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T-cell activation by recombinant immunoreceptors: Impact of the intracellular signalling domain on the stability of receptor expression and antigen-specific activation of grafted T cells

Gene Therapy volume 10, pages 1408–1419 (2003)Cite this article

Abstract

Recombinant immunoreceptors are modularily composed of extracellular antigen binding and intracellular signalling domains that are preferentially derived from CD3ζ or FcɛRIγ. The impact of the signalling domain on the stability of immuoreceptor expression and function is not completely understood. To address this issue, we generated and expressed a panel of recombinant ζ- and γ-chain immunoreceptors, respectively, in human peripheral blood T cells. The expression level of ζ-chain immunoreceptors in human T cells is significantly lower than those of the homologous γ-chain receptors. Low ζ-chain receptor expression in peripheral T cells is because of the intracellular signalling domain and independent of the FcɛRIγ or CD3ζ transmembrane region. Expression of both receptors decreases upon prolonged cultivation. Shortly after receptor engraftment, target cell lysis and induction of IFN-γ secretion are mediated with similar efficiency by ζ- and γ-chain immunoreceptors. Upon prolonged propagation, however, T-cell activation mediated by ζ-chain immunoreceptors is more efficient than by γ-chain receptors, indicating that the initial high expression level of γ-chain immunoreceptors compensates its lower activation capacity. Consequently, γ-chain immunoreceptors exhibit a higher threshold value for specific activation and are more pronouncedly inhibited by soluble ligand antigen compared to the homologous ζ-chain receptor. These findings have substantial consequences for the design of recombinant immunoreceptors for use in adoptive immunotherapy.

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Acknowledgements

This study was supported by grants from the Deutsche Forschungsgemeinschaft, Bonn, through SFB502, from the Deutsche Krebshilfe, Bonn (70-2235-Ab1), from the Zentrum für Molekulare Medizin Köln (ZMMK), and the Köln-Fortüne Programm, Faculty of Medicine, University of Cologne. We would like to thank Steven H. Itzkowitz, Gastrointestinal Research Laboratory, Department of Medicine, Mount Sinai School of Medicine, New York, NY, USA for supplying us with the tumor cell line LS-C.

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  1. C Heuser and A Hombach: CH and AH share the first coauthorship

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  1. Klinik I für Innere Medizin der Universität zu Köln, Köln, Germany and Zentrum für Molekulare Medizin Köln (ZMMK), Universität zu Köln, Köln, Germany

    C Heuser, A Hombach, C Lösch, K Manista & H Abken

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Heuser, C., Hombach, A., Lösch, C. et al. T-cell activation by recombinant immunoreceptors: Impact of the intracellular signalling domain on the stability of receptor expression and antigen-specific activation of grafted T cells. Gene Ther 10, 1408–1419 (2003). https://doi.org/10.1038/sj.gt.3302023

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