Journal
CELL METABOLISM
Volume 35, Issue 7, Pages 1132-+Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2023.05.001
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This study found that canagliflozin, a drug used to treat type 2 diabetes, compromises the function of T cells by inhibiting T cell receptor signaling and reducing c-Myc levels. This leads to impaired production of metabolic proteins and solute carriers. Importantly, T cells from patients with autoimmune disorders also showed impaired effector function after treatment with canagliflozin.
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.
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