Canagliflozin impairs T cell effector function via metabolic suppression in autoimmunity

Jenkins, Benjamin; Blagih, Julianna; Ponce-Garcia, Fernando M.; Canavan, Mary; Gudgeon, Nancy; Eastham, Simon; Hill, David; Hanlon, Megan; Eric, H.; Bishop, Emma; Rees, April; Cronin, James G.; Jury, Elizabeth C.; Dimeloe, Sarah; Veale, Douglas; Thornton, Catherine A.; Vousden, Karen H.; Finlay, David K.; Fearon, Ursula; Jones, Gareth Wyn; Sinclair, Linda V.; Vincent, Emma E.; Jones, Nicholas

doi:10.1016/j.cmet.2023.05.001

Cited by 32 publications

(13 citation statements)

References 49 publications

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“…Proteomics analysis was done as previously described 56 . CD8 hi and CD8 lo or MitoSnap+ and MitoSnap-daughter-cells following naïve CD8 + T cell activation were purified by FACS.…”

Section: Methodsmentioning

confidence: 99%

Inheritance of old mitochondria controls early CD8⁺T cell fate commitment and is regulated by autophagy

Borsa,

Lechuga-Vieco,

Kayvanjoo

et al. 2024

Preprint

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T cell immunity is impaired during ageing, particularly in memory responses needed for efficient vaccination. Autophagy and asymmetric cell division (ACD) are cell biological mechanisms key to memory formation, which undergo a decline upon ageing. However, despite the fundamental importance of these processes in cellular function, the link between ACD and in vivo fate decisions has remained highly correlative in T cells and in the field of mammalian ACD overall. Here we provide robust causal evidence linking ACD to in vivo T cell fate decisions and our data are consistent with the concept that initiation of asymmetric T cell fates is regulated by autophagy. Analysing the proteome of first-daughter CD8+T cells following TCR-triggered activation, we reveal that mitochondrial proteins rely on autophagy for their asymmetric inheritance and that damaged mitochondria are polarized upon first division. These results led us to evaluate whether mitochondria were asymmetrically inherited and to functionally address their impact on T cell fate. For this we used a novel mouse model that allows sequential tagging of mitochondria in mother and daughter cells, enabling their isolation and subsequent in vivo analysis of CD8+T cell progenies based on pre-mitotic cell cargo. Autophagy-deficient CD8+T cells showed impaired clearance and symmetric inheritance of old mitochondria, suggesting that degradation events promote asymmetry and are needed to generate T cells devoid of old organelles. Daughter cells inheriting old mitochondria are more glycolytic and upon adoptive transfer show reduced memory potential, whereas daughter cells that have not inherited old mitochondria from the mother cell are long-lived and expand upon cognate-antigen challenge. Proteomic and single-cell transcriptomic analysis of cells inheriting aged mitochondria suggest that their early fate divergence relies on one carbon metabolism as a consequence of poor mitochondrial quality and function. These findings increase our understanding of how T cell diversity is early-imprinted during division and will help foster the development of strategies to modulate T cell function.

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“…Proteomics analysis was done as previously described 56 . CD8 hi and CD8 lo or MitoSnap+ and MitoSnap-daughter-cells following naïve CD8 + T cell activation were purified by FACS.…”

Section: Methodsmentioning

confidence: 99%

Inheritance of old mitochondria controls early CD8⁺T cell fate commitment and is regulated by autophagy

Borsa,

Lechuga-Vieco,

Kayvanjoo

et al. 2024

Preprint

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“…7h–k and Extended Data Figs. 4h and 6f–i , Metabolite analysis was performed by LC–MS using a Q-Exactive Plus (Orbitrap) mass spectrometer (Thermo Fisher) coupled with a Vanquish UHPLC system (Thermo Fisher) as described previously 73 . Chromatographic separation was performed on a SeQuant ZIC-pHILIC (Merck) column (5-μm particle size, polymeric, 150 × 4.6 mm).…”

