Metabolic Adaptation of Human CD4+ and CD8+ T-Cells to T-Cell Receptor-Mediated Stimulation

Abstract

Linking immunometabolic adaptation to T-cell function provides insight for the development of new therapeutic approaches in multiple disease settings. T-cell activation and downstream effector functions of CD4+ and CD8+ T-cells are controlled by the strength of interaction between the T-cell receptor (TCR) and peptides presented by human leukocyte antigens (pHLA). The role of TCR–pHLA interactions in modulating T-cell metabolism is unknown. Here, for the first time, we explore the relative contributions of the main metabolic pathways to functional responses in human CD4+ and CD8+ T-cells. Increased expression of hexokinase II accompanied by higher basal glycolysis is demonstrated in CD4+ T-cells; cytokine production in CD8+ T-cells is more reliant on oxidative phosphorylation. Using antigen-specific CD4+ and CD8+ T-cell clones and altered peptide ligands, we demonstrate that binding affinity tunes the underlying metabolic shift. Overall, this study provides important new insight into how metabolic pathways are controlled during antigen-specific activation of human T-cells.

A novel strategy for single-cell metabolic analysis highlights dynamic changes in immune subpopulations

“…Together, Met-Flow confirms previously described metabolic inductions of glycolysis, OXPHOS and fatty acid synthesis in activated T cells 1,[27][28][29]…”

“…1c,Supplementary Fig. 2i), as both subsets similarly rely on glycolytic flux27 , however there is a significant difference in G6PD indicating a dissimilarity in capacity for flux through the PPP. Additionally, the relative correlation between immune subsets of a given phenotypic marker to each metabolic protein was measured.…”

Noninvasive rapid detection of metabolic adaptation in activated human T lymphocytes by hyperpolarized 13C magnetic resonance

“…This metabolic shift towards aerobic glycolysis leads to increased lactate production and is equivalent to the phenotype exhibited by cancer cells and first observed in 1956 by Otto Warburg 3 . This "Warburgian" behavior has been experimentally revealed in lymphocytes through several types of measurements: an increase in the expression of glucose and lactate transporters [4][5][6][7][8][9] , an increase in glucose uptake demonstrated with radioactive 2-deoxy-D-glucose 5,10 , an upregulation in enzymes involved in glycolysis, including lactate dehydrogenase (LDH) 11,12 , as well as the measurement of lactate accumulation either directly using enzymatic kits 5,13 , or indirectly by measuring the extracellular acidification rate (ECAR), which was shown to be highly correlated with the extracellular lactate production rate 14 . These metabolic adaptations are highlighted by the red arrows in Fig.…”

“…The most direct observation of variations in cellular glycolytic rate can be made through the measurement of the flux from glucose to pyruvate and lactate using isotopically labeled precursors. This is done either by determining the concentrations of 14 C-pyruvate and 14 C-lactate resulting from the uptake and metabolism of the radioactive precursor 14 C-glucose 15 , or by 13 C nuclear magnetic resonance (NMR), which provides a direct quantification of the metabolic products of 13 C-glucose in intact cells 16 . The notable advantage of the latter technique is that the metabolites can be measured noninvasively and it can therefore be used in vivo, although the lack of sensitivity of 13 C NMR severely limits its applications in humans.…”

Risk stratification of allogeneic stem cell recipients with respect to the potential for development of GVHD via their pre-transplant plasma lipid and metabolic signature

“…The T cell encounter alloantigens, undergo activation, perform functions such as cytokine secretion (IL-2, IL-4, IL-10, IL-12, IL-17 and interferon gamma by helper T cell subsets) and target lysis (granzyme and perforin secretion by cytotoxic T cells). These functions are accompanied by significant metabolic adaptations in the T cells, including increased glycolysis and oxygen consumption as well as cytokine production mentioned earlier 1 . As an example, higher levels of GLUT 1 expression have been observed in activated T cells, suggesting increased metabolic & biosynthetic rates 2 .…”