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.
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.
Chen
Ji-Li
JL
Weatherall Institute of Molecular Medicine, OX3 9DS, Oxford.
Morgan
Anthony J
AJ
Dept of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK.
Stewart-Jones
Guillaume
G
Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
Shepherd
Dawn
D
Weatherall Institute of Molecular Medicine, OX3 9DS, Oxford.
Bossi
Giovanna
G
Immunocore, Limited, 57c Milton Park, Abingdon, Oxon, OX14 4RX, UK.
Wooldridge
Linda
L
Dept of Infection, Immunity and Biochemistry, The Henry Wellcome Building, Cardiff University School of Medicine, Cardiff, CF14 4XN.
Hutchinson
Sarah L
SL
Weatherall Institute of Molecular Medicine, OX3 9DS, Oxford.
Sewell
Andrew K
AK
Dept of Infection, Immunity and Biochemistry, The Henry Wellcome Building, Cardiff University School of Medicine, Cardiff, CF14 4XN.
Griffiths
Gillian M
GM
Cambridge Institute for Medical Research, PO Box 139, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.
van der Merwe
P Anton
PA
Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK.
Jones
E Yvonne
EY
Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
Galione
Antony
A
Dept of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK.
Cerundolo
Vincenzo
V
Weatherall Institute of Molecular Medicine, OX3 9DS, Oxford.
D002118:Calcium / Q000378:metabolism*; D002999:Clone Cells; D018360:Crystallography, X-Ray; D003594:Cytoplasmic Granules / Q000276:immunology / Q000378:metabolism; D003601:Cytotoxicity Tests, Immunologic; D004721:Endoplasmic Reticulum / Q000276:immunology / Q000378:metabolism*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D009363:Neoplasm Proteins / Q000276:immunology* / Q000378:metabolism; D010446:Peptide Fragments / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D020033:Protein Isoforms / Q000276:immunology / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism* / Q000502:physiology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*
C067361:CD8 receptor; D018984:Epitopes, T-Lymphocyte; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D020033:Protein Isoforms; D011948:Receptors, Antigen, T-Cell; C504237:peptide NY-ESO-1 157-165; D002118:Calcium