Metabolic Control of Memory T-Cell Generation and Stemness

Abstract

The formation of long-lived memory T cells is a critical feature of the adaptive immune response. T cells undergo metabolic reprogramming to establish a functional memory population. While initial studies characterized key metabolic pathways necessary for memory T-cell development, recent findings highlight that metabolic regulation of memory T-cell subsets is diverse. Here we describe the different requirements for metabolic programs and metabolism-related signaling pathways in memory T-cell development. We further discuss the contribution of cellular metabolism to memory T-cell functional reprogramming and stemness within acute and chronic inflammatory environments. Last, we highlight knowledge gaps and propose approaches to determine the roles of metabolites and metabolic enzymes in memory T-cell fate. Understanding how cellular metabolism regulates a functionally diverse memory population will undoubtedly provide new therapeutic insights to modulate protective T-cell immunity in human disease.

Extracellular acidosis restricts one-carbon metabolism and preserves T cell stemness

“…Consistent with decreased SLC7A5 expression and methionine uptake in ↑[H + ]-exposed T cells, the expression of SLC7A5 was also significantly reduced in the LY108 + TIM-3 – progenitor-exhausted T cell population within tumors, suggesting that the MYC–SLC7A5–methionine regulatory axis may also operate in vivo. It is now apparent that less differentiated stem-like memory T cells have superior anti-tumor therapeutic effects owing to their long-term persistence and resistance to the development of dysfunction 51 , 74 . We herein have provided compelling evidence that long-term ↑[H + ]-conditioned CD8 + T cells showed enhanced persistence and superior anti-tumor ability in vivo, with a reduced terminally-exhausted T cell population (TCF1 − TIM-3 + ) and increased stem-like progenitor subset (TCF1 + TIM-3 – ) within tumors.…”

Optimization of metabolism to improve efficacy during CAR-T cell manufacturing

“…At this time, metabolism must to be converted from glycolysis to FAO [ 12 ]. Metabolism is a major driving factor that determines the fate of memory T cells [ 13 , 14 ]. Activated T cells regulate metabolism to control the number and types of metabolic intermediates, which are used to control the epigenetic response of key gene transcription and promote differentiation of T cells into memory T cells [ 15 , 16 ].…”

CD4+ T cell metabolism, gut microbiota, and autoimmune diseases: implication in precision medicine of autoimmune diseases

“…Various Tm cell subsets exhibit varying metabolic profiles. 59 , 60 Although CD8 + Tm cells mostly use fatty acids to generate energy via β-oxidation and OXPHOS, CD8 + effector Tm cells are less metabolically dependent on OXPHOS than CD8 + tissue-resident Tm cells and CD8 + central Tm cells. 61 However, metabolic features in CD4 + Tm cells are less investigated and need to be explored.…”