Staged development of long-lived T-cell receptor αβ TH17 resident memory T-cell population to Candida albicans after skin infection

Background Candida albicans is a dimorphic fungusto which human subjects are exposed early in life, and by adulthood, it is part of the mycobiomeof skin and other tissues. Neonatal skin lacks resident memory T (T RM ) cells, but in adults the C albicansskin test is a surrogate for immunocompetence. Young adult mice raised under specific pathogen-freeconditions are naive to C 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 to Candida species. Methods We examined both human skin T cells and the de novo and memory immune responses in a mouse model of C albicans skin infection. Results In mice the initial IL-17–producing cells after C albicansinfection were dermal γδ T cells, but by day 7, αβ T H 17 effector T cells were predominant. By day 30, the majority of C albicans–reactive IL-17–producing T cells were CD4 T RM cells. Intravital microscopyshowed 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 CD69and CD103, and localized to the papillary dermis. These established T RM cells produced IL-17 on challenge, whereas motile migratory memory T cellsdid not. T RM cells rapidly clear an infectious challenge with C albicansmore effectively than recirculating T cells, although both populations participate. We found that in normal human skin IL-17–producing CD4 + T RM cells that responded to C albicansin an MHC class II–restricted fashion could be identified readily. Conclusions These studies demonstrate that C albicansinfection of skin preferentially generates CD4 + IL-17–producing T RM cells, which mediate durable protective immunity.