Ca2+ release from the endoplasmic reticulum of NY-ESO-1-specific T cells is modulated by the affinity of TCR and by the use of the CD8 coreceptor

J Immunol. 2010 Feb 15;184(4):1829-1839. doi: 10.4049/jimmunol.0902103. Epub 2010 Jan 6.

Abstract

Although several cancer immunotherapy strategies are based on the use of analog peptides and on the modulation of the TCR affinity of adoptively transferred T cells, it remains unclear whether tumor-specific T cell activation by strong and weak TCR stimuli evoke different Ca(2+) signatures from the Ca(2+) intracellular stores and whether the amplitude of Ca(2+) release from the endoplasmic reticulum (ER) can be further modulated by coreceptor binding to peptide/MHC. In this study, we combined functional, structural, and kinetic measurements to correlate the intensity of Ca(2+) signals triggered by the stimulation of the 1G4 T cell clone specific to the tumor epitope NY-ESO-1(157-165). Two analogs of the NY-ESO-1(157-165) peptide, having similar affinity to HLA-A2 molecules, but a 6-fold difference in binding affinity for the 1G4 TCR, resulted in different Ca(2+) signals and T cell activation. 1G4 stimulation by the stronger stimulus emptied the ER of stored Ca(2+), even in the absence of CD8 binding, resulting in sustained Ca(2+) influx. In contrast, the weaker stimulus induced only partial emptying of stored Ca(2+), resulting in significantly diminished and oscillatory Ca(2+) signals, which were enhanced by CD8 binding. Our data define the range of TCR/peptide MHC affinities required to induce depletion of Ca(2+) from intracellular stores and provide insights into the ability of T cells to tailor the use of the CD8 coreceptor to enhance Ca(2+) release from the ER. This, in turn, modulates Ca(2+) influx from the extracellular environment, ultimately controlling T cell activation.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calcium / metabolism*
  • Clone Cells
  • Crystallography, X-Ray
  • Cytoplasmic Granules / immunology
  • Cytoplasmic Granules / metabolism
  • Cytotoxicity Tests, Immunologic
  • Endoplasmic Reticulum / immunology
  • Endoplasmic Reticulum / metabolism*
  • Epitopes, T-Lymphocyte / immunology*
  • Epitopes, T-Lymphocyte / metabolism
  • Humans
  • Lymphocyte Activation / immunology
  • Neoplasm Proteins / immunology*
  • Neoplasm Proteins / metabolism
  • Peptide Fragments / immunology*
  • Peptide Fragments / metabolism
  • Protein Binding / immunology
  • Protein Isoforms / immunology
  • Protein Isoforms / metabolism
  • Receptors, Antigen, T-Cell / metabolism*
  • Receptors, Antigen, T-Cell / physiology
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocyte Subsets / metabolism*

Substances

  • CD8 receptor
  • Epitopes, T-Lymphocyte
  • Neoplasm Proteins
  • Peptide Fragments
  • Protein Isoforms
  • Receptors, Antigen, T-Cell
  • peptide NY-ESO-1 157-165
  • Calcium

Associated data

  • PDB/3KLA