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Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells

Nature Immunology volume 10, pages 857–863 (2009)Cite this article

Abstract

Interleukin 22 (IL-22) is a cytokine produced by the TH-17 lineage of helper T cells and NK-22 subset of natural killer cells that acts on epithelial cells and keratinocytes and has been linked to skin homeostasis and inflammation. Here we characterize a population of human skin-homing memory CD4+ T cells that expressed the chemokine receptors CCR10, CCR6 and CCR4 and produced IL-22 but neither IL-17 nor interferon-γ (IFN-γ). Clones isolated from this population produced IL-22 only and had low or undetectable expression of the TH-17 and T helper type 1 (TH1) transcription factors RORγt and T-bet. The differentiation of T cells producing only IL-22 was efficiently induced in naive T cells by plasmacytoid dendritic cells in an IL-6- and tumor necrosis factor–dependent way. Our findings delineate a previously unknown subset of human CD4+ effector T cells dedicated to skin pathophysiology.

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Figure 1: Heterogeneity of IL-22-producing T cells in the CD4+CCR6+ memory subset.
Figure 2: CCR10+CCR6+CCR4+ skin-homing T cell populations are highly enriched for T cells that produce IL-22 only.
Figure 3: Transcription factor expression by TH-22 clones.
Figure 4: IL-6 and TNF promote TH-22 differentiation.
Figure 5: TH-22 cells are primed by pDCs in an IL-6- and TNF-dependent way.

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References

  1. Bromley, S.K., Mempel, T.R. & Luster, A.D. Orchestrating the orchestrators: chemokines in control of T cell traffic. Nat. Immunol. 9, 970–980 (2008).

    Article  CAS  Google Scholar 

  2. Szabo, S.J. et al. A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 100, 655–669 (2000).

    Article  CAS  Google Scholar 

  3. Zheng, W. & Flavell, R.A. The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell 89, 587–596 (1997).

    Article  CAS  Google Scholar 

  4. 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. Nat. Immunol. 6, 1123–1132 (2005).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  6. Liang, S.C. et al. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J. Exp. Med. 203, 2271–2279 (2006).

    Article  CAS  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  Google Scholar 

  8. 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  Google Scholar 

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

    Article  CAS  Google Scholar 

  10. Acosta-Rodriguez, E.V., Napolitani, G., Lanzavecchia, A. & Sallusto, F. Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17–producing human T helper cells. Nat. Immunol. 8, 942–949 (2007).

    Article  CAS  Google Scholar 

  11. 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  Google Scholar 

  12. 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  Google Scholar 

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

    Article  CAS  Google Scholar 

  14. Langrish, C.L. et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 201, 233–240 (2005).

    Article  CAS  Google Scholar 

  15. Korn, T. et al. IL-21 initiates an alternative pathway to induce proinflammatory TH17 cells. Nature 448, 484–487 (2007).

    Article  CAS  Google Scholar 

  16. Yang, L. et al. IL-21 and TGF-β are required for differentiation of human TH17 cells. Nature 454, 350–352 (2008).

    Article  CAS  Google Scholar 

  17. Wilson, N.J. et al. Development, cytokine profile and function of human interleukin 17–producing helper T cells. Nat. Immunol. 8, 950–957 (2007).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  19. Annunziato, F. et al. Phenotypic and functional features of human Th17 cells. J. Exp. Med. 204, 1849–1861 (2007).

    Article  CAS  Google Scholar 

  20. Butcher, E.C. & Picker, L.J. Lymphocyte homing and homeostasis. Science 272, 60–66 (1996).

    Article  CAS  Google Scholar 

  21. Kupper, T.S. & Fuhlbrigge, R.C. Immune surveillance in the skin: mechanisms and clinical consequences. Nat. Rev. Immunol. 4, 211–222 (2004).

    Article  CAS  Google Scholar 

  22. Salmi, M. & Jalkanen, S. Lymphocyte homing to the gut: attraction, adhesion, and commitment. Immunol. Rev. 206, 100–113 (2005).

