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Interplay between the TH17 and TReg cell lineages: a (co-)evolutionary perspective

Nature Reviews Immunology volume 9, pages 883–889 (2009)Cite this article

Abstract

The origins of the adaptive immune system and the basis for its unique association with vertebrate species have been a source of considerable speculation. In light of recent advances in our understanding of the developmental and functional links between the induced regulatory T cell and T helper 17 cell lineages, and their specialized relationship to the gut, we speculate that the co-evolution of these adaptive immune pathways might have given primitive vertebrates a means to benefit from the diversification of their commensal microbiota.

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Figure 1: A common requirement for transforming growth factor-β in the induced regulatory T cell and T helper 17 cell lineages.
Figure 2: Competitive antagonism between FOXP3 and ROR family members dictates induced regulatory T cell versus T helper 17 cell development.
Figure 3: Plasticity of induced regulatory T (TReg) cells and T helper 17 (TH17) cells indicated by epigenetic modifications of lineage-specifying transcription factors and cytokines.

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References

  1. Weaver, C. T., Harrington, L. E., Mangan, P. R., Gavrieli, M. & Murphy, K. M. Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity 24, 677–688 (2006).

    Article  CAS  PubMed  Google Scholar 

  2. Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006).

    Article  CAS  PubMed  Google Scholar 

  3. Harrington, L. E. et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nature Immunol. 6, 1123–1132 (2005).

    Article  CAS  Google Scholar 

  4. Mangan, P. R. et al. Transforming growth factor-β induces development of the TH17 lineage. Nature 441, 231–234 (2006).

    Article  CAS  PubMed  Google Scholar 

  5. Park, H. et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nature Immunol. 6, 1133–1141 (2005).

    Article  CAS  Google Scholar 

  6. Josefowicz, S. Z. & Rudensky, A. Control of regulatory T cell lineage commitment and maintenance. Immunity 30, 616–625 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Veldhoen, M., Hocking, R. J., Atkins, C. J., Locksley, R. M. & Stockinger, B. TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24, 179–189 (2006).

    Article  CAS  PubMed  Google Scholar 

  8. Ziegler, S. F. & Buckner, J. H. FOXP3 and the regulation of Treg/Th17 differentiation. Microbes Infect. 11, 594–598 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Locksley, R. M. Nine lives: plasticity among T helper cell subsets. J. Exp. Med. 206, 1643–1646 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Zhou, L., Chong, M. M. & Littman, D. R. Plasticity of CD4+ T cell lineage differentiation. Immunity 30, 646–655 (2009).

    Article  CAS  PubMed  Google Scholar 

  11. Khalturin, K., Panzer, Z., Cooper, M. D. & Bosch, T. C. Recognition strategies in the innate immune system of ancestral chordates. Mol. Immunol. 41, 1077–1087 (2004).

    Article  CAS  PubMed  Google Scholar 

  12. Huang, S. et al. Genomic analysis of the immune gene repertoire of amphioxus reveals extraordinary innate complexity and diversity. Genome Res. 18, 1112–1126 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Liongue, C. & Ward, A. C. Evolution of Class I cytokine receptors. BMC Evol. Biol. 7, 120 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Terajima, D. et al. Identification and sequence of seventy-nine new transcripts expressed in hemocytes of Ciona intestinalis, three of which may be involved in characteristic cell-cell communication. DNA Res. 10, 203–212 (2003).

    Article  CAS  PubMed  Google Scholar 

  15. Guo, P. et al. Dual nature of the adaptive immune system in lampreys. Nature 459, 796–801 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Pancer, Z., Mayer, W. E., Klein, J. & Cooper, M. D. Prototypic T cell receptor and CD4-like coreceptor are expressed by lymphocytes in the agnathan sea lamprey. Proc. Natl Acad. Sci. USA 101, 13273–13278 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hedrick, S. M. The acquired immune system: a vantage from beneath. Immunity 21, 607–615 (2004).

