Carbon source availability drives nutrient utilization in CD8+ T cells

How environmental nutrient availability impacts T cell 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+ T cells, independent of transcriptional changes in metabolic reprogramming. The presence of PCSs reduced glucose contribution to the TCA cycle and increased effector function of CD8+ T cells, with lactate directly fueling the TCA cycle. In fact, CD8+ T cells responding to Listeria infection preferentially consumed lactate over glucose as a TCA cycle substrate in vitro, with lactate enhancing T cell bioenergetic and biosynthetic capacity. Inhibiting lactate-dependent metabolism in CD8+ T cells by silencing lactate dehydrogenase A (Ldha) impaired both T cell metabolic homeostasis and proliferative expansion in vivo. Together, our data indicate that carbon source availability shapes T cell glucose metabolism and identifies lactate as a bioenergetic and biosynthetic fuel for CD8+ effector T cells. [Display omitted] •Environmental physiologic carbon sources (PCSs) alter glucose usage by CD8+ T cells•PCSs enhance CD8+ T cell bioenergetics, survival, and cytokine production•Lactate is a physiologic TCA cycle fuel for CD8+ T cells•Ldha regulates CD8+ T cell metabolism and effector responses in vivo Kaymak and Luda et al. report that environmental metabolite availability directly impacts glucose utilization and effector function of CD8+ T effector (Teff) cells, independent of transcriptional changes in metabolic programming. Lactate is a physiologic fuel for CD8+ Teff cells, serving as a preferred TCA cycle and biosynthetic substrate.