IL-17 Production by γδ+ T Cells Is Critical for Inducing Th17 Responses in the Female Genital Tract and Regulated by Estradiol and Microbiota

IL-17 can be produced by adaptive immune cells such as T_h17 cells and by immune cells that produce IL-17 without prior priming. This latter category, which we will refer to as "innate," includes innate cells such as NK cells and innate lymphoid cells and innate-like T cell populations such as NKT cells and γδ⁺ T cells. Studies in mucosal tissues have shown that the induction of T_h17 immunity is amplified by innate IL-17 produced within those tissues. However, the role of innate IL-17 and its effect on T_h17 induction in the female genital tract (FGT) is largely unknown. In this study, we characterize the primary source of IL-17-secreting vaginal cells and show that innate IL-17 plays a critical role in priming adaptive T_h17 responses in the FGT. Under homeostatic conditions, γδ⁺ T cells were the predominant source of innate IL-17 in the murine FGT, and this population was modulated by both the sex hormone estradiol and the presence of commensal microbiota. Compared with wild-type C57BL/6 mice, vaginal APCs isolated from IL-17A-deficient (IL-17A^-/- ) mice were severely impaired at priming T_h17 responses in APC-T cell cocultures. Furthermore, the defect in T_h17 induction in the absence of innate IL-17 was associated with impairment of IL-1β production by vaginal CD11c⁺ dendritic cells. Overall, our study describes a novel role for IL-17 in the FGT and further demonstrates the importance of factors in the vaginal microenvironment that can influence adaptive immune responses.