053 Lipid scavenger molecule CD36 regulates free fatty acid uptake and peripheral maintenance of tissue resident memory T cells

Abstract

The mechanism(s) by which tissue-resident memory T cells (TRM) survive in peripheral tissues for long periods of time remains obscure. Our recent studies revealed that CD8+ TRM generated by skin vaccinia virus (VACV) infection express strikingly high levels of several molecules involved in the uptake and intracellular transport of free fatty acids (FFA) and other lipids. These molecules include fatty acid binding protein 4 (Fabp4) and Fabp5. Using transgenic mouse models, we have showed mice deficient in both fabp4 and fabp5 develop TRM that were inferior in internalizing exogenous FFA, displayed reduced FFA b oxidation and ATP generation, and did not survive as long-term as WT TRM. Another molecule strongly upregulated in TRM is CD36, a cell surface receptor that binds FFA. The role of CD36 in the maintenance and survival of TRM remains unknown. Here we demonstrated that Cd36-/- TRM internalized labelled palmitate (C16 FFA) less efficiently than WT TRM. In vivo competitive experiments by transferring equal numbers of WT and cd36-/- OT-1 cells into the same recipient mice followed by VACVOVA infection showed there was a survival disadvantage of cd36-/- TRM in skin beginning at day 45, which became more pronounced through day 90. By contrast, no difference could be observed between cd36-/- and WT TCM over 90 days of experiment. In addition, the defects seen in cd36-/- TRM and fabp4-/-/fabp5-/- TRM are additive in cd36-/- fabp4-/-fabp5-/- OT-1 mice---TRM from these mice had a profound survival disadvantage. Overall, our data demonstrate that CD36 also participates in the lipid uptake and long-time maintenance of TRM in peripheral tissue. A more detailed understanding of the unique lipid metabolic programs intrinsic to TRM, and how these programs might be modified therapeutically, will facilitate treatment approaches to TRM-mediated diseases as well as TRM based vaccines.