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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

Chen, Ji-Li, Morgan, Anthony J., Stewart-Jones, Guillaume, Shepherd, Dawn, Bossi, Giovanna, Wooldridge, Linda, Hutchinson, Sarah L., Sewell, Andrew K., Griffiths, Gillian M., van der Merwe, P. Anton, Jones, E. Yvonne, Galione, Antony and Cerundolo, Vincenzo 2010. 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. The Journal of Immunology 184 (4) , pp. 1829-1839. 10.4049/jimmunol.0902103

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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 Ca2+ signatures from the Ca2+ intracellular stores and whether the amplitude of Ca2+ 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 Ca2+ signals triggered by the stimulation of the 1G4 T cell clone specific to the tumor epitope NY-ESO-1157–165. Two analogs of the NY-ESO-1157–165 peptide, having similar affinity to HLA-A2 molecules, but a 6-fold difference in binding affinity for the 1G4 TCR, resulted in different Ca2+ signals and T cell activation. 1G4 stimulation by the stronger stimulus emptied the ER of stored Ca2+, even in the absence of CD8 binding, resulting in sustained Ca2+ influx. In contrast, the weaker stimulus induced only partial emptying of stored Ca2+, resulting in significantly diminished and oscillatory Ca2+ signals, which were enhanced by CD8 binding. Our data define the range of TCR/peptide MHC affinities required to induce depletion of Ca2+ from intracellular stores and provide insights into the ability of T cells to tailor the use of the CD8 coreceptor to enhance Ca2+ release from the ER. This, in turn, modulates Ca2+ influx from the extracellular environment, ultimately controlling T cell activation.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Subjects: R Medicine > R Medicine (General)
R Medicine > RZ Other systems of medicine
Publisher: American Association of Immunologists
ISSN: 0022-1767
Last Modified: 30 Jun 2017 02:18
URI: http://orca-mwe.cf.ac.uk/id/eprint/24890

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