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Cancer Immunol Res. 2017 Aug;5(8):666-675. doi: 10.1158/2326-6066.CIR-17-0081. Epub 2017 Jun 22.

Modulation of Endoplasmic Reticulum Stress Controls CD4+ T-cell Activation and Antitumor Function.

Author information

1
Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina.
2
Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina.
3
Department of Orthopaedic Surgery, Medical University of South Carolina, Charleston, South Carolina.
4
Department of Pharmaceutical and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina.
5
Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina. zihai@musc.edu.
6
First Affiliated Hospital, Zhengzhou University School of Medicine, Zhengzhou, China.

Abstract

The endoplasmic reticulum (ER) is an energy-sensing organelle with intimate ties to programming cell activation and metabolic fate. T-cell receptor (TCR) activation represents a form of acute cell stress and induces mobilization of ER Ca2+ stores. The role of the ER in programming T-cell activation and metabolic fate remains largely undefined. Gp96 is an ER protein with functions as a molecular chaperone and Ca2+ buffering protein. We hypothesized that the ER stress response may be important for CD4+ T-cell activation and that gp96 may be integral to this process. To test our hypothesis, we utilized genetic deletion of the gp96 gene Hsp90b1 in a CD4+ T cell-specific manner. We show that gp96-deficient CD4+ T cells cannot undergo activation-induced glycolysis due to defective Ca2+ mobilization upon TCR engagement. We found that activating naïve CD4+ T cells while inhibiting ER Ca2+ exchange, through pharmacological blockade of the ER Ca2+ channel inositol trisphosphate receptor (IP3R), led to a reduction in cytosolic Ca2+ content and generated a pool of CD62Lhigh/CD44low CD4+ T cells compared with wild-type (WT) matched controls. In vivo IP3R-inhibited CD4+ T cells exhibited elevated tumor control above WT T cells. Together, these data show that ER-modulated cytosolic Ca2+ plays a role in defining CD4+ T-cell phenotype and function. Factors associated with the ER stress response are suitable targets for T cell-based immunotherapies. Cancer Immunol Res; 5(8); 666-75. ©2017 AACR.

PMID:
28642246
PMCID:
PMC5585019
DOI:
10.1158/2326-6066.CIR-17-0081
[Indexed for MEDLINE]
Free PMC Article

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