Decision letter for "High glucose distinctively regulates Ca <sup>2+</sup> influx in cytotoxic T lymphocytes upon target‐recognition and Thapsigargin‐stimulation"

AbstractThe killing efficiency of cytotoxic T lymphocytes (CTLs) is tightly regulated by intracellular Ca2+ concentration. Glucose is the key energy source for CTLs, lack of which significantly impairs CTL activation, proliferation and effector functions. The impact of high glucose on Ca2+ influx in CTLs remains largely elusive. In this work, we stimulated primary human CD8+ T cells in medium containing either 25 mM (high glucose, HG) or 5.6 mM glucose (normal glucose, NG). We found that store-operated calcium entry (SOCE) induced by thapsigargin (Tg) is elevated in HG-cultured CTLs compared to their counterparts in NG. Unexpectedly, the Ca2+ influx elicited by recognition of target cells is reduced in HG-cultured CTLs. Under HG condition, STIM1 and STIM2, the calcium sensors in the endoplasmic reticulum (ER), were down-regulated; ORAI1, the main structural component of calcium-release activated channels, remained unchanged, whereas ORAI2 and ORAI3 were up-regulated. The fraction of necrosis of HG-cultured CTLs was enhanced after killing without affecting glucose uptake. Thus, our findings reveal that HG has a distinctive impact on Tg-evoked SOCE and target recognition-induced Ca2+ influx in CTLs and causes more CTL death after killing, suggesting a novel regulatory role of high glucose on modulating CTL functions.

Metabolic reprogramming of cytotoxic T lymphocytes by high glucose enhances pancreatic beta cell apoptosis via TRAIL

10.1101/2021.08.04.455060 ◽

2021 ◽

Author(s):

Wenjuan Yang ◽

Andreas Denger ◽

Caroline Diener ◽

Frederic Kueppers ◽

Leticia Soriano-Baguet ◽

...

Keyword(s):

Vitamin D ◽

T Lymphocytes ◽

Beta Cells ◽

Cytotoxic T Lymphocytes ◽

High Glucose ◽

Pancreatic Beta Cells ◽

Metabolic Reprogramming ◽

Diabetic Patients ◽

Beta Cell Apoptosis ◽

The Impact

Cytotoxic T lymphocytes (CTLs) are involved in development of diabetes. However, the impact of excessive glucose on CTL effector functions remains largely elusive. Here, we report that metabolic processes in CTLs are reprogrammed by high glucose (HG). TNF-related apoptosis inducing ligand (TRAIL) is substantially up-regulated in CTLs in environments with HG both in vitro and in vivo in a diabetic mouse model and in diabetic patients. The PI3K-Akt-NFκB axis and non-mitochondrial reactive oxygen species (ROS) are both involved in HG-induced TRAIL upregulation in CTLs. TRAILhigh CTLs induce apoptosis of insulin-producing beta cells. Metformin and Vitamin D synergistically reduce HG-enhanced expression of TRAIL in CTLs and coherently protect beta cells from TRAIL-mediated apoptosis. 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.

Surface structures involved in target recognition by human cytotoxic T lymphocytes

Science ◽

10.1126/science.6981845 ◽

1982 ◽

Vol 218 (4571) ◽

pp. 471-473 ◽

Cited By ~ 170

Author(s):

S. Meuer ◽

R. Hussey ◽

J. Hodgdon ◽

T Hercend ◽

S. Schlossman ◽

...

Keyword(s):

T Lymphocytes ◽

Cytotoxic T Lymphocytes ◽

Target Recognition ◽

Surface Structures

Eradication of an intraocular tumor by tumor-specific cytotoxic T lymphocytes

Immunology Letters ◽

10.1016/s0165-2478(97)88686-5 ◽

1997 ◽

Vol 56 (1-3) ◽

pp. 453-454

Author(s):

L Schurmans

Keyword(s):

T Lymphocytes ◽

Cytotoxic T Lymphocytes ◽

Intraocular Tumor