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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.","bibjson":{"author":[{"initials":"JL","lastname":"Chen","name":"Chen JL"},{"initials":"AJ","lastname":"Morgan","name":"Morgan AJ"},{"initials":"G","lastname":"Stewart-Jones","name":"Stewart-Jones G"},{"initials":"D","lastname":"Shepherd","name":"Shepherd D"},{"initials":"G","lastname":"Bossi","name":"Bossi G"},{"initials":"L","lastname":"Wooldridge","name":"Wooldridge L"},{"initials":"SL","lastname":"Hutchinson","name":"Hutchinson SL"},{"initials":"AK","lastname":"Sewell","name":"Sewell AK"},{"initials":"GM","lastname":"Griffiths","name":"Griffiths GM"},{"initials":"PA","lastname":"van der Merwe","name":"van der Merwe PA"},{"initials":"EY","lastname":"Jones","name":"Jones EY"},{"initials":"A","lastname":"Galione","name":"Galione A"},{"initials":"V","lastname":"Cerundolo","name":"Cerundolo V"}],"identifier":[{"id":"10.4049/jimmunol.0902103","type":"doi"},{"id":"20053942","type":"pubmed"}],"issue":["4"],"journal":{"iso_abbreviation":"J. 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