    Article  CAS  Google Scholar 

  23. Sallusto, F. & Mackay, C.R. Chemoattractants and their receptors in homeostasis and inflammation. Curr. Opin. Immunol. 16, 724–731 (2004).

    Article  CAS  Google Scholar 

  24. Acosta-Rodriguez, E.V. et al. Surface phenotype and antigenic specificity of human interleukin 17–producing T helper memory cells. Nat. Immunol. 8, 639–646 (2007).

    Article  CAS  Google Scholar 

  25. Singh, S.P., Zhang, H.H., Foley, J.F., Hedrick, M.N. & Farber, J.M. Human T cells that are able to produce IL-17 express the chemokine receptor CCR6. J. Immunol. 180, 214–221 (2008).

    Article  CAS  Google Scholar 

  26. Reboldi, A. et al. C–C chemokine receptor 6–regulated entry of TH-17 cells into the CNS through the choroid plexus is required for the initiation of EAE. Nat. Immunol. 10, 514–523 (2009).

    Article  CAS  Google Scholar 

  27. Sallusto, F., Lenig, D., Mackay, C.R. & Lanzavecchia, A. Flexible programs of chemokine receptor expression on human polarized T helper 1 and 2 lymphocytes. J. Exp. Med. 187, 875–883 (1998).

    Article  CAS  Google Scholar 

  28. Lord, G.M. et al. T-bet is required for optimal proinflammatory CD4+ T-cell trafficking. Blood 106, 3432–3439 (2005).

    Article  CAS  Google Scholar 

  29. Sigmundsdottir, H. & Butcher, E.C. Environmental cues, dendritic cells and the programming of tissue-selective lymphocyte trafficking. Nat. Immunol. 9, 981–987 (2008).

    Article  CAS  Google Scholar 

  30. Sigmundsdottir, H. et al. DCs metabolize sunlight-induced vitamin D3 to 'program' T cell attraction to the epidermal chemokine CCL27. Nat. Immunol. 8, 285–293 (2007).

    Article  CAS  Google Scholar 

  31. Iwata, M. et al. Retinoic acid imprints gut-homing specificity on T cells. Immunity 21, 527–538 (2004).

    Article  CAS  Google Scholar 

  32. Cella, M. et al. A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity. Nature 457, 722–725 (2009).

    Article  CAS  Google Scholar 

  33. Zenewicz, L.A. et al. Innate and adaptive interleukin-22 protects mice from inflammatory bowel disease. Immunity 29, 947–957 (2008).

    Article  CAS  Google Scholar 

  34. Luci, C. et al. Influence of the transcription factor RORγt on the development of NKp46+ cell populations in gut and skin. Nat. Immunol. 10, 75–82 (2009).

    Article  CAS  Google Scholar 

  35. Wolk, K. & Sabat, R. Interleukin-22: a novel T- and NK-cell derived cytokine that regulates the biology of tissue cells. Cytokine Growth Factor Rev. 17, 367–380 (2006).

    Article  CAS  Google Scholar 

  36. Wolk, K. et al. IL-22 regulates the expression of genes responsible for antimicrobial defense, cellular differentiation, and mobility in keratinocytes: a potential role in psoriasis. Eur. J. Immunol. 36, 1309–1323 (2006).

    Article  CAS  Google Scholar 

  37. McGeachy, M.J. et al. TGF-β and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain TH-17 cell–mediated pathology. Nat. Immunol. 8, 1390–1397 (2007).

    Article  CAS  Google Scholar 

  38. Zheng, Y. et al. Interleukin-22, a TH17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature 445, 648–651 (2007).

    Article  CAS  Google Scholar 

  39. Ma, H.L. et al. IL-22 is required for Th17 cell-mediated pathology in a mouse model of psoriasis-like skin inflammation. J. Clin. Invest. 118, 597–607 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Boniface, K. et al. A role for T cell-derived interleukin 22 in psoriatic skin inflammation. Clin. Exp. Immunol. 150, 407–415 (2007).

