T-cell activation by recombinant receptors: CD28 costimulation is required for interleukin 2 secretion and receptor-mediated T-cell proliferation but does not affect receptor-mediated target cell lysis.
Recombinant T-cell receptors with antibody-like specificity are successfully used to direct CTLs toward a MHC-independent immune response against target cells. Here we monitored the specific activation of receptor grafted CTLs in the context of CD28 costimulation. Peripheral blood T cells were retrovirally engrafted with recombinant anti-CD30 and anti-carcinoembryonic antigen receptors, respectively, that harbor either the Fc epsilonRI-gamma or the CD3-zeta intracellular signaling domain. Cross-linking of recombinant receptors by solid-phase bound ligand, i.e., CD30 and a carcinoembryonic antigen receptor-specific anti-idiotypic antibody, respectively, induces IFN-gamma secretion that is further enhanced by CD28 costimulation of grafted T cells. Induction of interleukin (IL)-2 secretion, in contrast, requires CD28 costimulation in addition to receptor cross-linking, irrespective of T-cell preactivation by anti-CD3 monoclonal antibody plus IL-2 or by anti-CD3 monoclonal antibody plus anti-CD28 monoclonal antibody. Accordingly, induction of IL-2 secretion upon receptor cross-linking by membrane-bound antigen requires CD28/B7 costimulation whereas IFN-gamma secretion and cell proliferation does not. The efficiency of cytolysis by receptor-grafted CTLs does not depend on and is not affected by CD28 costimulation. The data demonstrate that CTL proliferation, cytokine secretion, and cytolysis upon receptor cross-linking are differentially modulated by CD28 costimulation and that cytolysis does not require B7 expression on target cells.
Klinik I für Innere Medizin, Labor Tumorgenetik, Universität zu Köln, Germany.
A
A
Hombach
D
D
Sent
C
C
Schneider
C
C
Heuser
D
D
Koch
C
C
Pohl
B
B
Seliger
H
H
Abken
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology; D051940:B7-2 Antigen; D018106:CD28 Antigens / Q000276:immunology*; D016466:CHO Cells; D002272:Carcinoembryonic Antigen / Q000276:immunology; D002352:Carrier Proteins / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D018920:Coculture Techniques; D006224:Cricetinae; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism*; D017730:Ki-1 Antigen / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D016254:Mutagenesis, Insertional; D017434:Protein Structure, Tertiary; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis / Q000097:blood / Q000235:genetics / Q000276:immunology*; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014162:Transfection
D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; C497964:CD86 protein, human; D002272:Carcinoembryonic Antigen; D002352:Carrier Proteins; D007376:Interleukin-2; D017730:Ki-1 Antigen; D008562:Membrane Glycoproteins; D011948:Receptors, Antigen, T-Cell; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; C065686:carcinoembryonic antigen binding protein, human; D007371:Interferon-gamma