2, pp. 375–387, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  97. A. Awasthi, Y. Carrier, J. P. S. Peron et al., “A dominant function for interleukin 27 in generating interleukin 10-producing anti-inflammatory T cells,” Nature Immunology, vol. 8, no. 12, pp. 1380–1389, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  98. S. Gregori, D. Tomasoni, V. Pacciani et al., “Differentiation of type 1 T regulatory cells (Tr1) by tolerogenic DC-10 requires the IL-10-dependent ILT4/HLA-G pathway,” Blood, vol. 116, no. 6, pp. 935–944, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  99. C. Pot, H. Jin, A. Awasthi et al., “Cutting edge: IL-27 induces the transcription factor c-Maf, cytokine IL-21, and the costimulatory receptor ICOS that coordinately act together to promote differentiation of IL-10-producing Tr1 cells,” Journal of Immunology, vol. 183, no. 2, pp. 797–801, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  100. L. Apetoh, F. J. Quintana, C. Pot et al., “The Aryl hydrocarbon Receptor (AhR) interacts with c-Maf to promote the differentiation of IL-27-induced regulatory type 1 (TR1) cells,” Nature Immunology, vol. 11, no. 9, pp. 854–861, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  101. C. G. Vinuesa, S. G. Tangye, B. Moser, and C. R. Mackay, “Follicular B helper T cells in antibody responses and autoimmunity,” Nature Reviews Immunology, vol. 5, no. 11, pp. 853–865, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  102. D. Breitfeld, L. Ohl, E. Kremmer et al., “Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production,” Journal of Experimental Medicine, vol. 192, no. 11, pp. 1545–1551, 2000. View at Publisher · View at Google Scholar · View at Scopus
  103. A. Vogelzang, H. M. McGuire, D. Yu, J. Sprent, C. R. Mackay, and C. King, “A fundamental role for interleukin-21 in the generation of T follicular helper cells,” Immunity, vol. 29, no. 1, pp. 127–137, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  104. R. I. Nurieva, Y. Chung, D. Hwang et al., “Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages,” Immunity, vol. 29, no. 1, pp. 138–149, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  105. S. K. Halonen, G. A. Taylor, and L. M. Weiss, “Gamma interferon-induced inhibition of Toxoplasma gondii in astrocytes is mediated by IGTP,” Infection and Immunity, vol. 69, no. 9, pp. 5573–5576, 2001. View at Publisher · View at Google Scholar · View at Scopus
  106. H. Akiba, K. Takeda, Y. Kojima et al., “The role of ICOS in the CXCR5+ follicular B helper T cell maintenance in vivo,” Journal of Immunology, vol. 175, no. 4, pp. 2340–2348, 2005. View at Google Scholar · View at Scopus
  107. L. Bossaller, J. Burger, R. Draeger et al., “ICOS deficiency is associated with a severe reduction of CXCR5 +CD4 germinal center Th Cells,” Journal of Immunology, vol. 177, no. 7, pp. 4927–4932, 2006. View at Google Scholar · View at Scopus
  108. R. I. Nurieva, Y. Chung, G. J. Martinez et al., “Bcl6 mediates the development of T follicular helper cells,” Science, vol. 325, no. 5943, pp. 1001–1005, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  109. D. Bending, H. De La Peña, 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. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  110. Y. K. Lee, H. Turner, C. L. Maynard et al., “Late developmental plasticity in the T helper 17 lineage,” Immunity, vol. 30, no. 1, pp. 92–107, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  111. L. Xu, A. Kitani, I. Fuss, and W. Strober, “Cutting edge: regulatory T cells induce CD4+CD25 -Foxp3- T cells or are self-induced to become Th17 cells in the absence of exogenous TGF-β,” Journal of Immunology, vol. 178, no. 11, pp. 6725–6729, 2007. View at Google Scholar · View at Scopus
  112. M. Tsuji, N. Komatsu, S. Kawamoto et al., “Preferential generation of follicular B helper T cells from Foxp3 + T cells in gut Peyer's patches,” Science, vol. 323, no. 5920, pp. 1488–1492, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  113. Y. Zheng, A. Chaudhry, A. Kas et al., “Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control TH2 responses,” Nature, vol. 458, no. 7236, pp. 351–356, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  114. G. del Prete, “Human Th1 and Th2 lymphocytes: their role in the pathophysiology of atopy,” Allergy, vol. 47, no. 5, pp. 450–455, 1992. View at Google Scholar · View at Scopus
