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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 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.

SUBMITTER: Thaxton JE 

PROVIDER: S-EPMC5585019 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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

Thaxton Jessica E JE   Wallace Caroline C   Riesenberg Brian B   Zhang Yongliang Y   Paulos Chrystal M CM   Beeson Craig C CC   Liu Bei B   Li Zihai Z  

Cancer immunology research 20170622 8


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<sup>2+</sup> 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<sup>2+</sup> buffering protein. We hypothesized that the ER stress respons  ...[more]

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