Abstract
How environmental nutrient availability impacts Tcell metabolism and function remains poorly understood. Here, we report that the presence of physiologic carbon sources (PCSs) in cell culture medium broadly impacts glucose utilization by CD8+ Tcells, independent of transcriptional changes in metabolic reprogramming. The presence of PCSs reduced glucose contribution to the TCA cycle and increased effector function of CD8+ Tcells, with lactate directly fueling the TCA cycle. In fact, CD8+ Tcells responding to Listeria infection preferentially consumed lactate over glucose as a TCA cycle substrate invitro, with lactate enhancing Tcell bioenergetic and biosynthetic capacity. Inhibiting lactate-dependent metabolism in CD8+ Tcells by silencing lactate dehydrogenase A (Ldha) impaired both Tcell metabolic homeostasis and proliferative expansion invivo. Together, our data indicate that carbon source availability shapes Tcell glucose metabolism and identifies lactate as a bioenergetic and biosynthetic fuel for CD8+ effector Tcells.
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