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 Ca 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 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 in a CD4 T cell-specific manner. We show that gp96-deficient CD4 T cells cannot undergo activation-induced glycolysis due to defective Ca mobilization upon TCR engagement. We found that activating naïve CD4 T cells while inhibiting ER Ca exchange, through pharmacological blockade of the ER Ca channel inositol trisphosphate receptor (IPR), led to a reduction in cytosolic Ca content and generated a pool of CD62L/CD44 CD4 T cells compared with wild-type (WT) matched controls. IPR-inhibited CD4 T cells exhibited elevated tumor control above WT T cells. Together, these data show that ER-modulated cytosolic Ca 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. .