title: Pathogen-induced human TH17 cells produce IFN-γ or IL-10 and are regulated by IL-1β.
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.
authors.affiliation: Institute for Research in Biomedicine, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland. christina.zielinski@charite.de
authors.forename: Christina E
authors.initials: CE
authors.lastname: Zielinski
authors.forename: Federico
authors.initials: F
authors.lastname: Mele
authors.forename: Dominik
authors.initials: D
authors.lastname: Aschenbrenner
authors.forename: David
authors.initials: D
authors.lastname: Jarrossay
authors.forename: Francesca
authors.initials: F
authors.lastname: Ronchi
authors.forename: Marco
authors.initials: M
authors.lastname: Gattorno
authors.forename: Silvia
authors.initials: S
authors.lastname: Monticelli
authors.forename: Antonio
authors.initials: A
authors.lastname: Lanzavecchia
authors.forename: Federica
authors.initials: F
authors.lastname: Sallusto
mesh_terms: D017951:Antigen Presentation / Q000276:immunology; D002176:Candida albicans / Q000276:immunology*; D002454:Cell Differentiation; D015536:Down-Regulation; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis*; D016753:Interleukin-10 / Q000096:biosynthesis*; D020381:Interleukin-17 / Q000096:biosynthesis; D053583:Interleukin-1beta / Q000276:immunology*; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000276:immunology; D008213:Lymphocyte Activation; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D013211:Staphylococcus aureus / Q000276:immunology*; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D020381:Interleukin-17; D053583:Interleukin-1beta; D007376:Interleukin-2; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539900:RORC protein, human; D050799:STAT5 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma