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

Cancer Immunol Res. 2017 Aug;5(8):666-675. doi: 10.1158/2326-6066.CIR-17-0081. Epub 2017 Jun 22.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • CD4-Positive T-Lymphocytes / immunology
  • Calcium / metabolism
  • Endoplasmic Reticulum Stress / genetics
  • Endoplasmic Reticulum Stress / immunology*
  • Glycolysis
  • Humans
  • Hyaluronan Receptors / immunology
  • Inositol 1,4,5-Trisphosphate Receptors / immunology
  • L-Selectin / immunology
  • Lymphocyte Activation / immunology
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / immunology*
  • Neoplasms / immunology*
  • Neoplasms / pathology
  • Neoplasms / therapy
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology*

Substances

  • Hyaluronan Receptors
  • Inositol 1,4,5-Trisphosphate Receptors
  • Membrane Glycoproteins
  • Receptors, Antigen, T-Cell
  • endoplasmin
  • L-Selectin
  • Calcium