Cancer immunology research

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

PMID 28642246


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 Ca(2+) 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 Ca(2+) 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 Ca(2+) mobilization upon TCR engagement. We found that activating naïve CD4(+) T cells while inhibiting ER Ca(2+) exchange, through pharmacological blockade of the ER Ca(2+) channel inositol trisphosphate receptor (IP3R), led to a reduction in cytosolic Ca(2+) content and generated a pool of CD62L(high)/CD44(low) 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 Ca(2+) 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.