Canagliflozin impairs T cell effector function via metabolic suppression in autoimmunityMore about Open Access at the Crick
Authors listBenjamin J Jenkins Julianna Blagih Fernando M Ponce-Garcia Mary Canavan Nancy Gudgeon Simon Eastham David Hill Megan M Hanlon Eric H Ma Emma L Bishop April Rees James G Cronin Elizabeth C Jury Sarah K Dimeloe Douglas J Veale Catherine A Thornton Karen Vousden David K Finlay Ursula Fearon Gareth W Jones Linda V Sinclair Emma E Vincent Nicholas Jones
Augmented T cell function leading to host damage in autoimmunity is supported by metabolic dysregulation, making targeting immunometabolism an attractive therapeutic avenue. Canagliflozin, a type 2 diabetes drug, is a sodium glucose co-transporter 2 (SGLT2) inhibitor with known off-target effects on glutamate dehydrogenase and complex I. However, the effects of SGLT2 inhibitors on human T cell function have not been extensively explored. Here, we show that canagliflozin-treated T cells are compromised in their ability to activate, proliferate, and initiate effector functions. Canagliflozin inhibits T cell receptor signaling, impacting on ERK and mTORC1 activity, concomitantly associated with reduced c-Myc. Compromised c-Myc levels were encapsulated by a failure to engage translational machinery resulting in impaired metabolic protein and solute carrier production among others. Importantly, canagliflozin-treated T cells derived from patients with autoimmune disorders impaired their effector function. Taken together, our work highlights a potential therapeutic avenue for repurposing canagliflozin as an intervention for T cell-mediated autoimmunity.
Journal Cell Metabolism
Issue number 7