Cannabinoid CB 2 receptor activation drives glucose uptake, shifting T cell metabolism
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Cannabinoid receptor 2 (CB 2 R) is highly expressed on immune cells, but its role in T cell metabolism remains unclear. Here, we show that CB 2 R activation rapidly increases glucose uptake in human Jurkat T cells and drives a broader metabolic reprogramming away from glycolysis toward oxidative metabolism and the pentose phosphate pathway. Pharmacological CB 2 R activation increased mitochondrial mass, spare respiratory capacity, proton leak, and NADPH production, while CB 2 R inverse agonism produced the opposite effects. These metabolic changes were accompanied by upregulation of key pentose phosphate pathway enzymes, including GALT and TALDO1, and were abolished in CNR2-deficient cells, confirming receptor dependence. In primary human lamina propria mononuclear cells, CB 2 R signalling also influenced memory and gut-homing-associated T cell phenotypes, including integrin α4β7 expression. Together, these findings identify CB 2 R as a regulator of T cell bioenergetics and suggest that cannabinoid signalling may promote metabolic states linked to memory and tissue-homing functions in chronic intestinal inflammation.
Brief Summary
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CB 2 R agonist-mediated increased glucose uptake in human T cells is lost in CNR2-deficient cells, suggesting that the response is receptor-dependent.
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CB 2 R activation rewires T-cell metabolism toward increased oxidative phosphorylation, spare respiratory capacity, mitochondrial mass, and pentose phosphate pathway metabolism, including higher NADPH and PPP-enzyme expression.
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In primary human intestinal immune cells, CB 2 R also promotes gut-homing and memory-associated T-cell phenotypes, including α4β7 and CD103 integrin induction ex vivo, suggesting a possible link to exacerbation of chronic intestinal inflammation.
