Staged development of long-lived T-cell receptor αβ TH17 resident memory T-cell population toCandida albicansafter skin infection

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Background:Candida albicansis a dimorphic fungus to which human subjects are exposed early in life, and by adulthood, it is part of the mycobiome of skin and other tissues. Neonatal skin lacks resident memory T (TRM) cells, but in adults theC albicansskin test is a surrogate for immunocompetence. Young adult mice raised under specific pathogen-free conditions are naive toC albicansand have been shown recently to have an immune system resembling that of neonatal human subjects.Objective:We studied the evolution of the adaptive cutaneous immune response toCandidaspecies.Methods:We examined both human skin T cells and thede novoand memory immune responses in a mouse model ofC albicansskin infection.Results:In mice the initial IL-17–producing cells afterC albicansinfection were dermal γδ T cells, but by day 7, αβ TH17 effector T cells were predominant. By day 30, the majority ofC albicans–reactive IL-17–producing T cells were CD4 TRM cells. Intravital microscopy showed that CD4 effector T cells were recruited to the site of primary infection and were highly motile 10 days after infection. Between 30 and 90 days after infection, these CD4 T cells became increasingly sessile, acquired expression of CD69 and CD103, and localized to the papillary dermis. These established TRM cells produced IL-17 on challenge, whereas motile migratory memory T cells did not. TRM cells rapidly clear an infectious challenge withC albicansmore effectively than recirculating T cells, although both populations participate. We found that in normal human skin IL-17–producing CD4+ TRM cells that responded toC albicansin an MHC class II–restricted fashion could be identified readily.Conclusions:These studies demonstrate thatC albicansinfection of skin preferentially generates CD4+ IL-17–producing TRM cells, which mediate durable protective immunity.

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