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Nature. 2017 Mar 9;543(7644):252-256. doi: 10.1038/nature21379. Epub 2017 Feb 20.

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

Author information

1
Department of Dermatology and Harvard Skin Disease Research Center, Brigham and Women's Hospital, Boston, Harvard Medical School, Boston, Massachusetts, USA.
2
Department of Biostatistics and Computational Biology, Center for Functional Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
3
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
4
Department of Cancer Biology, Dana Farber Cancer Institute, Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
5
Department of Dermatology, Rockefeller University, New York, New York, USA.
6
Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
7
Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts, USA.

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 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.

PMID:
28219080
PMCID:
PMC5509051
DOI:
10.1038/nature21379
[Indexed for MEDLINE]
Free PMC Article

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