Journal
NATURE
Volume 484, Issue 7395, Pages 514-U139Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature10957
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Funding
- German Research Foundation (DFG) [Zi 1262/1-1]
- Swiss National Science Foundation [131092, 126027]
- Institute of Arthritis Research (IAR)
- Helmut Horten Foundation
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IL-17-producing CD4(+) T helper cells (T(H)17) have been extensively investigated in mouse models of autoimmunity(1). However, the requirements for differentiation and the properties of pathogen-induced human T(H)17 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(H)17 cells with distinct effector function and differentiation requirements. Candida albicans-specific T(H)17 cells produced IL-17 and IFN-gamma, but no IL-10, whereas Staphylococcus aureus-specific T(H)17 cells produced IL-17 and could produce IL-10 upon restimulation. IL-6, IL-23 and IL-1 beta contributed to T(H)17 differentiation induced by both pathogens, but IL-1 beta was essential in C. albicans-induced T(H)17 differentiation to counteract the inhibitory activity of IL-12 and to prime IL-17/IFN-gamma double-producing cells. In addition, IL-1 beta inhibited IL-10 production in differentiating and in memory T(H)17 cells, whereas blockade of IL-1 beta in vivo led to increased IL-10 production by memory T(H)17 cells. We also show that, after restimulation, T(H)17 cells transiently downregulated IL-17 production through a mechanism that involved IL-2-induced activation of STAT5 and decreased expression of ROR-gamma t. Taken together these findings demonstrate that by eliciting different cytokines C. albicans and S. aureus prime T(H)17 cells that produce either IFN-gamma or IL-10, and identify IL-1 beta and IL-2 as pro-and anti-inflammatory regulators of T(H)17 cells both at priming and in the effector phase.
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