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

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

doi:10.3389/fimmu.2022.831680

Abstract

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 in vitro and in vivo. Non-mitochondrial reactive oxygen species, NFκB and PI3K/Akt are essential in HG-induced TRAIL upregulation in CTLs. TRAILhigh 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 TRAILhigh CTLs might contribute to the destruction of pancreatic beta cells in a hyperglycemia condition.

Highlights

An elevated level of blood glucose is a typical symptom for diabetes, a metabolic disease
These findings suggest that tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) expression in cytotoxic T lymphocytes (CTLs) is up-regulated by high glucose (HG) and that glucose levels correlate with TRAIL expression in vivo in the context of diabetes
Since glucose uptake and transport play an essential role for overall glucose metabolism, we examined the expression of glucose transporter 1 (Glut1) and found that its expression was downregulated at mRNA level in HG-CTLs (Figure S2B), at the protein level it remained unchanged (Figures S2C, D)

Summary

Introduction

An elevated level of blood glucose is a typical symptom for diabetes, a metabolic disease. Type 1 diabetes has been identified as an autoimmune disease, for which Cytotoxic T lymphocytes (CTLs) play an important role in destroying the insulin-producing pancreatic beta-cells in an antigen specific manner [2]. For type 2 diabetes, CTLs, along with other factors, are reported to be associated with its initiation and progression [3]. LGs are reoriented towards the CTL-target contact site, termed the immunological synapse (IS), and their cytotoxic content will be released into the cleft, resulting in direct lysis or apoptosis of target cells [5]. It is reported that with excessive glucose, calcium influx elicited upon conjugation with target cells is reduced [9] and CTL killing efficiency is elevated partially regulated by Ca2+ without affecting lytic granule pathway and FasL expression [10]

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