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

FABP4 and FABP5 are important for the maintenance, longevity and function of CD8 + tissue-resident memory T cells, which use oxidative metabolism of exogenous free fatty acids to persist in tissues and to mediate protective immunity. Lipid uptake in tissue-resident memory T cells Tissue-resident memory T (T RM ) cells are found in the skin, where they protect the host against pathogens, but it has not been clear how they manage to survive long-term. Thomas Kupper and colleagues now report that these cells are more dependent on exogenous free fatty acid uptake than are central memory and effector memory T cells. They show that T RM cells express high levels of several molecules that mediate the uptake and intracellular transport of lipids, including fatty-acid-binding proteins 4 and 5 (FABP4 and FABP5), and implicate Fabp4 and Fabp5 as critical mediators of exogenous fatty acid uptake in murine and human T RM cells. Tissue-resident memory T (T RM ) cells persist indefinitely in epithelial barrier tissues and protect the host against pathogens 1 , 2 , 3 , 4 . However, the biological pathways that enable the long-term survival of T RM cells are obscure 4 , 5 . 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 F