Dermal innate-like T cells mediate anti-fungal immunity through direct sensing of mycoflora-derived metabolites 2463

Description IL-17, produced by Type 3 lymphocytes (T3L) Th17, Tγδ17, MAIT17, and ILC3 cells, is a critical mediator of anti-fungal immunity. IL-17 production by T3L is regulated by Pattern Recognition Receptors (PRRs), cytokine receptors, or through T cell Receptor (TCR) recognition of antigen. The T3L response to mycoflora is vital for host tolerance and promotion of tissue barrier fitness. Here we show that skin commensal fungus Malassezia furfur is directly recognized by a subset of dermal Tγδ17 cells (Vγ2+), leading to expansion and IL-17 production upon topical association. Mechanistically, Vγ2+ Tγδ17 cells sensing of M. furfur is independent of canonical MHC molecules, IL-23R, IL-1R, and CARD9-dependent PAMPs. Furthermore, supernatant from M. furfur stimulates specifically Vγ2+ Tγδ17 cells to produce IL-17 both in vitro and in vivo, suggesting that secreted fungal molecule(s) directly activates Vγ2+ Tγδ17. cells. The molecular basis of this novel interaction is currently being deciphered. Most critically, mice previously associated with M. furfur are armed with protection against lethal doses of other pathogenic fungal species. This primed protection is strictly dependent on Vγδ2+ Tγδ17 cells as no other T3L subsets can perform the same function. Our studies suggest that a subset of dermal innate-like Tγδ17 cells surveil local tissue environment through sensing of fungal-derived metabolites to mediate systemic cross-protection against other pathogens that are controlled by IL-17. Funding Sources Supported by T32 AI007349-33.