Abstract

Tissue-resident memory T (TRM) cells persist indefinitely in epithelial barrier tissues and protect the host against pathogens1,2,3,4. However, the biological pathways that enable the long-term survival of TRM cells are obscure4,5. 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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Acknowledgements

We thank B. Moss (US National Institute of Health (NIH)) for providing rVACV expressing the OT-I T cell epitope OVA257–264, as well as WR-VACV. This work was supported by NIH grants R01AI041707 (T.S.K.), R01AI127654 (T.S.K.), TR01AI097128 (T.S.K. and R.A.C.) and R01AR063962 (R.A.C.). C.O.P. was supported by a grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI14C1799).

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Affiliations

  1. Department of Dermatology and Harvard Skin Disease Research Center, Brigham and Women’s Hospital, Boston, Harvard Medical School, Boston, Massachusetts, USA

    • Youdong Pan
    • , Tian Tian
    • , Chang Ook Park
    • , Serena Y. Lofftus
    • , John T. O’Malley
    • , Ahmed Gehad
    • , Jessica E. Teague
    • , Sherrie J. Divito
    • , Robert Fuhlbrigge
    • , Rachael A. Clark
    •  & Thomas S. Kupper
  2. Department of Biostatistics and Computational Biology, Center for Functional Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

    • Shenglin Mei
  3. Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA

    • Xing Liu
  4. Department of Cancer Biology, Dana Farber Cancer Institute, Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA

    • Chi Luo
    •  & Pere Puigserver
  5. Department of Dermatology, Rockefeller University, New York, New York, USA

    • James G. Krueger
  6. Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA

    • Gökhan S. Hotamisligil
  7. Dana-Farber/Brigham and Women’s Cancer Center, Boston, Massachusetts, USA

    • Rachael A. Clark
    •  & Thomas S. Kupper

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Contributions

Y.P. and T.S.K. conceived the project, designed experiments and analysed the data. Y.P., T.T., C.O.P., S.Y.L., X.L., J.T.O. and A.G. performed the experiments and helped to analyse the data. J.T.O., A.G., J.E.T., J.G.K. and R.A.C helped with human skin sample collection, processing, experiments and data analysis. S.M. helped to analyse the microarray data. C.L. and P.P. helped with Seahorse metabolism experiments. S.J.D., R.F. and G.S.H. helped with mice experiments and analysing data. Y.P. and T.S.K. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Thomas S. Kupper.

Reviewer Information Nature thanks F. Carbone and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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https://doi.org/10.1038/nature21379

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