AUTHOR=Yang Wenjuan , Denger Andreas , Diener Caroline , Küppers Frederic , Soriano-Baguet Leticia , Schäfer Gertrud , Yanamandra Archana K. , Zhao Renping , Knörck Arne , Schwarz Eva C. , Hart Martin , Lammert Frank , Roma Leticia Prates , Brenner Dirk , Christidis Grigorios , Helms Volkhard , Meese Eckart , Hoth Markus , Qu Bin 

TITLE=Unspecific CTL Killing Is Enhanced by High Glucose via TNF-Related Apoptosis-Inducing Ligand

JOURNAL=Frontiers in Immunology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.831680

DOI=10.3389/fimmu.2022.831680

ISSN=1664-3224

ABSTRACT=<p>TNF-related apoptosis inducing ligand (TRAIL) is expressed on cytotoxic T lymphocytes (CTLs) and TRAIL is linked to progression of diabetes. However, the impact of high glucose on TRAIL expression and its related killing function in CTLs still remains largely elusive. Here, we report that TRAIL is substantially up-regulated in CTLs in environments with high glucose (HG) both <italic>in vitro</italic> and <italic>in vivo</italic>. Non-mitochondrial reactive oxygen species, NFκB and PI3K/Akt are essential in HG-induced TRAIL upregulation in CTLs. TRAIL<sup>high</sup> CTLs induce apoptosis of pancreatic beta cell line 1.4E7. Treatment with metformin and vitamin D reduces HG-enhanced expression of TRAIL in CTLs and coherently protects 1.4E7 cells from TRAIL-mediated apoptosis. Our work suggests that HG-induced TRAIL<sup>high</sup> CTLs might contribute to the destruction of pancreatic beta cells in a hyperglycemia condition.</p>