  115. H. W. Murray, B. Y. Rubin, and S. M. Carriero, “Human mononuclear phagocyte antiprotozoal mechanisms: Oxygen-dependent vs oxygen-independent activity against intracellular Toxoplasma gondii,” Journal of Immunology, vol. 134, no. 3, pp. 1982–1988, 1985. View at Google Scholar
  116. U. Boehm, T. Klamp, M. Groot, and J. C. Howard, “Cellular responses to interferon-γ,” Annual Review of Immunology, vol. 15, pp. 749–795, 1997. View at Publisher · View at Google Scholar · View at PubMed
  117. T. Melzer, A. Duffy, L. M. Weiss, and S. K. Halonen, “The gamma interferon (IFN-γ)-inducible GTP-binding protein IGTP is necessary for Toxoplasma vacuolar disruption and induces parasite egression in IFN-γ-stimulated astrocytes,” Infection and Immunity, vol. 76, no. 11, pp. 4883–4894, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  118. G. A. Taylor, C. G. Feng, and A. Sher, “p47 GTPases: regulators of immunity to intracellular pathogens,” Nature Reviews Immunology, vol. 4, no. 2, pp. 100–109, 2004. View at Google Scholar · View at Scopus
  119. E. Y. Chiang, G. A. Kolumam, X. Yu et al., “Targeted depletion of lymphotoxin-α-expressing T H 1 and T H 17 cells inhibits autoimmune disease,” Nature Medicine, vol. 15, no. 7, pp. 766–773, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  120. W. E. Suen, C. M. Bergman, P. Hjelmström, and N. H. Ruddle, “A critical role for lymphotoxin in experimental allergic encephalomyelitis,” Journal of Experimental Medicine, vol. 186, no. 8, pp. 1233–1240, 1997. View at Publisher · View at Google Scholar · View at Scopus
  121. H. P. Kim, J. Imbert, and W. J. Leonard, “Both integrated and differential regulation of components of the IL-2/IL-2 receptor system,” Cytokine and Growth Factor Reviews, vol. 17, no. 5, pp. 349–366, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  122. L. Gattinoni, C. A. Klebanoff, D. C. Palmer et al., “Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8+ T cells,” Journal of Clinical Investigation, vol. 115, no. 6, pp. 1616–1626, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  123. M. A. Williams, A. J. Tyznik, and M. J. Bevan, “Interleukin-2 signals during priming are required for secondary expansion of CD8+ memory T cells,” Nature, vol. 441, no. 7095, pp. 890–893, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  124. T. Y. Wuest, J. Willette-Brown, S. K. Durum, and A. A. Hurwitz, “The influence of IL-2 family cytokines on activation and function of naturally occurring regulatory T cells,” Journal of Leukocyte Biology, vol. 84, no. 4, pp. 973–980, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  125. C. L. Sokol, N. Q. Chu, S. Yu, S. A. Nish, T. M. Laufer, and R. Medzhitov, “Basophils function as antigen-presenting cells for an allergen-induced T helper type 2 response,” Nature Immunology, vol. 10, no. 7, pp. 713–720, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  126. J. W. Steinke and L. Borish, “Th2 cytokines and asthma. Interleukin-4: its role in the pathogenesis of asthma, and targeting it for asthma treatment with interleukin-4 receptor antagonists,” Respiratory Research, vol. 2, no. 2, pp. 66–70, 2001. View at Publisher · View at Google Scholar · View at Scopus
  127. C. Doucet, D. Brouty-Boyé, C. Pottin-Clemenceau, C. Jasmin, G. W. Canonica, and B. Azzarone, “IL-4 and IL-13 specifically increase adhesion molecule and inflammatory cytokine expression in human lung fibroblasts,” International Immunology, vol. 10, no. 10, pp. 1421–1433, 1998. View at Publisher · View at Google Scholar · View at Scopus
  128. M. Martinez-Moczygemba and D. P. Huston, “Biology of common β receptor-signaling cytokines: IL-3, IL-5, and GM-CSF,” Journal of Allergy and Clinical Immunology, vol. 112, no. 4, pp. 653–665, 2003. View at Publisher · View at Google Scholar · View at Scopus
  129. F. F. Little, W. W. Cruikshank, and D. M. Center, “IL-9 stimulates release of chemotactic factors from human bronchial epithelial cells,” American Journal of Respiratory Cell and Molecular Biology, vol. 25, no. 3, pp. 347–352, 2001. View at Google Scholar · View at Scopus
