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Survival of tissue-resident memory T cells requires exogenous lipid uptake and metabolism

 Youdong Pan  ;  Tian Tian  ;  Chang Ook Park  ;  Serena Y. Lofftus  ;  Shenglin Mei  ;  Xing Liu  ;  Chi Luo  ;  John T. O’Malley  ;  Ahmed Gehad  ;  Jessica E. Teague  ;  Sherrie J. Divito  ;  Robert Fuhlbrigge  ;  Pere Puigserver  ;  James G. Krueger  ;  Gökhan S. Hotamisligil  ;  Rachael A. Clark  ;  Thomas S. Kupper 
 NATURE, Vol.543(7644) : 252-256, 2017 
Journal Title
Issue Date
Animals ; Biological Transport ; CD8-Positive T-Lymphocytes/cytology* ; CD8-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/metabolism* ; Cell Survival ; Fatty Acid-Binding Proteins/deficiency ; Fatty Acid-Binding Proteins/metabolism ; Fatty Acids, Nonesterified/metabolism* ; Female ; Humans ; Immunologic Memory/immunology* ; Lipid Metabolism* ; Mice ; Neoplasm Proteins/deficiency ; Neoplasm Proteins/metabolism ; Oxidation-Reduction ; Psoriasis ; Skin/cytology ; Skin/immunology ; Skin/virology ; Vaccinia/immunology ; Vaccinia/prevention & control ; Vaccinia virus/immunology
Tissue-resident memory T (TRM) cells persist indefinitely in epithelial barrier tissues and protect the host against pathogens. However, the biological pathways that enable the long-term survival of TRM cells are obscure. Here we show that mouse CD8+ TRM cells generated by viral infection of the skin differentially express high levels of several molecules that mediate lipid uptake and intracellular transport, including fatty-acid-binding proteins 4 and 5 (FABP4 and FABP5). We further show that T-cell-specific deficiency of Fabp4 and Fabp5 (Fabp4/Fabp5) impairs exogenous free fatty acid (FFA) uptake by CD8+ TRM cells and greatly reduces their long-term survival in vivo, while having no effect on the survival of central memory T (TCM) cells in lymph nodes. In vitro, CD8+ TRM cells, but not CD8+ TCM cells, demonstrated increased mitochondrial oxidative metabolism in the presence of exogenous FFAs; this increase was not seen in Fabp4/Fabp5 double-knockout CD8+ TRM cells. The persistence of CD8+ TRM cells in the skin was strongly diminished by inhibition of mitochondrial FFA β-oxidation in vivo. Moreover, skin CD8+ TRM cells that lacked Fabp4/Fabp5 were less effective at protecting mice from cutaneous viral infection, and lung Fabp4/Fabp5 double-knockout CD8+ TRM cells generated by skin vaccinia virus (VACV) infection were less effective at protecting mice from a lethal pulmonary challenge with VACV. Consistent with the mouse data, increased FABP4 and FABP5 expression and enhanced extracellular FFA uptake were also demonstrated in human CD8+ TRM cells in normal and psoriatic skin. These results suggest that FABP4 and FABP5 have a critical role in the maintenance, longevity and function of CD8+ TRM cells, and suggest that CD8+ TRM cells use exogenous FFAs and their oxidative metabolism to persist in tissue and to mediate protective immunity.
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1. College of Medicine (의과대학) > Dept. of Dermatology (피부과학교실) > 1. Journal Papers
Yonsei Authors
Park, Chang Ook(박창욱) ORCID logo https://orcid.org/0000-0003-3856-1201
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