Journal
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Volume 142, Issue 2, Pages 647-662Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2017.09.042
Keywords
Resident memory T cells; T-RM; Candida albicans; IL-17; T(H)17; CD4(+) T-RM
Categories
Funding
- National Institutes of Health [R01AI041707, R01AI127654, R01AR065807, TR01AI097128, R01AR063962]
- Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea [HI14C1324, HI14C1799]
- NATIONAL CANCER INSTITUTE [R01CA203721] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R01AI041707, R01AI097128, R01AI127654] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [R01AR063962, R01AR065807, P30AR069625] Funding Source: NIH RePORTER
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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.
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