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

• Published in: Nature (London) 2012-04, Vol.484 (7395), p.514-518
• Main Authors: Zielinski, Christina E., Mele, Federico, Aschenbrenner, Dominik, Jarrossay, David, Ronchi, Francesca, Gattorno, Marco, Monticelli, Silvia, Lanzavecchia, Antonio, Sallusto, Federica
• Format: Article
• Language: English
• Subjects: 631/250/127; 631/326/421; Analysis of the immune response. Humoral and cellular immunity; Antigen Presentation - immunology; Autoimmunity; Biological and medical sciences; Candida albicans; Candida albicans - immunology; Cell Differentiation; Down-Regulation; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Genetic research; Humanities and Social Sciences; Humans; Immunobiology; Immunologic Memory - immunology; Interferon-gamma - biosynthesis; Interleukin-10 - biosynthesis; Interleukin-17 - biosynthesis; Interleukin-1beta - immunology; Interleukin-2 - antagonists & inhibitors; Interleukin-2 - immunology; letter; Lymphocyte Activation; multidisciplinary; Nuclear Receptor Subfamily 1, Group F, Member 3 - genetics; Nuclear Receptor Subfamily 1, Group F, Member 3 - metabolism; Organs and cells involved in the immune response; Science; Staphylococcus aureus; Staphylococcus aureus - immunology; STAT5 Transcription Factor - metabolism; T cells; Th17 Cells - cytology; Th17 Cells - immunology; Th17 Cells - metabolism; Th17 Cells - secretion; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature10957

Infection with Candida albicans and Staphylococcus aureus gives rise to T H 17 cells with different properties; microbe-induced T-cell differentiation is shown here to depend on the balance between polarizing cytokines rather than absolute amounts. Microbe-specific T H 17 cells Infections with both Candida albicans and Staphylococcus aureus give rise to interleukin-17-producing T helper (T H 17) cells in humans. However, the mechanisms by which the helper cells are primed are different for the two pathogens, and the responding T H 17 cells have different functional properties. Here, microbe-induced T-cell differentiation is shown to depend on the balance between polarizing cytokines, rather than absolute amounts of each. 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-γ, 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-1β contributed to T H 17 differentiation induced by both pathogens, but IL-1β was essential in C. albicans -induced T H 17 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 H 17 cells, whereas blockade of IL-1β 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-γt. Taken together these findings demonstrate that by eliciting different cytokines C. albicans and S. aureus prime T H 17 cells that produce either IFN-γ or IL-10, and identify IL-1β and IL-2 as pro- and anti-inflammatory regulators of T H 17 cells both at priming and in the effector phase.