The Francis Crick Institute
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Canagliflozin impairs T cell effector function via metabolic suppression in autoimmunity.

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journal contribution
posted on 2023-07-13, 10:05 authored by Benjamin 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 H 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.


Crick (Grant ID: CC2073, Grant title: Vousden CC2073)