Pathogen-induced Human TH17 Cells Produce IFN-γ or IL-10 and Are Regulated by IL-1β

Nature. 2012 Apr 26;484(7395):514-8. doi: 10.1038/nature10957.

Abstract

IL-17-producing CD4+ T helper cells (TH17) have been extensively investigated in mouse models of autoimmunity. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigen Presentation / immunology
  • Candida albicans / immunology*
  • Cell Differentiation
  • Down-Regulation
  • Humans
  • Immunologic Memory / immunology
  • Interferon-gamma / biosynthesis*
  • Interleukin-10 / biosynthesis*
  • Interleukin-17 / biosynthesis
  • Interleukin-1beta / immunology*
  • Interleukin-2 / antagonists & inhibitors
  • Interleukin-2 / immunology
  • Lymphocyte Activation
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
  • STAT5 Transcription Factor / metabolism
  • Staphylococcus aureus / immunology*
  • Th17 Cells / cytology
  • Th17 Cells / immunology*
  • Th17 Cells / metabolism*
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Interleukin-17
  • Interleukin-1beta
  • Interleukin-2
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • RORC protein, human
  • STAT5 Transcription Factor
  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • Interferon-gamma