T cell activation by antibody-like immunoreceptors: The position of the binding epitope within the target molecule determines the efficiency of activation of redirected T cells

Andreas A. Hombach, Verena Schildgen, Claudia Heuser, Ricarda Finnern, David E. Gilham, Hinrich Abken

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Recombinant TCRs confer specificity to T cells and trigger their activation. Receptors with Ab-derived binding domains have the advantages of MHC-independent Ag recognition and of targeting a variety of chemically different molecules. We explored the impact of the position of a defined epitope within the target molecule on the efficacy of receptor-mediated T cell activation. T cells were grafted with recombinant immunoreceptors that recognize either the membrane distal N or the proximal A3 domain of carcinoembryonic Ag (CEA). Upon binding to isolated, solid-phase immobilized CEA, receptor-mediated T cell activation correlates with the binding efficiency, irrespectively, of the epitope position. Upon binding to CEA expressed on the cell membrane, in contrast, the A3 epitope mediates more efficiently T cell activation than the N epitope, although the N epitope is bound with higher affinity. The CEA N epitope when expressed in a more membrane proximal position, however, activated receptor grafted T cells with higher efficiency than in the distal position. The position of the targeted epitope within the molecule obviously has major impact on the efficacy of T cell activation independently of the binding efficiency of the immunoreceptor. Copyright © 2007 by The American Association of Immunologists, Inc.
    Original languageEnglish
    Pages (from-to)4650-4657
    Number of pages7
    JournalJournal of Immunology
    Volume178
    Issue number7
    Publication statusPublished - 1 Apr 2007

    Keywords

    • Antibodies/chemistry/immunology/pharmacology
    • Carcinoembryonic Antigen/chemistry/*immunology
    • Epitopes/chemistry/*immunology
    • Humans
    • *Lymphocyte Activation
    • Protein Structure, Tertiary
    • Receptors, Immunologic/chemistry/genetics/*immunology
    • Recombinant Proteins/chemistry/genetics/immunology
    • T-Lymphocytes/drug effects/*immunology

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