Leddy, R. S.; Phelan, H. M.; Connolly, C.; Wehrmann, F.; Winter, D. C.; Brennan, L.; O'Connell, D.; Aherne, C. M.; Collins, C. B.

Cannabinoid receptor 2 (CB2R) is highly expressed on immune cells, but its role in T cell metabolism remains unclear. Here, we show that CB2R 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 CB2R activation increased mitochondrial mass, spare respiratory capacity, proton leak, and NADPH production, while CB2R 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, CB2R signalling also influenced memory and gut-homing-associated T cell phenotypes, including integrin 4{beta}7 expression. Together, these findings identify CB2R 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.