γδ T cells respond directly and selectively to the skin commensal yeastMalasseziafor IL-17-dependent fungal control

Abstract

ABSTRACTStable microbial colonization of the skin depends on tight control by the host immune system. The lipid-dependent yeastMalasseziatypically colonizes skin as a harmless commensal and is subject to host type 17 immunosurveillance, but this fungus has also been associated with diverse skin pathologies in both humans and animals. Using a murine model ofMalasseziaexposure, we show that Vγ4+dermal γδ T cells expand rapidly and are the major source of IL-17A mediating fungal control in colonized skin. A pool of memory-likeMalassezia-responsive Vγ4+T cells persisted in the skin, were enriched in draining lymph nodes even after fungal clearance, and were protective upon fungal re-exposure up to several weeks later. Induction of γδT17 immunity depended on IL-23 and IL-1 family cytokine signalling, whereas Toll-like and C-type lectin receptors were dispensable. Furthermore, Vγ4+T cells fromMalassezia-exposed hosts were able to respond directly and selectively toMalassezia-derived ligands, independently of antigen-presenting host cells. Reactivity of human γδ T cells againstMalasseziaspp. confirmed the relevance of this fungus-specific response across different host species. The fungal moieties detected were shared across diverse species of theMalasseziagenus, but not conserved in other Basidiomycota or Ascomycota. These data provide novel mechanistic insight into the induction and maintenance of type 17 immunosurveillance of skin commensal colonization that has significant implications for cutaneous health.AUTHOR SUMMARYMalasseziais the most abundant fungus living on our skin and is usually harmless, but this microbe has also been shown to play a role in pathological conditions such as eczema and dermatitis. Here, we investigated how a population of Vγ4+γδ T cells protect mouse skin against fungal overgrowth. While generally considered part of the innate immune system, we found that γδ T cells were maintained long afterMalasseziawas cleared from the skin of experimentally-infected animals. These cells displayed memory-like features and were highly efficient at fighting the fungus after a secondary challenge. We observed that classic fungal pattern recognition receptors were not involved, and that antigen-presenting cells were not required to generateMalassezia-protective γδ T cells. Finally, we confirmed that γδ T cells can recogniseMalassezia, both in mice and human hosts. The fungal structure that triggers these responses was highly specific toMalasseziaand was not conserved among other fungi. Our results highlight for the first time an important role for γδ T cells in preventing uncontrolled growth of the most abundant skin fungus. These findings have implications for severalMalassezia-associated pathologies including eczema, dermatitis, and potentially even cancer.