Bispecific antibody-mediated target cell-specific costimulation of resting T cells via CD5 and CD28.
Induction of T-cell activation requires multiple signals provided by cell surface receptor interactions and/or cytokines. T-cell stimulation via the T-cell receptor/CD3 complex provides an important initial activation event which, when combined with the proper costimulatory signals, results in an activated effector T cell. In this report, we have investigated the effectiveness of epithelial glycoprotein-2- (EGP-2) positive tumor target cells to induce specific T-cell stimulation via CD3, CD5, and CD28 using various combinations of bispecific monoclonal antibodies (BsMab) directed against CD3, CD5, or CD28 on the one hand and the pancarcinoma-associated antigen EGP-2 on the other. Induction of T-cell activation was investigated by assessment of CD69 expression, induction of proliferation, and acquirement of cytolytic potential. EGP-2-specific induction of T-cell activation was observed using combinations of BsMab which simultaneous ligated CD3/CD5, CD3/CD28, or CD3/CD5/CD28 with EGP-2. Activation with CD3-, CD5-, or CD28-based BsMab alone did not result in significant induction of T-cell activation in the presence or absence of EGP-2-positive target cells. Simultaneous ligation via CD5/CD28 resulted in partial T-cell activation, including CD69 up-regulation and increased cytolytic activity. Stimulation via CD3 and CD5 or CD28 could be further increased by the addition of exogenously added recombinant Interleukin 2. In contrast, T-cell activation by simultaneous ligation of CD3/CD5/CD28 could not be further augmented by addition of exogenous interleukin 2, indicating that T-cell activation via the combination of CD3, CD5, and CD28 results in complete T-cell activation. Our results show that rapid and target cell-specific induction of T cells is possible using combinations of BsMab directed against different costimulatory molecules. Simultaneous costimulation via CD3/CD5/CD28 results in the most complete activation of T cells.
Kroesen
B J
BJ
Department of Clinical Immunology, University Hospital Groningen, The Netherlands.
Bakker
A
A
van Lier
R A
RA
The
H T
HT
de Leij
L
L
D018033:Antibodies, Bispecific / Q000276:immunology*; D015703:Antigens, CD / Q000502:physiology*; D000951:Antigens, Neoplasm / Q000032:analysis / Q000276:immunology; D018106:CD28 Antigens / Q000502:physiology*; D017252:CD3 Complex / Q000502:physiology; D018956:CD5 Antigens; D015815:Cell Adhesion Molecules / Q000032:analysis / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D000071858:Epithelial Cell Adhesion Molecule; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D008213:Lymphocyte Activation; D013601:T-Lymphocytes / Q000276:immunology*; D014407:Tumor Cells, Cultured
D018033:Antibodies, Bispecific; D015703:Antigens, CD; D000951:Antigens, Neoplasm; D018106:CD28 Antigens; D017252:CD3 Complex; D018956:CD5 Antigens; D015815:Cell Adhesion Molecules; D000071858:Epithelial Cell Adhesion Molecule; D007376:Interleukin-2