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Tissue-resident memory T (T RM ) cells persist indefinitely in epithelial barrier tissues and protect the host against pathogens. However, the biological pathways that enable the long-term survival of T RM cells are obscure. Here we show that mouse CD8 + T RM 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 + T RM cells and greatly reduces their long-term survival in vivo, while having no effect on the survival of central memory T (T CM ) cells in lymph nodes. In vitro, CD8 + T RM cells, but not CD8 + T CM cells, demonstrated increased mitochondrial oxidative metabolism in the presence of exogenous FFAs; this increase was not seen in Fabp4/Fabp5 double-knockout CD8 + T RM cells. The persistence of CD8 + T RM cells in the skin was strongly diminished by inhibition of mitochondrial FFA β-oxidation in vivo. Moreover, skin CD8 + T RM cells that lacked Fabp4/Fabp5 were less effective at protecting mice from cutaneous viral infection, and lung Fabp4/Fabp5 double-knockout CD8 + T RM 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 + T RM 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 + T RM cells, and suggest that CD8 + T RM cells use exogenous FFAs and their oxidative metabolism to persist in tissue and to mediate protective immunity.

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