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

Abstract

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. Tissue-resident memory T (TRM) 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 TRM 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 TRM cells. 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.