Staged development of long-lived T-cell receptor alpha beta T(H)17 resident memory T-cell population to Candida albicans after skin infection

Background: Candida albicans is 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 (T-RM) cells, but in adults the C albicans skin test is a surrogate for immunocompetence. Young adult mice raised under specific pathogen-free conditions are naive to C albicans and 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 albicans infection were dermal gamma delta T cells, but by day 7, alpha beta TH17 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 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 T-RM cells produced IL-17 on challenge, whereas motile migratory memory T cells did not. T-RM cells rapidly clear an infectious challenge with C albicans more 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 albicans in an MHC class II-restricted fashion could be identified readily. Conclusions: These studies demonstrate that C albicans infection of skin preferentially generates CD4(+) IL-17-producing T-RM cells, which mediate durable protective immunity.