bioRxiv2023
Stable microbial colonization of the skin depends on tight control by the host immune system. The lipid-dependent yeast Malassezia typically 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 of Malassezia exposure, we show that V{gamma}4+ dermal {gamma}{delta} T cells expand rapidly and are the major source of IL-17A mediating fungal control in colonized skin. A pool of memory-like Malassezia-responsive V{gamma}4+ 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 {gamma}{delta}T17 immunity depended on IL-23 and IL-1 family cytokine signalling, whereas Toll-like and C-type lectin receptors were dispensable. Furthermore, V{gamma}4+ T cells from Malassezia-exposed hosts were able to respond directly and selectively to Malassezia-derived ligands, independently of antigen-presenting host cells. Reactivity of human {gamma}{delta} T cells against Malassezia spp. confirmed the relevance of this fungus-specific response across different host species. The fungal moieties detected were shared across diverse species of the Malassezia genus, 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 SUMMARYMalassezia is 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 V{gamma}4+ {gamma}{delta} T cells protect mouse skin against fungal overgrowth. While generally considered part of the innate immune system, we found that {gamma}{delta} T cells were maintained long after Malassezia was 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 generate Malassezia-protective {gamma}{delta} T cells. Finally, we confirmed that {gamma}{delta} T cells can recognise Malassezia, both in mice and human hosts. The fungal structure that triggers these responses was highly specific to Malassezia and was not conserved among other fungi. Our results highlight for the first time an important role for {gamma}{delta} T cells in preventing uncontrolled growth of the most abundant skin fungus. These findings have implications for several Malassezia-associated pathologies including eczema, dermatitis, and potentially even cancer.