scholarly journals High glucose attenuates Ca2+ influx in cytotoxic T lymphocytes upon target recognition

2020 ◽  
Author(s):  
Huajiao Zou ◽  
Gertrud Schwär ◽  
Renping Zhao ◽  
Dalia Alansary ◽  
Deling Yin ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
High Glucose ◽  
Calcium Release ◽  
Target Recognition ◽  
Target Cells ◽  
Calcium Sensors ◽  
Store Operated Calcium Entry ◽  
Normal Glucose ◽  
The Impact

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.

scholarly journals High glucose distinctively regulates Ca 2+ influx in cytotoxic T lymphocytes upon target recognition and thapsigargin stimulation

2020 ◽  
Vol 50 (12) ◽  
pp. 2095-2098
Author(s):  
Huajiao Zou ◽  
Wenjuan Yang ◽  
Gertrud Schwär ◽  
Renping Zhao ◽  
Dalia Alansary ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
High Glucose ◽  
Target Recognition

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

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.

scholarly journals High Glucose Enhances Cytotoxic T Lymphocyte-Mediated Cytotoxicity

2021 ◽  
Vol 12 ◽  
Author(s):  
Jie Zhu ◽  
Wenjuan Yang ◽  
Xiangda Zhou ◽  
Dorina Zöphel ◽  
Leticia Soriano-Baguet ◽  
...  
Keyword(s):  
High Glucose ◽  
Fas Ligand ◽  
Cytotoxic T Lymphocyte ◽  
Target Cells ◽  
Dependent Manner ◽  
Lytic Granules ◽  
Normal Glucose ◽  
Infected Cells ◽  
Killing Function ◽  
The Impact

Cytotoxic T lymphocytes (CTLs) are key players to eliminate tumorigenic or pathogen-infected cells using lytic granules (LG) and Fas ligand (FasL) pathways. Depletion of glucose leads to severely impaired cytotoxic function of CTLs. However, the impact of excessive glucose on CTL functions still remains largely unknown. Here we used primary human CD8+ T cells, which were stimulated by CD3/CD28 beads and cultured in medium either containing high glucose (HG, 25 mM) or normal glucose (NG, 5.6 mM). We found that in HG-CTLs, glucose uptake and glycolysis were enhanced, whereas proliferation remained unaltered. Furthermore, CTLs cultured in HG exhibited an enhanced CTL killing efficiency compared to their counterparts in NG. Unexpectedly, expression of cytotoxic proteins (perforin, granzyme A, granzyme B and FasL), LG release, cytokine/cytotoxic protein release and CTL migration remained unchanged in HG-cultured CTLs. Interestingly, additional extracellular Ca2+ diminished HG-enhanced CTL killing function. Our findings suggest that in an environment with excessive glucose, CTLs could eliminate target cells more efficiently, at least for a certain period of time, in a Ca2+-dependent manner.

scholarly journals HLA restriction of human cytotoxic T lymphocytes specific for influenza virus. Poor recognition of virus associated with HLA A2.

1978 ◽  
Vol 148 (6) ◽  
pp. 1458-1467 ◽  
Author(s):  
A McMichael
Keyword(s):  
Influenza Virus ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Influenza A ◽  
Human Peripheral Blood ◽  
Peripheral Blood Lymphocytes ◽  
The Other ◽  
Target Cells ◽  
Surface Molecules ◽  
Human Peripheral Blood Lymphocytes

Cytotoxic T lymphocytes (CTL), specific for influenza A/X31 virus, were generated from human peripheral blood lymphocytes. These CTL lysed target cells that were infected with the same virus and that shared HLA A or B locus antigens. Minimal lysis was observed when HLA-D antigens were shared. Not all HLA A and B antigens were equally effective. Efficient lysis of target cells was seen when HLA A1, A3, B7, B8, B27 and BW21 were shared with the CTL, but when HLA A2 was the only shared antigen lysis was usually minimal. This deficiency in CTL function associated with HLA A2 was not absolute. It is suggested that the function of this antigen might be influenced by other surface molecules on the cell and in particular the other HLA products.

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