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.
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.
Hombach
Andreas A
AA
Klinik I für Innere Medizin, Tumorgenetik, Kliniken der Universität zu Köln and Zentrum für Molekulare Medizin Köln, Josef-Stelzmann Strasse 9, Köln, Germany.
Schildgen
Verena
V
Heuser
Claudia
C
Finnern
Ricarda
R
Gilham
David E
DE
Abken
Hinrich
H
D000906:Antibodies / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology; D002272:Carcinoembryonic Antigen / Q000737:chemistry / Q000276:immunology*; D000939:Epitopes / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation; D017434:Protein Structure, Tertiary; D011971:Receptors, Immunologic / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
D000906:Antibodies; D002272:Carcinoembryonic Antigen; D000939:Epitopes; D011971:Receptors, Immunologic; D011994:Recombinant Proteins