In addition to supporting Teff cell expansion and survival ( Macintyre et al., 2014), glucose has been linked to regulation of effector cytokine production in CD8 + Teff cells ( Blagih et al., 2015 Cham and Gajewski, 2005 Chang et al., 2013). Glucose has traditionally been held as the primary fuel for T cell metabolic needs and effector function, as glucose is rapidly taken up by activated T cells and is a major substrate fueling central carbon metabolism (i.e., glycolysis the pentose phosphate pathway serine, glycine, and one-carbon metabolism the TCA cycle and nucleotide metabolism) in T cells ( Frauwirth et al., 2002 Wang et al., 2011). Our understanding of cellular metabolism has been aided by advances in metabolomics and 13C-based stable isotope labeling (SIL) techniques that facilitate tracking of metabolite usage in cells and tissues ( Jang et al., 2018). T cells display flexibility in metabolic pathway utilization and bioenergetic capacity to function in different environments in vivo ( Chapman and Chi, 2022), but the metabolites that fuel the TCA cycle and biosynthetic metabolism in CD8 + T cells, particularly in vivo, have yet to be fully defined. One of the fundamental adaptable biological programs supporting T cells-from cellular homeostasis to effector function-is cellular metabolism ( Buck et al., 2017 O’Neill et al., 2016 Olenchock et al., 2017). Differentiation into CD8 + Teff cells is marked by acquisition of effector functions, such as cytolytic activity and cytokine production ( Badovinac et al., 2004 Obar et al., 2011 Teixeiro et al., 2009). In response to antigenic stimulation and appropriate costimulation, CD8 + T cells undergo sequential phases of activation starting with clonal expansion and differentiation into T effector (Teff) cells that control the threat, ultimately transitioning to memory (Tmem) cells that provide long-term protective immunity ( Kaech and Cui, 2012). 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.ĬD8 + T cells are critical for type I adaptive immune responses against pathogens (i.e., bacteria and viruses) and tumors ( Tscharke et al., 2015 Williams and Bevan, 2007). 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. 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.
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.
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. How environmental nutrient availability impacts T cell metabolism and function remains poorly understood.
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