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.

cAMP response element modulator α controls IL2 and IL17A expression during CD4 lineage commitment and subset distribution in lupus

“…Various T helper cell subsets are involved in host defense, and a tight balance between these populations and the subsequently produced pro-and anti-inflammatory cytokines is essential for immune homeostasis (1,2). A growing body of literature documents that a disruption of this balance can result in chronic inflammation and autoimmunity or increased susceptibility to infections.…”

“…Primed CD4 + T cells either migrate to sites of inflammation or persist as circulating effector memory CD4 + T cells. Central memory CD4 + T cells migrate to secondary lymphatic tissues, where they wait for a secondary challenge to exert enhanced immune responses (2,3). Sallusto et al (1999) and others demonstrated that naive, central, and effector memory CD4 + T-cell subsets are defined by the absence or presence of surface markers, including the chemokine receptor CCR7 that reflects tissue-homing capacities to lymph nodes (3).…”

Innate and adaptive effects of inflammasomes on T cell responses

“…The use of knockout mouse strains highlighted the role of caspase-1 and ASC in Th17 priming during Candida albicans infection [42 ]. C. albicans-induced IL-1b drives the differentiation of Th17 cells secreting IL-17 alongside with IFN-g [47 ].…”

IL-10: A Paradigm for Counterregulatory Cytokines

“…IL-10 was not only produced by Tr1 cells, but also promoted their differentiation (7). Recently, it also was shown that Staphylococcus aureus priming of naive human T cells generated IL-10-producing Th17 cells (regulatory Th17 cells), potentially as an intrinsic mechanism to suppress excessive inflammation in response to infection (8,9). Studies using in vivo infection with Toxoplasma gondii and Leishmania major revealed that Tbet 1 Th1 cells also secreted IL-10 (10, 11).…”