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.
Recombinant immunoreceptors are modularily composed of extracellular antigen binding and intracellular signalling domains that are preferentially derived from CD3zeta or Fc epsilon RIgamma. The impact of the signalling domain on the stability of immunoreceptor expression and function is not completely understood. To address this issue, we generated and expressed a panel of recombinant zeta- and gamma-chain immunoreceptors, respectively, in human peripheral blood T cells. The expression level of zeta-chain immunoreceptors in human T cells is significantly lower than those of the homologous gamma-chain receptors. Low zeta-chain receptor expression in peripheral T cells is because of the intracellular signalling domain and independent of the Fc epsilon RIgamma or CD3zeta transmembrane region. Expression of both receptors decreases upon prolonged cultivation. Shortly after receptor engraftment, target cell lysis and induction of IFN-gamma secretion are mediated with similar efficiency by zeta- and gamma-chain immunoreceptors. Upon prolonged propagation, however, T-cell activation mediated by zeta-chain immunoreceptors is more efficient than by gamma-chain receptors, indicating that the initial high expression level of gamma-chain immunoreceptors compensates its lower activation capacity. Consequently, gamma-chain immunoreceptors exhibit a higher threshold value for specific activation and are more pronouncedly inhibited by soluble ligand antigen compared to the homologous zeta-chain receptor. These findings have substantial consequences for the design of recombinant immunoreceptors for use in adoptive immunotherapy.
Heuser
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Klinik I für Innere Medizin der Universität zu Köln, Köln, Germany.
Hombach
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Lösch
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Manista
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Abken
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D002460:Cell Line; D002478:Cells, Cultured; D005818:Genetic Engineering; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007139:Immunoglobulin epsilon-Chains / Q000235:genetics; D007371:Interferon-gamma / Q000378:metabolism; D008213:Lymphocyte Activation; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics; D011994:Recombinant Proteins / Q000008:administration & dosage; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D007139:Immunoglobulin epsilon-Chains; D011948:Receptors, Antigen, T-Cell; D016692:Receptors, Antigen, T-Cell, gamma-delta; D011994:Recombinant Proteins; D007371:Interferon-gamma