Section: Methodsmentioning

confidence: 99%

Phenotypic profiling of solute carriers characterizes serine transport in cancer

Papalazarou,

Newman,

Huerta-Uribe

et al. 2023

Nat Metab

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Serine is a vital amino acid in tumorigenesis. While cells can perform de novo serine synthesis, most transformed cells rely on serine uptake to meet their increased biosynthetic requirements. Solute carriers (SLCs), a family of transmembrane nutrient transport proteins, are the gatekeepers of amino acid acquisition and exchange in mammalian cells and are emerging as anticancer therapeutic targets; however, the SLCs that mediate serine transport in cancer cells remain unknown. Here we perform an arrayed RNAi screen of SLC-encoding genes while monitoring amino acid consumption and cell proliferation in colorectal cancer cells using metabolomics and high-throughput imaging. We identify SLC6A14 and SLC25A15 as major cytoplasmic and mitochondrial serine transporters, respectively. We also observe that SLC12A4 facilitates serine uptake. Dual targeting of SLC6A14 and either SLC25A15 or SLC12A4 diminishes serine uptake and growth of colorectal cancer cells in vitro and in vivo, particularly in cells with compromised de novo serine biosynthesis. Our results provide insight into the mechanisms that contribute to serine uptake and intracellular handling.

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Section: Basic Researchmentioning

confidence: 99%

“…In recent years, the role of SGLT2i in mediating immune response has attracted great attention. Canagliflozin has been shown to inhibit CD4 + T cell activation and reduce cancer myelocytomatosis oncogene (cMyc) to prevent metabolic reprogramming and immune inflammation ( Jenkins et al, 2023 ). Consistently, a study by Zhao et al revealed that empagliflozin can inhibit the over-activated SGLT2 in lupus kidney glomeruli, prevent the activation of mechanistic target of rapamycin complex 1 (mTORC1), and delay glomerular injury in lupus kidney ( Zhao et al, 2023 ).…”

Section: Cardiorenal Protection Of Sglt2i Glp-1ras and Dpp-4imentioning

confidence: 99%

Emerging role of antidiabetic drugs in cardiorenal protection

Fu,

Huo,

Mao

et al. 2024

Front. Pharmacol.

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The global prevalence of diabetes mellitus (DM) has led to widespread multi-system damage, especially in cardiovascular and renal functions, heightening morbidity and mortality. Emerging antidiabetic drugs sodium-glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1RAs), and dipeptidyl peptidase-4 inhibitors (DPP-4i) have demonstrated efficacy in preserving cardiac and renal function, both in type 2 diabetic and non-diabetic individuals. To understand the exact impact of these drugs on cardiorenal protection and underlying mechanisms, we conducted a comprehensive review of recent large-scale clinical trials and basic research focusing on SGLT2i, GLP-1RAs, and DPP-4i. Accumulating evidence highlights the diverse mechanisms including glucose-dependent and independent pathways, and revealing their potential cardiorenal protection in diabetic and non-diabetic cardiorenal disease. This review provides critical insights into the cardiorenal protective effects of SGLT2i, GLP-1RAs, and DPP-4i and underscores the importance of these medications in mitigating the progression of cardiovascular and renal complications, and their broader clinical implications beyond glycemic management.

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Canagliflozin impairs T cell effector function via metabolic suppression in autoimmunity

Cited by 32 publications

References 49 publications

Inheritance of old mitochondria controls early CD8⁺T cell fate commitment and is regulated by autophagy

Inheritance of old mitochondria controls early CD8⁺T cell fate commitment and is regulated by autophagy

Phenotypic profiling of solute carriers characterizes serine transport in cancer

Emerging role of antidiabetic drugs in cardiorenal protection

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Canagliflozin impairs T cell effector function via metabolic suppression in autoimmunity

Cited by 32 publications

References 49 publications

Inheritance of old mitochondria controls early CD8+T cell fate commitment and is regulated by autophagy

Inheritance of old mitochondria controls early CD8+T cell fate commitment and is regulated by autophagy

Phenotypic profiling of solute carriers characterizes serine transport in cancer

Emerging role of antidiabetic drugs in cardiorenal protection

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Inheritance of old mitochondria controls early CD8⁺T cell fate commitment and is regulated by autophagy

Inheritance of old mitochondria controls early CD8⁺T cell fate commitment and is regulated by autophagy