    Article  CAS  PubMed  Google Scholar 

  18. Pancer, Z. & Cooper, M. D. The evolution of adaptive immunity. Annu. Rev. Immunol. 24, 497–518 (2006).

    Article  CAS  PubMed  Google Scholar 

  19. Hooper, L. V. & Gordon, J. I. Commensal host–bacterial relationships in the gut. Science 292, 1115–1118 (2001).

    Article  CAS  PubMed  Google Scholar 

  20. McFall-Ngai, M. Adaptive immunity: care for the community. Nature 445, 153 (2007).

    Article  CAS  PubMed  Google Scholar 

  21. Ley, R. E., Lozupone, C. A., Hamady, M., Knight, R. & Gordon, J. I. Worlds within worlds: evolution of the vertebrate gut microbiota. Nature Rev. Microbiol. 6, 776–788 (2008).

    Article  CAS  Google Scholar 

  22. Gomez, G. D. & Balcazar, J. L. A review on the interactions between gut microbiota and innate immunity of fish. FEMS Immunol. Med. Microbiol. 52, 145–154 (2008).

    Article  CAS  PubMed  Google Scholar 

  23. Rawls, J. F., Mahowald, M. A., Ley, R. E. & Gordon, J. I. Reciprocal gut microbiota transplants from zebrafish and mice to germ-free recipients reveal host habitat selection. Cell 127, 423–433 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Colonna, M. Interleukin-22-producing natural killer cells and lymphoid tissue inducer-like cells in mucosal immunity. Immunity 31, 15–23 (2009).

    Article  CAS  PubMed  Google Scholar 

  25. Roark, C. L., Simonian, P. L., Fontenot, A. P., Born, W. K. & O'Brien, R. L. γδ T cells: an important source of IL-17. Curr. Opin. Immunol. 20, 353–357 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Wostmann, B. S., Larkin, C., Moriarty, A. & Bruckner-Kardoss, E. Dietary intake, energy metabolism, and excretory losses of adult male germfree Wistar rats. Lab. Anim. Sci. 33, 46–50 (1983).

    CAS  PubMed  Google Scholar 

  27. Backhed, F., Ley, R. E., Sonnenburg, J. L., Peterson, D. A. & Gordon, J. I. Host–bacterial mutualism in the human intestine. Science 307, 1915–1920 (2005).

    Article  PubMed  Google Scholar 

  28. Hooper, L. V. Do symbiotic bacteria subvert host immunity? Nature Rev. Microbiol. 7, 367–374 (2009).

    Article  CAS  Google Scholar 

  29. Weaver, C. T., Hatton, R. D., Mangan, P. R. & Harrington, L. E. IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu. Rev. Immunol. 25, 821–852 (2007).

    Article  CAS  PubMed  Google Scholar 

  30. Mucida, D. et al. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317, 256–260 (2007).

    Article  CAS  PubMed  Google Scholar 

  31. Sun, C. M. et al. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J. Exp. Med. 204, 1775–1785 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Benson, M. J., Pino-Lagos, K., Rosemblatt, M. & Noelle, R. J. 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, 1765–1774 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Coombes, J. L. et al. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-β and retinoic acid-dependent mechanism. J. Exp. Med. 204, 1757–1764 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Ouyang, W., Kolls, J. K. & Zheng, Y. The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity 28, 454–467 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Raftery, L. A. & Sutherland, D. J. TGF-β family signal transduction in Drosophila development: from Mad to Smads. Dev. Biol. 210, 251–268 (1999).

    Article  CAS  PubMed  Google Scholar 

  36. Kaiser, P., Rothwell, L., Avery, S. & Balu, S. Evolution of the interleukins. Dev. Comp. Immunol. 28, 375–394 (2004).

    Article  CAS  PubMed  Google Scholar 

  37. Malagoli, D., Conklin, D., Sacchi, S., Mandrioli, M. & Ottaviani, E. A putative helical cytokine functioning in innate immune signalling in Drosophila melanogaster. Biochim. Biophys. Acta 1770, 974–978 (2007).

    Article  CAS  PubMed  Google Scholar 

  38. Schulenburg, H., Hoeppner, M. P., Weiner, J. & Bornberg-Bauer, E. Specificity of the innate immune system and diversity of C-type lectin domain (CTLD) proteins in the nematode Caenorhabditis elegans. Immunobiology 213, 237–250 (2008).

    Article  CAS  PubMed  Google Scholar 

  39. Wahl, S. M. Transforming growth factor-β: innately bipolar. Curr. Opin. Immunol. 19, 55–62 (2007).

    Article  CAS  PubMed  Google Scholar 

  40. Franchini, A., Malagoli, D. & Ottaviani, E. Cytokines and invertebrates: TGF-β and PDGF. Curr. Pharm. Des. 12, 3025–3031 (2006).

