Oral-Resident Natural Th17 Cells and γδ T Cells Control Opportunistic Candida albicans Infections

Oropharyngeal candidiasis (OPC) is an opportunistic mucosal infection caused by the commensal Candida albicans. To date, there is a paucity of research focusing on oral mucosal immune responses and fungal immunity. Individuals with rare genetic defects have shown the protective role of Th17-associated cytokines IL-23 and IL-17 to OPC. OPC is frequent in HIV/AIDS, implicating adaptive immunity. It has long been assumed that classic iTh17 cells are the primary source of IL-17 in OPC. However, multiple innate cell populations can produce IL-17, though their role in oral immunity is largely unknown. Since rodents are naïve to Candida albicans, we used a mouse OPC model to focus on innate antifungal immunity. T cell receptor rearrangement is required, as Rag1-/-, SCID, IL-7Rα-/- mice are susceptible to OPC. However, classic iTh17, NK and NKT cells were dispensable. Using fate-tracking IL-17 reporter mice, we found that IL-17 is produced within 1-2 d by tongue-resident populations of γδ T cells and CD3⁺CD4⁺CD44^hiTCRβ⁺CCR6⁺ natural Th17 (nTh17) cells, but not by innate lymphoid cells (ILCs) or NK cells. The role of γδ T cells during dermal candidiasis is well understood, and this cell type is known to mediate host defense at mucosal surfaces through the production of IL-17. To date the function of nTh17 cells is poorly understood, and little is known about the role of nTh17 cells in infections. This is the first demonstration of a host-protective activity for nTh17 cells, and suggests that this population serves as a mucosal sentinel that controls oral pathogens.