Oral epithelial cells orchestrate innate type 17 responses to through the virulence factor candidalysin.

is a dimorphic commensal fungus that causes severe oral infections in immunodeficient patients. Invasion of hyphae into oral epithelium is an essential virulence trait. Interleukin-17 (IL-17) signaling is required for both innate and adaptive immunity to During the innate response, IL-17 is produced by γδ T cells and a poorly understood population of innate-acting CD4 αβ T cell receptor (TCRαβ) cells, but only the TCRαβ cells expand during acute infection. Confirming the innate nature of these cells, the TCR was not detectably activated during the primary response, as evidenced by mice that report antigen-specific signaling through the TCR. Rather, the expansion of innate TCRαβ cells was driven by both intrinsic and extrinsic IL-1R signaling. Unexpectedly, there was no requirement for CCR6/CCL20-dependent recruitment or prototypical fungal pattern recognition receptors. However, mutants that cannot switch from yeast to hyphae showed impaired TCRαβ cell proliferation and expression. This prompted us to assess the role of candidalysin, a hyphal-associated peptide that damages oral epithelial cells and triggers production of inflammatory cytokines including IL-1. Candidalysin-deficient strains failed to up-regulate or drive the proliferation of innate TCRαβ cells. Moreover, candidalysin signaled synergistically with IL-17, which further augmented the expression of IL-1α/β and other cytokines. Thus, IL-17 and , via secreted candidalysin, amplify inflammation in a self-reinforcing feed-forward loop. These findings challenge the paradigm that hyphal formation per se is required for the oral innate response and demonstrate that establishment of IL-1- and IL-17-dependent innate immunity is induced by tissue-damaging hyphae.