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Pathogen-induced human TH17 cells produce IFN-γ or IL-10 and are regulated by IL-1β

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IL-17-producing CD4+ T helper cells (TH17) have been extensively investigated in mouse models of autoimmunity1. However, the requirements for differentiation and the properties of pathogen-induced human TH17 cells remain poorly defined. Using an approach that combines the in vitro priming of naive T cells with the ex vivo analysis of memory T cells, we describe here two types of human TH17 cells with distinct effector function and differentiation requirements. Candida albicans-specific TH17 cells produced IL-17 and IFN-γ, but no IL-10, whereas Staphylococcus aureus-specific TH17 cells produced IL-17 and could produce IL-10 upon restimulation. IL-6, IL-23 and IL-1β contributed to TH17 differentiation induced by both pathogens, but IL-1β was essential in C. albicans-induced TH17 differentiation to counteract the inhibitory activity of IL-12 and to prime IL-17/IFN-γ double-producing cells. In addition, IL-1β inhibited IL-10 production in differentiating and in memory TH17 cells, whereas blockade of IL-1β in vivo led to increased IL-10 production by memory TH17 cells. We also show that, after restimulation, TH17 cells transiently downregulated IL-17 production through a mechanism that involved IL-2-induced activation of STAT5 and decreased expression of ROR-γt. Taken together these findings demonstrate that by eliciting different cytokines C. albicans and S. aureus prime TH17 cells that produce either IFN-γ or IL-10, and identify IL-1β and IL-2 as pro- and anti-inflammatory regulators of TH17 cells both at priming and in the effector phase.

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Figure 1: In vitro priming of human naive T cells with C. albicans or S. aureus induces T H17 cells that produce either IFN-γ or IL-10.
Figure 2: Cytokine production by C. albicans- and S. aureus-specific memory T H17 cells.
Figure 3: Cytokine requirements for T H17 differentiation induced by C. albicans and S. aureus.
Figure 4: Downregulation of ROR-γt and IL-2-mediated activation of STAT5 limit IL-17 production in activated T H17 clones.

Change history

  • 25 April 2012

    A present address was added for C.E.Z.


  1. 1

    Korn, T., Bettelli, E., Oukka, M. & Kuchroo, V. K. IL-17 and Th17 Cells. Annu. Rev. Immunol. 27, 485–517 (2009)

    CAS  Article  Google Scholar 

  2. 2

    Romani, L. Immunity to fungal infections. Nature Rev. Immunol. 11, 275–288 (2011)

    CAS  Article  Google Scholar 

  3. 3

    Milner, J. D. et al. Impaired TH17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature 452, 773–776 (2008)

    ADS  CAS  Article  Google Scholar 

  4. 4

    Ma, C. S. et al. Deficiency of Th17 cells in hyper IgE syndrome due to mutations in STAT3 . J. Exp. Med. 205, 1551–1557 (2008)

    CAS  Article  Google Scholar 

  5. 5

    Puel, A. et al. Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity. Science 332, 65–68 (2011)

    ADS  CAS  Article  Google Scholar 

  6. 6

    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)

    CAS  Article  Google Scholar 

  7. 7

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

    CAS  Article  Google Scholar 

  8. 8

    Jankovic, D. et al. Conventional T-bet+Foxp3 Th1 cells are the major source of host-protective regulatory IL-10 during intracellular protozoan infection. J. Exp. Med. 204, 273–283 (2007)

    CAS  Article  Google Scholar 

  9. 9

    Saraiva, M. et al. Interleukin-10 production by Th1 cells requires interleukin-12-induced STAT4 transcription factor and ERK MAP kinase activation by high antigen dose. Immunity 31, 209–219 (2009)

    CAS  Article  Google Scholar 

  10. 10

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

    CAS  Article  Google Scholar 

  11. 11

    Ghoreschi, K. et al. Generation of pathogenic TH17 cells in the absence of TGF-β signalling. Nature 467, 967–971 (2010)

    ADS  CAS  Article  Google Scholar 

  12. 12

    Stumhofer, J. S. et al. Interleukins 27 and 6 induce STAT3-mediated T cell production of interleukin 10. Nature Immunol. 8, 1363–1371 (2007)

    CAS  Article  Google Scholar 

  13. 13

    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. Nature Immunol. 8, 1390–1397 (2007)

    CAS  Article  Google Scholar 

  14. 14

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

    CAS  Article  Google Scholar 

  15. 15

    Yang, X. P. et al. Opposing regulation of the locus encoding IL-17 through direct, reciprocal actions of STAT3 and STAT5. Nature Immunol. 12, 247–254 (2011)

