Interleukin-17 overcomes inhibition of Th1 immune responses following mycobacterial exposure (168.2)

Abstract

Abstract Tuberculosis (TB) caused by the intracellular pathogen Mycobacterium tuberculosis, remains a worldwide health problem. Generation of effective T helper cell type 1 (Th1) responses are required for immunity against intracellular bacteria. However, multiple bacteria successfully inhibit the direct pathway of induction of Th1 responses, promoting the production of factors such as prostaglandin E2 (PGE2) and interleukin (IL-10), that suppress IL-12 and interferon gamma (IFNγ) production. Here, in a model of Mycobacterium bovis Bacille Calmette Guerin (BCG) vaccination, we demonstrate that a nominal Th1-suppresive factor, PGE2, can promote an alternative pathway of induction of Th1 immunity that is mediated by IL-23-dependent IL-17 induction. We show that PGE2 limits early Th1 responses via IL-10 production but also drives Th17 responses via IL-23 production. IL-17 then functions to overcome PGE2-IL-10-mediated Th1 inhibition and drive Th1 immunity following BCG exposure. Therefore, we demonstrate that PGE2-induced IL-17 response allows overcoming BCG-induced PGE2- and IL-10-mediated inhibition of IL-12 production and Th1 responses. The currently described alternative IL-17-dependent pathway of induction of Th1 immunity helps to understand the complex role of PGE2 in the regulation of immune responses and helps to design new therapeutic approaches in chronic intracellular infections.