IL‐23‐dependent IL‐17 drives Th1‐cell responses following Mycobacterium bovis BCG vaccination

Abstract

AbstractThe generation of effective type 1 T helper (Th1)‐cell responses is required for immunity against intracellular bacteria. However, some intracellular bacteria require interleukin (IL)‐17 to drive Th1‐cell immunity and subsequent protective host immunity. Here, in a model of Mycobacterium bovis Bacille Calmette–Guerin (BCG) vaccination in mice, we demonstrate that the dependence on IL‐17 to drive Th1‐cell responses is a host mechanism to overcome bacteria‐induced IL‐10 inhibitory effects. We show that BCG‐induced prostaglandin‐E2 (PGE2) promotes the production of IL‐10 which limits Th1‐cell responses, while simultaneously inducing IL‐23 and Th17‐cell differentiation. The ability of IL‐17 to downregulate IL‐10 and induce IL‐12 production allows the generation of subsequent Th1‐cell responses. Accordingly, BCG‐induced Th17‐cell responses precede the generation of Th1‐cell responses in vivo, whereas the absence of the IL‐23 pathway decreases BCG vaccine‐induced Th17 and Th1‐cell immunity and subsequent vaccine‐induced protection upon M. tuberculosis challenge. Importantly, in the absence of IL‐10, BCG‐induced Th1‐cell responses occur in an IL‐17‐independent manner. These novel data demonstrate a role for the IL‐23/IL‐17 pathway in driving Th1‐cell responses, specifically to overcome IL‐10‐mediated inhibition and, furthermore, show that in the absence of IL‐10, the generation of BCG‐induced Th1‐cell immunity is IL‐17 independent.