Effector T cells require fatty acid metabolism during murine graft-versus-host disease

Abstract

Key Points• T cells activated during GVHD increase their dependence upon fatty acid oxidation. • This dependence is not observed following acute activation or during normal immune reconstitution, suggesting novel therapeutic targets.Activated T cells require increased energy to proliferate and mediate effector functions, but the metabolic changes that occur in T cells following stimulation in vivo are poorly understood, particularly in the context of inflammation. We have previously shown that T cells activated during graft-versus-host disease (GVHD) primarily rely on oxidative phosphorylation to synthesize adenosine 59-triphosphate. Here, we demonstrate that alloreactive effector T cells (T eff ) use fatty acids (FAs) as a fuel source to support their in vivo activation. Alloreactive T cells increased FA transport, elevated levels of FA oxidation enzymes, up-regulated transcriptional coactivators to drive oxidative metabolism, and increased their rates of FA oxidation. Importantly, increases in FA transport and up-regulation of FA oxidation machinery occurred specifically in T cells during GVHD and were not seen in T eff following acute activation. Pharmacological blockade of FA oxidation decreased the survival of alloreactive T cells but did not influence the survival of T cells during normal immune reconstitution. These studies suggest that pathways controlling FA metabolism might serve as therapeutic targets to treat GVHD and other T-cell-mediated immune diseases. (Blood. 2013;122(18):3230-3237)

Anaplerotic Metabolism of Alloreactive T Cells Provides a Metabolic Approach To Treat Graft-Versus-Host Disease

“…2A). This finding is consistent with increased glutamine-dependent anaplerosis, because we previously showed that total fatty acid uptake and oxidation increase in alloreactive T cells, excluding decreased uptake / utilization as an alternative explanation (Byersdorfer et al, 2013). In addition, among the 13 C-containing isotopomers of ribose, the molar enrichment of m2 species is significantly enhanced (Supplemental Fig.…”

“…2B), the limited use of glutamine for fatty acid synthesis in alloreactive T cells is unlikely to result from an increase in reductive carboxylation. Together with recent data showing that alloreactive T cells actively import fatty acids from extracellular sources, our results suggest fatty acid uptake is used in preference to de novo synthesis (Byersdorfer et al, 2013).…”

“…Instead, mitochondrial oxidative activity coupled to ATP synthesis supports energy production (Gatza et al, 2011;Byersdorfer et al, 2013;Saha et al, 2013). Without a large change in glucose uptake and consumption, other metabolic adaptations must occur in alloreactive T cells in vivo to support biosynthesis.…”

Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality

“…Although memory T cells preferentially utilize FA metabolism (41,70), Teffs can also rely on FAO during GVHD (65). Increased FA uptake and FAO, and enhanced susceptibility to pharmacologic inhibition of FAO by etomoxir in WT donor T cells, suggest that PD-L1 provides a cell-intrinsic positive stimulus for FA metabolism in alloreactive T cells undergoing clonal expansion, which may further support T cell survival, extending in vitro studies by others using human T cells (45).…”

“…These include induction of aerobic glycolysis (61), OXPHOS (62), glutaminolysis, and increase in synthesis of biomolecules (63). T cell metabolism has also been shown to require lipid synthesis (64) or oxidation (65) and amino acid uptake (66). We (22) and others (67) have shown that GVHD results in high metabolic demands for Teffs, increasing their dependency on aerobic glycolysis.…”