3KLA

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

Summary for 3KLA

• Entry DOI: 10.2210/pdb3kla/pdb
• Descriptor: HLA class I histocompatibility antigen, A-2 alpha chain, Beta-2-microglobulin, NYESO-1 peptide analogue, ... (4 entities in total)
• Functional Keywords: mhc, tumour, immunology, disulfide bond, glycoprotein, immune response, membrane, mhc i, transmembrane, immunoglobulin domain, immune system
• Biological source: Homo sapiens (human); More
• Cellular location: Membrane; Single-pass type I membrane protein: P01892; Secreted: P61769; Cytoplasm: P78358
• Total number of polymer chains: 6
• Total formula weight: 89675.84

Authors

Chen, J.L.,Morgan, A.J.,Stewart-Jones, G.,Shepherd, D.,Bossi, G.,Wooldridge, L. (deposition date: 2009-11-07, release date: 2010-02-16, Last modification date: 2021-10-13)

Primary citation

Chen, J.L.,Morgan, A.J.,Stewart-Jones, G.,Shepherd, D.,Bossi, G.,Wooldridge, L.,Hutchinson, S.L.,Sewell, A.K.,Griffiths, G.M.,van der Merwe, P.A.,Jones, E.Y.,Galione, A.,Cerundolo, V.
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., 184:1829-1839, 2010

PubMed 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.

PubMed: 20053942
DOI: 10.4049/jimmunol.0902103

Experimental method

X-RAY DIFFRACTION (1.65 Å)