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

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 <i>Hsp90b1</i> 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 CD62L^high/CD44^low CD4⁺ T cells compared with wild-type (WT) matched controls. <i>In vivo</i> 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. <i>Cancer Immunol Res; 5(8); 666-75. ©2017 AACR</i>.