    Article  CAS  Google Scholar 

  41. Reiss, Y., Proudfoot, A.E., Power, C.A., Campbell, J.J. & Butcher, E.C. CC chemokine receptor (CCR)4 and the CCR10 ligand cutaneous T cell-attracting chemokine (CTACK) in lymphocyte trafficking to inflamed skin. J. Exp. Med. 194, 1541–1547 (2001).

    Article  CAS  Google Scholar 

  42. Seder, R.A., Darrah, P.A. & Roederer, M. T-cell quality in memory and protection: implications for vaccine design. Nat. Rev. Immunol. 8, 247–258 (2008).

    Article  CAS  Google Scholar 

  43. Hughes, T. et al. Stage three immature human natural killer cells found in secondary lymphoid tissue constitutively and selectively express the TH17 cytokine interleukin-22. Blood 113, 4008–4010 (2009).

    Article  CAS  Google Scholar 

  44. Wolk, K. et al. IL-22 increases the innate immunity of tissues. Immunity 21, 241–254 (2004).

    Article  CAS  Google Scholar 

  45. Messi, M. et al. Memory and flexibility of cytokine gene expression as separable properties of human TH1 and TH2 lymphocytes. Nat. Immunol. 4, 78–86 (2003).

    Article  CAS  Google Scholar 

  46. Rivino, L. et al. Chemokine receptor expression identifies Pre-T helper (Th)1, Pre-Th2, and nonpolarized cells among human CD4+ central memory T cells. J. Exp. Med. 200, 725–735 (2004).

    Article  CAS  Google Scholar 

  47. Trifari, S., Kaplan, C.D., Tran, E.H., Crellin, N.K. & Spitz, H. Identification of a human helper T cell population that produces abundant IL-22 and is distinct from TH-17, TH1 and TH2 cells. Nat. Immunol. advance online publication, doi:10.1038/ni1770 (5 July 2009).

  48. Homey, B. et al. CCL27–CCR10 interactions regulate T cell-mediated skin inflammation. Nat. Med. 8, 157–165 (2002).

    Article  CAS  Google Scholar 

  49. Gilliet, M., Cao, W. & Liu, Y.J. Plasmacytoid dendritic cells: sensing nucleic acids in viral infection and autoimmune diseases. Nat. Rev. Immunol. 8, 594–606 (2008).

    Article  CAS  Google Scholar 

  50. Albanesi, C. et al. Chemerin expression marks early psoriatic skin lesions and correlates with plasmacytoid dendritic cell recruitment. J. Exp. Med. 206, 249–258 (2009).

    Article  CAS  Google Scholar 

  51. Lande, R. et al. Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature 449, 564–569 (2007).

    Article  CAS  Google Scholar 

  52. Nograles, K.E. et al. IL-22-producing “T22” T cells account for upregulated IL-22 in atopic dermatitis despite reduced IL-17-producing TH17 T cells. J. Allergy Clin. Immunol. 123, 1244–1252 (2009).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank G. Napolitani for discussions; A. Cavani (Istituto Dermopatico dell'Immacolata) for T cells from psoriatic skin lesions; and M. Roederer (US National Institutes of Health) for the Spice and Pestle software. Supported by the Swiss National Science Foundation (31-101962 to F.S.), the European Commission Framework Programme 6 (Innovative Chemokine-based Therapeutic Strategies for Autoimmunity and Chronic Inflammation; LSB-CT-2005-518167) and the Helmut Horten Foundation (to the Institute for Research in Biomedicine).

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  1. Thomas Duhen and Rebekka Geiger: These authors contributed equally to this work.

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  1. Institute for Research in Biomedicine, Bellinzona, Switzerland

    Thomas Duhen, Rebekka Geiger, David Jarrossay, Antonio Lanzavecchia & Federica Sallusto

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Contributions

T.D. designed and did experiments and analyzed data; R.G. did experiments and analyzed data; D.J. sorted T cell populations; A.L. wrote the manuscript; and F.S. designed experiments, analyzed data, wrote the manuscript and provided overall direction.

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Correspondence to Federica Sallusto.

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Duhen, T., Geiger, R., Jarrossay, D. et al. Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells. Nat Immunol 10, 857–863 (2009). https://doi.org/10.1038/ni.1767

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