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High glucose enhances antigen-independent CTL killing via TRAIL

  • Cytotoxic T lymphocytes (CTLs) are involved in development of diabetes. However, the impact of excessive glucose on CTL-mediated antigen-independent killing remains elusive. Here, we report that TNF-related apoptosis inducing ligand (TRAIL) is substantially up- regulated in CTLs in environments with high glucose (HG) both in vitro and in vivo. The PI3K- Akt-NFκB axis and non-mitochondrial reactive oxygen species are essential in HG-induced TRAIL upregulation in CTLs. TRAILhigh CTLs induce apoptosis of pancreatic beta cell line 1.4E7. Metformin and Vitamin D synergistically reduce HG-enhanced expression of TRAIL in CTLs and coherently protect 1.4E7 cells from TRAIL-mediated apoptosis. Notably, in patients with diabetes, correlation between Vitamin D concentrations in plasma and glucose levels is linked to HG-enhanced TRAIL expression on CTLs. Microarray data reveal that OXCT2, an important enzyme in ketone body catabolism, is a promising target in response to vitamin D. Our work not only reveals a novel mechanism of CTL involvement in progression of diabetes, but also establishes CTLs as a target for combined metformin and vitamin D therapy to protect pancreatic beta cells of diabetic patients.Competing Interest StatementThe authors have declared no competing interest.

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Document Type:Preprint
Author:Wenjuan Yang, Andreas DengerORCiD, Caroline DienerORCiD, Frederic Küppers, Leticia Soriano-BaguetORCiD, Gertrud SchäferORCiD, Archana K. YanamandraORCiD, Renping ZhaoORCiD, Arne KnörckORCiD, Eva C. SchwarzORCiD, Martin Hart, Frank LammertORCiD, Leticia Prates RomaORCiD, Dirk BrennerORCiD, Grigorios ChristidisORCiD, Volkhard HelmsORCiD, Eckart MeeseORCiD, Markus HothORCiD, Bin QuORCiD
Parent Title (English):bioRxiv
First Page:1
Last Page:29
Year of Completion:2021
Date of first Publication:2021/10/25
Release Date:2023/06/27
DDC classes:600 Technik, Medizin, angewandte Wissenschaften / 610 Medizin, Gesundheit
Open Access:Open Access
Signature:INM 2021/136_preprint
Licence (German):License LogoCreative Commons - CC BY-ND - Namensnennung - Keine Bearbeitungen 4.0 International