Canagliflozin impairs T cell effector function via metabolic suppression in autoimmunity

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. JonesLinda V. Sinclair, Emma E. Vincent, Nicholas Jones (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)
55 Downloads (Pure)

Abstract

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.
Original languageEnglish
Pages (from-to)1132-1146
Number of pages15
JournalCell Metabolism
Volume35
Issue number7
Early online date24 May 2023
DOIs
Publication statusPublished - 11 Jul 2023

Keywords

  • immunometabolism
  • T cell
  • CD4 T cell
  • gliflozins
  • canagliflozin
  • autoimmunity
  • human
  • CD4 T cell

ASJC Scopus subject areas

  • Molecular Biology
  • Physiology
  • Cell Biology

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