    CAS  Article  Google Scholar 

  16. 16

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

    CAS  Article  Google Scholar 

  17. 17

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

    CAS  Article  Google Scholar 

  18. 18

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

    ADS  CAS  Article  Google Scholar 

  19. 19

    Manel, N., Unutmaz, D. & Littman, D. R. The differentiation of human TH-17 cells requires transforming growth factor-β and induction of the nuclear receptor RORγt. Nature Immunol. 9, 641–649 (2008)

    CAS  Article  Google Scholar 

  20. 20

    Cosmi, L. et al. Human interleukin 17-producing cells originate from a CD161+CD4+ T cell precursor. J. Exp. Med. 205, 1903–1916 (2008)

    CAS  Article  Google Scholar 

  21. 21

    Volpe, E. et al. A critical function for transforming growth factor-β, interleukin 23 and proinflammatory cytokines in driving and modulating human TH-17 responses. Nature Immunol. 9, 650–657 (2008)

    CAS  Article  Google Scholar 

  22. 22

    Napolitani, G., Acosta-Rodriguez, E. V., Lanzavecchia, A. & Sallusto, F. Prostaglandin E2 enhances Th17 responses via modulation of IL-17 and IFN-γ production by memory CD4+ T cells. Eur. J. Immunol. 39, 1301–1312 (2009)

    CAS  Article  Google Scholar 

  23. 23

    Smeekens, S. P. et al. The Candida Th17 response is dependent on mannan- and β-glucan-induced prostaglandin E2. Int. Immunol. 22, 889–895 (2010)

    CAS  Article  Google Scholar 

  24. 24

    Laurence, A. et al. Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity 26, 371–381 (2007)

    CAS  Article  Google Scholar 

  25. 25

    Hoyer, K. K., Dooms, H., Barron, L. & Abbas, A. K. Interleukin-2 in the development and control of inflammatory disease. Immunol. Rev. 226, 19–28 (2008)

    CAS  Article  Google Scholar 

  26. 26

    Gattorno, M. et al. Pattern of interleukin-1β secretion in response to lipopolysaccharide and ATP before and after interleukin-1 blockade in patients with CIAS1 mutations. Arthritis Rheum. 56, 3138–3148 (2007)

    CAS  Article  Google Scholar 

  27. 27

    Geiger, R., Duhen, T., Lanzavecchia, A. & Sallusto, F. Human naive and memory CD4+ T cell repertoires specific for naturally processed antigens analyzed using libraries of amplified T cells. J. Exp. Med. 206, 1525–1534 (2009)

    CAS  Article  Google Scholar 

  28. 28

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

    CAS  Article  Google Scholar 

  29. 29

    Crome, S. Q., Wang, A. Y., Kang, C. Y. & Levings, M. K. The role of retinoic acid-related orphan receptor variant 2 and IL-17 in the development and function of human CD4+ T cells. Eur. J. Immunol. 39, 1480–1493 (2009)

    CAS  Article  Google Scholar 

  30. 30

    Mayoral, R. J. & Monticelli, S. Stable overexpression of miRNAs in bone marrow-derived murine mast cells using lentiviral expression vectors. Methods Mol. Biol. 667, 205–214 (2010)

    CAS  Article  Google Scholar 

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We thank O. Petrini and C. Fragoso for providing microorganisms, and M. Levings for providing the RORC lentiviral vector. We thank A. Rossetti for technical assistance, D. Baumjohann for artwork and S. Jacob and M. Uguccioni for critical reading of the manuscript. This work was supported by a fellowship of the German Research Foundation (DFG) to C.E.Z (Zi 1262/1-1) and by grants from the Swiss National Science Foundation (N. 131092 to F.S. and 126027 to A.L.) and the Institute of Arthritis Research (IAR). A.L. is supported by the Helmut Horten Foundation.

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C.E.Z. designed and performed experiments, analysed the data and wrote the manuscript, D.J. performed the sorting and analysed data, F.R. performed and analysed experiments in the mouse system, F.M., D.A., and S.M. performed experiments to address the mechanism of IL-17 downregulation and analysed the data, M.G. provided the samples from CAPS patients and analysed the data, A.L. wrote the manuscript, F.S. provided overall supervision, analysed the data and wrote the manuscript.

Corresponding authors

Correspondence to Christina E. Zielinski or Federica Sallusto.

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The authors declare no competing financial interests.

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Zielinski, C., Mele, F., Aschenbrenner, D. et al. Pathogen-induced human TH17 cells produce IFN-γ or IL-10 and are regulated by IL-1β. Nature 484, 514–518 (2012).

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