“Natural” Th17 cells control Candida albicans infections in the oral mucosa (MUC7P.749)

Oropharyngeal candidiasis (OPC) is an opportunistic mucosal infection caused by the commensal fungus Candida albicans. To date, there is a paucity of research on oral mucosal immunity in general and to fungi in particular. Humans with rare mutations have revealed a vital protective role of IL-17 signaling to OPC. It has long been assumed that conventional “iTh17” cells produce IL-17. However, many innate populations also produce IL-17, but their role in oral immunity is unknown. Since rodents are naive to C. albicans, we evaluated OPC in a murine model. T cell receptor rearrangement is required for immunity, since Rag1-/-, SCID and IL-7Rα-/- mice are susceptible to OPC. However, iTh17, NK and NKT cells were dispensable. We identified a CD3+CD4+CD44hiTCRβ+ tissue-resident population in tongue that produces IL-17 rapidly upon Candida exposure. These were phenotypically identical to ‘natural Th17’ cells, a recently described, thymically derived innate lymphocyte population whose function is highly enigmatic. Development of nTh17 and iTh17 cells involves differential AKT/mTOR pathways, with nTh17 cells requiring mTORC2, and iTH17 cells requiring mTORC1. Consistently, mice deficient in the mTORC2 subunit Rictor were highly susceptible to OPC, whereas mice treated with rapamycin, which selectively targets mTORC1, were similar to WT mice. Therefore, innate immunity to Candida requires nTh17 cells, whose presence in the oral mucosa ideally positions them to control oral pathogens.