    Article  CAS  PubMed  Google Scholar 

  41. Allen, J. B. et al. Rapid onset synovial inflammation and hyperplasia induced by transforming growth factor β. J. Exp. Med. 171, 231–247 (1990).

    Article  CAS  PubMed  Google Scholar 

  42. Brandes, M. E., Allen, J. B., Ogawa, Y. & Wahl, S. M. Transforming growth factor β1 suppresses acute and chronic arthritis in experimental animals. J. Clin. Invest. 87, 1108–1113 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Haddad, G., Hanington, P. C., Wilson, E. C., Grayfer, L. & Belosevic, M. Molecular and functional characterization of goldfish (Carassius auratus L.) transforming growth factor β. Dev. Comp. Immunol. 32, 654–663 (2008).

    Article  CAS  PubMed  Google Scholar 

  44. Yang, M. & Zhou, H. Grass carp transforming growth factor-β1 (TGF-β1): molecular cloning, tissue distribution and immunobiological activity in teleost peripheral blood lymphocytes. Mol. Immunol. 45, 1792–1798 (2008).

    Article  CAS  PubMed  Google Scholar 

  45. Brustle, A. et al. The development of inflammatory TH-17 cells requires interferon-regulatory factor 4. Nature Immunol. 8, 958–966 (2007).

    Article  Google Scholar 

  46. Quintana, F. J. et al. Control of Treg and TH17 cell differentiation by the aryl hydrocarbon receptor. Nature 453, 65–71 (2008).

    Article  CAS  PubMed  Google Scholar 

  47. Schraml, B. U. et al. The AP-1 transcription factor Batf controls TH17 differentiation. Nature 460, 405–409 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Veldhoen, M. et al. The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453, 106–109 (2008).

    Article  CAS  PubMed  Google Scholar 

  49. Zhang, F., Meng, G. & Strober, W. Interactions among the transcription factors Runx1, RORγt and Foxp3 regulate the differentiation of interleukin 17-producing T cells. Nature Immunol. 9, 1297–1306 (2008).

    Article  CAS  Google Scholar 

  50. Ivanov, I. I. et al. The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126, 1121–1133 (2006).

    Article  CAS  PubMed  Google Scholar 

  51. Yang, X. O. et al. T helper 17 lineage differentiation is programmed by orphan nuclear receptors RORα and RORγ. Immunity 28, 29–39 (2008).

    Article  CAS  PubMed  Google Scholar 

  52. Zheng, Y. & Rudensky, A. Y. Foxp3 in control of the regulatory T cell lineage. Nature Immunol. 8, 457–462 (2007).

    Article  CAS  Google Scholar 

  53. Yang, X. O. et al. Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity 29, 44–56 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Zhou, L. et al. IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nature Immunol. 8, 967–974 (2007).

    Article  CAS  Google Scholar 

  55. Zhou, L. et al. TGF-β-induced Foxp3 inhibits TH17 cell differentiation by antagonizing RORγt function. Nature 453, 236–240 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Du, J., Huang, C., Zhou, B. & Ziegler, S. Isoform-specific inhibition of RORα-mediated transcriptional activation by human FOXP3. J. Immunol. 180, 4785–4792 (2008).

    Article  CAS  PubMed  Google Scholar 

  57. Ichiyama, K. et al. Foxp3 inhibits RORγt-mediated IL-17A mRNA transcription through direct interaction with RORγt. J. Biol. Chem. 283, 17003–17008 (2008).

    Article  CAS  PubMed  Google Scholar 

  58. Deknuydt, F., Bioley, G., Valmori, D. & Ayyoub, M. IL-1β and IL-2 convert human Treg into TH17 cells. Clin. Immunol. 131, 298–307 (2009).

    Article  CAS  PubMed  Google Scholar 

  59. Beriou, G. et al. IL-17 producing human peripheral regulatory T cells retain suppressive function. Blood 113, 4240–4249 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Koenen, H. J. et al. Human CD25highFoxp3pos regulatory T cells differentiate into IL-17-producing cells. Blood 112, 2340–2352 (2008).

