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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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.
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). https://doi.org/10.1038/nature10957
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