  130. T. A. Wynn, “IL-13 effector functions,” Annual Review of Immunology, vol. 21, pp. 425–456, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  131. K. N. Couper, D. G. Blount, and E. M. Riley, “IL-10: the master regulator of immunity to infection,” Journal of Immunology, vol. 180, no. 9, pp. 5771–5777, 2008. View at Google Scholar · View at Scopus
  132. 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. View at Publisher · View at Google Scholar · View at Scopus
  133. 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. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  134. S. J. Ballantyne, J. L. Barlow, H. E. Jolin et al., “Blocking IL-25 prevents airway hyperresponsiveness in allergic asthma,” Journal of Allergy and Clinical Immunology, vol. 120, no. 6, pp. 1324–1331, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  135. D. M. Zaiss, L. Yang, P. R. Shah, J. J. Kobie, J. F. Urban, and T. R. Mosmann, “Amphiregulin, a TH2 cytokine enhancing resistance to nematodes,” Science, vol. 314, no. 5806, p. 1746, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  136. J. Xing, Y. Wu, and B. Ni, “Th9: a new player in asthma pathogenesis?” Journal of Asthma, vol. 48, no. 2, pp. 115–125, 2011. View at Publisher · View at Google Scholar · View at PubMed
  137. 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. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  138. C. T. Weaver, L. E. Harrington, P. R. Mangan, M. Gavrieli, and K. M. Murphy, “Th17: an effector CD4 T cell lineage with regulatory T Cell ties,” Immunity, vol. 24, no. 6, pp. 677–688, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  139. 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. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  140. S. L. Gaffen, “Structure and signalling in the IL-17 receptor family,” Nature Reviews Immunology, vol. 9, no. 8, pp. 556–567, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  141. T. A. Moseley, D. R. Haudenschild, L. Rose, and A. H. Reddi, “Interleukin-17 family and IL-17 receptors,” Cytokine and Growth Factor Reviews, vol. 14, no. 2, pp. 155–174, 2003. View at Publisher · View at Google Scholar · View at Scopus
  142. 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. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  143. W. J. Leonard and R. Spolski, “Interleukin-21: a modulator of lymphoid proliferation, apoptosis and differentiation,” Nature Reviews Immunology, vol. 5, no. 9, pp. 688–698, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  144. S. J. Aujla, Y. R. Chan, M. Zheng et al., “IL-22 mediates mucosal host defense against Gram-negative bacterial pneumonia,” Nature Medicine, vol. 14, no. 3, pp. 275–281, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  145. L. A. Zenewicz, G. D. Yancopoulos, D. M. Valenzuela, A. J. Murphy, M. Karow, and R. A. Flavell, “Interleukin-22 but not interleukin-17 provides protection to hepatocytes during acute liver inflammation,” Immunity, vol. 27, no. 4, pp. 647–659, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  146. S. Sakaguchi, M. Ono, R. Setoguchi et al., “Foxp3+CD25+CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease,” Immunological Reviews, vol. 212, pp. 8–27, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  147. W. Ouyang, S. Rutz, N. K. Crellin, P. A. Valdez, and S. G. Hymowitz, “Regulation and functions of the IL-10 family of cytokines in inflammation and disease,” Annual Review of Immunology, vol. 29, pp. 71–109, 2011. View at Publisher · View at Google Scholar · View at PubMed
  148. C. Asseman, S. Mauze, M. W. Leach, R. L. Coffman, and F. Powrie, “An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation,” Journal of Experimental Medicine, vol. 190, no. 7, pp. 995–1004, 1999. View at Publisher · View at Google Scholar · View at Scopus
  149. M. Jutel and C. Akdis, “T-cell regulatory mechanisms in specific immunotherapy,” Chemical Immunology and Allergy, vol. 94, pp. 158–177, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  150. M. O. Li, Y. Y. Wan, and R. A. Flavell, “T Cell-Produced Transforming Growth Factor-β1 Controls T Cell Tolerance and Regulates Th1- and Th17-Cell Differentiation,” Immunity, vol. 26, no. 5, pp. 579–591, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  151. N. Fazilleau, L. Mark, L. J. McHeyzer-Williams, and M. G. McHeyzer-Williams, “Follicular helper T Cells: lineage and location,” Immunity, vol. 30, no. 3, pp. 324–335, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus