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.

Journal article

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.

Authors: Chen, J; Morgan, A; Stewart-Jones, G; Shepherd, D; Bossi, G

• Publication status: Published
• Journal: Journal of Immunology
• Volume: 184
• Issue: 4
• Pages: 1829-1839
• Publication date: 2010-02-01
• DOI: 10.4049/jimmunol.0902103
• EISSN: 1550-6606
• ISSN: 0022-1767
• Language: English
• Keywords: Protein Isoforms; Endoplasmic Reticulum; Protein Binding; Peptide Fragments; Crystallography, X-Ray; Epitopes, T-Lymphocyte; Humans; Cytoplasmic Granules; Clone Cells; Receptors, Antigen, T-Cell; Neoplasm Proteins; T-Lymphocyte Subsets; Lymphocyte Activation; Calcium; Cytotoxicity Tests, Immunologic