    Article  CAS  PubMed  Google Scholar 

  61. Osorio, F. et al. DC activated via dectin-1 convert Treg into IL-17 producers. Eur. J. Immunol. 38, 3274–3281 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Sharma, M. D. et al. Indoleamine 2, 3-dioxygenase controls conversion of Foxp3+ Tregs to TH17-like cells in tumor-draining lymph nodes. Blood 113, 6102–6111 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Voo, K. S. et al. Identification of IL-17-producing FOXP3+ regulatory T cells in humans. Proc. Natl Acad. Sci. USA 106, 4793–4798 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Lochner, M. et al. In vivo equilibrium of proinflammatory IL-17+ and regulatory IL-10+ Foxp3+ RORγt+ T cells. J. Exp. Med. 205, 1381–1393 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Chung, Y. et al. Critical regulation of early Th17 cell differentiation by interleukin-1 signaling. Immunity 30, 576–587 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Ono, M. et al. Foxp3 controls regulatory T-cell function by interacting with AML1/Runx1. Nature 446, 685–689 (2007).

    Article  CAS  PubMed  Google Scholar 

  67. Zheng, Y. et al. Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control TH2 responses. Nature 458, 351–356 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Maynard, C. L. & Weaver, C. T. Diversity in the contribution of interleukin-10 to T-cell-mediated immune regulation. Immunol. Rev. 226, 219–233 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Berger, S. L. The complex language of chromatin regulation during transcription. Nature 447, 407–412 (2007).

    Article  CAS  PubMed  Google Scholar 

  70. Wei, G. et al. Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity 30, 155–167 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Wilson, C. B., Rowell, E. & Sekimata, M. Epigenetic control of T-helper-cell differentiation. Nature Rev. Immunol. 9, 91–105 (2009).

    Article  CAS  Google Scholar 

  72. Lexberg, M. H. et al. Th memory for interleukin-17 expression is stable in vivo. Eur. J. Immunol. 38, 2654–2664 (2008).

    Article  CAS  PubMed  Google Scholar 

  73. Lee, Y. K. et al. Late developmental plasticity in the T helper 17 lineage. Immunity 30, 92–107 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Li, B. et al. FOXP3 interactions with histone acetyltransferase and class II histone deacetylases are required for repression. Proc. Natl Acad. Sci. USA 104, 4571–4576 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Samanta, A. et al. TGF-β and IL-6 signals modulate chromatin binding and promoter occupancy by acetylated FOXP3. Proc. Natl Acad. Sci. USA 105, 14023–14027 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Macpherson, A. J., McCoy, K. D., Johansen, F. E. & Brandtzaeg, P. The immune geography of IgA induction and function. Mucosal Immunol. 1, 11–22 (2008).

    Article  CAS  PubMed  Google Scholar 

  77. Tsuji, M. et al. Preferential generation of follicular B helper T cells from Foxp3+ T cells in gut Peyer's patches. Science 323, 1488–1492 (2009).

    Article  CAS  PubMed  Google Scholar 

  78. Du Pasquier, L. & Bernard, C. C. Active suppression of the allogeneic histocompatibility reactions during the metamorphosis of the clawed toad Xenopus. Differentiation 16, 1–7 (1980).

    Article  CAS  PubMed  Google Scholar 

  79. Tsutsui, S., Nakamura, O. & Watanabe, T. Lamprey (Lethenteron japonicum) IL-17 upregulated by LPS-stimulation in the skin cells. Immunogenetics 59, 873–882 (2007).

    Article  CAS  PubMed  Google Scholar 

  80. Rolff, J. Why did the acquired immune system of vertebrates evolve? Dev. Comp. Immunol. 31, 476–482 (2007).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by grants AI35783, AI57956 and DK71176 from the United States National Institutes of Health and by the University of Alabama at Birmingham Mucosal HIV and Immunobiology Center. We thank members of our laboratory for helpful comments and offer our apologies to colleagues whose work could not be adequately discussed or cited owing to space limitations.

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  1. Casey T. Weaver and Robin D. Hatton are at the Department of Pathology, BBRB 870, University Station, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA. cweaver@uab.edu; rdzialo@uab.edu,

    Casey T. Weaver & Robin D. Hatton

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    Casey T. Weaver & Robin D. Hatton

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Weaver, C., Hatton, R. Interplay between the TH17 and TReg cell lineages: a (co-)evolutionary perspective. Nat Rev Immunol 9, 883–889 (2009). https://doi.org/10.1038/nri2660

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