TY - JOUR
T1 - Pathogen-induced human T H17 cells produce IFN-γ or IL-10 and are regulated by IL-1β
AU - Zielinski, Christina E.
AU - Mele, Federico
AU - Aschenbrenner, Dominik
AU - Jarrossay, David
AU - Ronchi, Francesca
AU - Gattorno, Marco
AU - Monticelli, Silvia
AU - Lanzavecchia, Antonio
AU - Sallusto, Federica
PY - 2012/4/26
Y1 - 2012/4/26
N2 - IL-17-producing CD4 + T helper cells (T H17) have been extensively investigated in mouse models of autoimmunity 1. However, the requirements for differentiation and the properties of pathogen-induced human T H17 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 T H17 cells with distinct effector function and differentiation requirements. Candida albicans-specific T H17 cells produced IL-17 and IFN-γ, but no IL-10, whereas Staphylococcus aureus-specific T H17 cells produced IL-17 and could produce IL-10 upon restimulation. IL-6, IL-23 and IL-1β contributed to T H17 differentiation induced by both pathogens, but IL-1β was essential in C. albicans-induced T H17 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 T H17 cells, whereas blockade of IL-1β in vivo led to increased IL-10 production by memory T H17 cells. We also show that, after restimulation, T H17 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 T H17 cells that produce either IFN-γ or IL-10, and identify IL-1β and IL-2 as pro-and anti-inflammatory regulators of T H17 cells both at priming and in the effector phase.
AB - IL-17-producing CD4 + T helper cells (T H17) have been extensively investigated in mouse models of autoimmunity 1. However, the requirements for differentiation and the properties of pathogen-induced human T H17 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 T H17 cells with distinct effector function and differentiation requirements. Candida albicans-specific T H17 cells produced IL-17 and IFN-γ, but no IL-10, whereas Staphylococcus aureus-specific T H17 cells produced IL-17 and could produce IL-10 upon restimulation. IL-6, IL-23 and IL-1β contributed to T H17 differentiation induced by both pathogens, but IL-1β was essential in C. albicans-induced T H17 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 T H17 cells, whereas blockade of IL-1β in vivo led to increased IL-10 production by memory T H17 cells. We also show that, after restimulation, T H17 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 T H17 cells that produce either IFN-γ or IL-10, and identify IL-1β and IL-2 as pro-and anti-inflammatory regulators of T H17 cells both at priming and in the effector phase.
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U2 - 10.1038/nature10957
DO - 10.1038/nature10957
M3 - Article
C2 - 22466287
AN - SCOPUS:84860241847
VL - 484
SP - 514
EP - 518
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7395
ER -