TY  - JOUR
U1  - Zeitschriftenartikel, wissenschaftlich - nicht begutachtet (unreviewed)
A1  - Yang, Wenjuan
A1  - Denger, Andreas
A1  - Diener, Caroline
A1  - Küppers, Frederic
A1  - Soriano-Baguet, Leticia
A1  - Schäfer, Gertrud
A1  - Yanamandra, Archana K.
A1  - Zhao, Renping
A1  - Knörck, Arne
A1  - Schwarz, Eva C.
A1  - Hart, Martin
A1  - Lammert, Frank
A1  - Prates Roma, Leticia
A1  - Brenner, Dirk
A1  - Christidis, Grigorios
A1  - Helms, Volkhard
A1  - Meese, Eckart
A1  - Hoth, Markus
A1  - Qu, Bin
T1  - High glucose enhances antigen-independent CTL killing via TRAIL
T2  - bioRxiv
N2  - 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.
KW  - immunology
Y1  - 2021
UN  - https://nbn-resolving.org/urn:nbn:de:bsz:291:415-7155
U6  - https://doi.org/10.1101/2021.08.04.455060
DO  - https://doi.org/10.1101/2021.08.04.455060
SP  - 1
EP  - 29
ER  -