Despite the strong evidence of Th17 cells modulating host responses to various forms of candidiasis, no role of the Th17 pathway of immunity could be demonstrated at any level for fungal burden, PMN migration and S100 alarmin production in the vagina during experimental vaginal candidiasis. All Masitinib 790299-79-5 strains of mice deficient in cytokines of Th17-lineage were equally susceptible to vaginal colonization with Candida compared to wild-type mice. Likewise, all animals were able to elicit a robust vaginal PMN response and S100 induction/secretion by vaginal epithelium following inoculation. Although these findings were unexpected based on the strong role of the Th17 response in PMN migration and induction of S100 alarmins, the lack of roles for the Th17 pathway may be explained two-fold. First, previous studies showed that vaginal epithelial cells are a primary source of S100 alarmins following vaginal inoculation with Candida where early Candida adherence to vaginal epithelium within the first 24 h is a critical event in initiating the PMN response. Thus, the S100 alarmin induction during vaginal infection is mediated exclusively by a direct interaction between epithelial cells and Candida. Our current data extends this to exclude any role for Th17 in the process. Second, while host responses by CD4+ T cells are generally required for protection against mucosal candidiasis, no role has been shown for either local or systemic CD4+ T cells against VVC. The lack of a protective role for CD4+ T cells is further supported by accumulating evidence of immunomodulatory mechanisms towards adaptive responses. Hence, it may not be surprising that this also includes Th17-type responses as well as Th22 cells. Of note, there is the possibility that IL-17 and IL-22 are produced by other cellular sources. These may include cd T cells and other innate lymphoid cells in the vaginal mucosa that may act on epithelial cells and contribute to the induction of S100 alarmin-mediated inflammation during vaginal infection. However, while IL-17 and IL-22 were increased moderately in wild-type mice following inoculation, both cytokines were virtually negligible in IL-23p192/2 mice, suggesting that the cytokines by these other cell sources is minimal at best. Despite strong evidence shown here against a role for Th17 cells and the fact that Th17 cells are known to be the major producer of IL-17 and IL-22, we recognize that IL-22 alone still may be a driving force in the PMN response and that IL-22 derived from innate immune cells could initiate the S100 response in vaginal epithelial cells. However, our results from IL-222/2 mice showing elevated vaginal S100 alarmins and PMN infiltration in response to Candida at equivalent levels to wild-type mice reduces the possibility of IL-22 being a primary cytokine in the S100 response. Furthermore, the epithelial cell S100 alarmin response occurs concomitantly with the exclusive presence of PMNs within 48 h post-inoculation. Thus, it is unlikely that contributions of S100 alarmins are made by other nonresident innate or adaptive cells. However, we recognize that other resident innate cells could contribute at low levels. Once the S100 alarmins and PMNs are present, the inflammatory process is in place and continues for a considerable time. Hence, the role for the Th17 pathway in this model would likely be evident early as much as later in the infection. Taken together, we hypothesize that the vaginal S100 induction and accompanied PMN response are initiated.