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

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 maybe 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 naive 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. (C)2017 AACR.