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Staged development of long-lived T-cell receptor ?? TH17 resident memory T-cell population to Candida albicans after skin infection - 04/08/18

Doi : 10.1016/j.jaci.2017.09.042 
Chang Ook Park, MD, PhD a, e, Xiujun Fu, MD, PhD b, Xiaodong Jiang, MD, PhD a, Youdong Pan, PhD a, Jessica E. Teague, PhD a, Nicholas Collins, PhD c, Tian Tian, MD, PhD a, John T. O'Malley, MD, PhD a, Ryan O. Emerson, PhD d, Ji Hye Kim, MS e, Yookyung Jung, PhD b, Rei Watanabe, MD, PhD a, Robert C. Fuhlbrigge, MD, PhD a, Francis R. Carbone, PhD c, Thomas Gebhardt, MD, PhD c, Rachael A. Clark, MD, PhD a, Charles P. Lin, PhD b, Thomas S. Kupper, MD a,
a Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass 
b Center for Systems Biology and Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, Mass 
c Department of Microbiology and Immunology, University of Melbourne, Parkville, Australia 
d Adaptive Biotechnologies, Seattle, Wash 
e Department of Dermatology and Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea 

Corresponding author: Thomas S. Kupper, MD, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, 77 Ave Louis Pasteur, Boston, MA 02115.Department of DermatologyBrigham and Women's HospitalHarvard Medical School77 Ave Louis PasteurBostonMA02115

Abstract

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 (TRM) 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 γδ T cells, but by day 7, αβ TH17 effector T cells were predominant. By day 30, the majority of C 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 with C albicans more effectively than recirculating T cells, although both populations participate. We found that in normal human skin IL-17–producing CD4+ TRM 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 TRM cells, which mediate durable protective immunity.

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Key words : Resident memory T cells, TRM, Candida albicans, IL-17, TH17, CD4+ TRM

Abbreviations used : AC, CD62L, DC, GFP, HK, KLRG-1, MV, SPF, Rag, TMM, TRM


Plan


 Supported by National Institutes of Health grants R01AI041707, R01AI127654, and R01AR065807 (to T.S.K.), TR01AI097128 (to T.S.K. and R.A.C.), and R01AR063962 (to R.A.C.). C.O.P. was supported by a grant from the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI14C1324, HI14C1799).
 Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.


© 2017  American Academy of Allergy, Asthma & Immunology. Publié par Elsevier Masson SAS. Tous droits réservés.
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Vol 142 - N° 2

P. 647-662 - août 2018 Retour au numéro
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