title: Survival of tissue-resident memory T cells requires exogenous lipid uptake and metabolism.
abstract: 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 TRMcells are obscure. Here we show that mouse CD8+TRMcells 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+TRMcells 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+TRMcells, but not CD8+TCMcells, demonstrated increased mitochondrial oxidative metabolism in the presence of exogenous FFAs; this increase was not seen in Fabp4/Fabp5 double-knockout CD8+TRMcells. The persistence of CD8+TRMcells in the skin was strongly diminished by inhibition of mitochondrial FFA β-oxidation in vivo. Moreover, skin CD8+TRMcells that lacked Fabp4/Fabp5 were less effective at protecting mice from cutaneous viral infection, and lung Fabp4/Fabp5 double-knockout CD8+TRMcells 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+TRMcells in normal and psoriatic skin. These results suggest that FABP4 and FABP5 have a critical role in the maintenance, longevity and function of CD8+TRMcells, and suggest that CD8+TRMcells use exogenous FFAs and their oxidative metabolism to persist in tissue and to mediate protective immunity.
authors.affiliation: Department of Dermatology and Harvard Skin Disease Research Center, Brigham and Women's Hospital, Boston, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Youdong
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Department of Dermatology and Harvard Skin Disease Research Center, Brigham and Women's Hospital, Boston, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Tian
authors.initials: T
authors.lastname: Tian
authors.affiliation: Department of Dermatology and Harvard Skin Disease Research Center, Brigham and Women's Hospital, Boston, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Chang Ook
authors.initials: CO
authors.lastname: Park
authors.affiliation: Department of Dermatology and Harvard Skin Disease Research Center, Brigham and Women's Hospital, Boston, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Serena Y
authors.initials: SY
authors.lastname: Lofftus
authors.affiliation: Department of Biostatistics and Computational Biology, Center for Functional Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Shenglin
authors.initials: S
authors.lastname: Mei
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Xing
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Cancer Biology, Dana Farber Cancer Institute, Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Chi
authors.initials: C
authors.lastname: Luo
authors.affiliation: Department of Dermatology and Harvard Skin Disease Research Center, Brigham and Women's Hospital, Boston, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: John T
authors.initials: JT
authors.lastname: O'Malley
authors.affiliation: Department of Dermatology and Harvard Skin Disease Research Center, Brigham and Women's Hospital, Boston, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Gehad
authors.affiliation: Department of Dermatology and Harvard Skin Disease Research Center, Brigham and Women's Hospital, Boston, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Teague
authors.affiliation: Department of Dermatology and Harvard Skin Disease Research Center, Brigham and Women's Hospital, Boston, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Sherrie J
authors.initials: SJ
authors.lastname: Divito
authors.affiliation: Department of Dermatology and Harvard Skin Disease Research Center, Brigham and Women's Hospital, Boston, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Fuhlbrigge
authors.affiliation: Department of Cancer Biology, Dana Farber Cancer Institute, Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Pere
authors.initials: P
authors.lastname: Puigserver
authors.affiliation: Department of Dermatology, Rockefeller University, New York, New York, USA.
authors.forename: James G
authors.initials: JG
authors.lastname: Krueger
authors.affiliation: Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
authors.forename: Gökhan S
authors.initials: GS
authors.lastname: Hotamisligil
authors.affiliation: Department of Dermatology and Harvard Skin Disease Research Center, Brigham and Women's Hospital, Boston, Harvard Medical School, Boston, Massachusetts, USA.|Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts, USA.
authors.forename: Rachael A
authors.initials: RA
authors.lastname: Clark
authors.affiliation: Department of Dermatology and Harvard Skin Disease Research Center, Brigham and Women's Hospital, Boston, Harvard Medical School, Boston, Massachusetts, USA.|Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts, USA.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Kupper
mesh_terms: D000818:Animals; D001692:Biological Transport; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D002470:Cell Survival; D050556:Fatty Acid-Binding Proteins / Q000172:deficiency / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D005260:Female; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology*; D050356:Lipid Metabolism; D051379:Mice; D009363:Neoplasm Proteins / Q000172:deficiency / Q000378:metabolism; D010084:Oxidation-Reduction; D011565:Psoriasis; D012867:Skin / Q000166:cytology / Q000276:immunology / Q000821:virology; D014615:Vaccinia / Q000276:immunology / Q000517:prevention & control; D014616:Vaccinia virus / Q000276:immunology
chemical_list: C493410:FABP4 protein, human; C493412:FABP5 protein, human; C493411:Fabp4 protein, mouse; C082667:Fabp5 protein, mouse; D050556:Fatty Acid-Binding Proteins; D005230:Fatty Acids, Nonesterified; D009363:Neoplasm Proteins