Oral-resident natural Th17 cells and gamma delta T cells control opportunistic Candida albicans infections

Conti et al. show that IL-17 is produced by tongue-resident populations of gamma delta T cells and nTh17 cells in response to oropharyngeal candidiasis in mice. Oropharyngeal candidiasis (OPC) is an opportunistic fungal infection caused by Candida albicans. OPC is frequent in HIV/AIDS, implicating adaptive immunity. Mice are naive to Candida, yet IL-17 is induced within 24 h of infection, and susceptibility is strongly dependent on IL-17R signaling. We sought to identify the source of IL-17 during the early innate response to candidiasis. We show that innate responses to Candida require an intact TCR, as SCID, IL-7R alpha -/-, and Rag1-/- mice were susceptible to OPC, and blockade of TCR signaling by cyclosporine induced susceptibility. Using fate-tracking IL-17 reporter mice, we found that IL-17 is produced within 1-2 d by tongue-resident populations of gamma delta T cells and CD3+CD4+CD44hiTCR beta +CCR6+ natural Th17 (nTh17) cells, but not by TCR-deficient innate lymphoid cells (ILCs) or NK cells. These cells function redundantly, as TCR- beta -/- and TCR- delta -/- mice were both resistant to OPC. Whereas gamma delta T cells were previously shown to produce IL-17 during dermal candidiasis and are known to mediate host defense at mucosal surfaces, nTh17 cells are poorly understood. The oral nTh17 population expanded rapidly after OPC, exhibited high TCR- beta clonal diversity, and was absent in Rag1-/-, IL-7R alpha -/-, and germ-free mice. These findings indicate that nTh17 and gamma delta T cells, but not ILCs, are key mucosal sentinels that control oral pathogens.