Article Alert: Reductive carboxylation shapes T cell differentiation

The transition of antigen-specific naïve T cells into effector T cells (T_E) is marked by a change to anabolic metabolism. Reductive carboxylation of glutamine (RC), facilitated by isocitrate dehydrogenase (IDH) 1 and IDH2, is known to occur in cancer cells to generate citrate, a major source of acetyl-CoA for cell growth and function. Though a similar process was thought to be active in CD8⁺ T cells, the mechanistic basis of this and how it influences the function and differentiation of T_E cells was an open question.

A new study by Jaccard et al. sheds new light onto the role of RC in shaping T cell phenotypes (1). The authors used metabolic labeling, RNA-seq data analysis, and other techniques to find that T_E indeed reductively carboxylate glutamine to an extent not noted in memory T cells (T_M), which highlighted the distinctive reductive metabolite profile seen in T_E versus the more oxidative profile of T_M. In addition, they discovered that the RC in T_E is mediated by IDH2 as well as by transcriptional and metabolic reconfiguration dictated by HIF-1α. Interestingly, the absence of IDH2 does not impede the expansion of T_E functions but rather enhances T_M differentiation. Excitingly, when IDH2 was inhibited during ex vivo generation of chimeric antigen receptor (CAR) T cells, T_M were enriched and increased antitumor activity in melanoma, leukemia, and multiple myeloma models was noted. The researchers then identified specific chromatin changes that explain how IDH2 inactivation maintains chromosome accessibility of genes necessary for T_M differentiation. The findings by Jaccard et al. are potentially revolutionary in terms of next-generation CAR T cell development, where IDH2 inhibition may leverage an increased T_M presence to expand the durability and efficacy of CAR T-based therapies.

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