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

• Published in: Cancer research (Chicago, Ill.) Ill.), 2001-03, Vol.61 (5), p.1976-1982
• Main Authors: HOMBACH, Andreas, SENT, Dagmar, SCHNEIDER, Claudia, HEUSER, Claudia, KOCH, Dimitra, POHL, Christoph, SELIGER, Barbara, ABKEN, Hinrich
• Format: Article
• Language: English
• Subjects: Animals; Antigens, CD - genetics; Antigens, CD - immunology; Antineoplastic agents; B7-1 Antigen - genetics; B7-1 Antigen - immunology; B7-2 Antigen; Biological and medical sciences; Carcinoembryonic Antigen - immunology; Carrier Proteins - immunology; CD28 Antigens - immunology; Cell Division - immunology; CHO Cells; Coculture Techniques; Cricetinae; Cytotoxicity, Immunologic - immunology; Humans; Immunotherapy; Interferon-gamma - secretion; Interleukin-2 - secretion; Ki-1 Antigen - immunology; Lymphocyte Activation - immunology; Medical sciences; Membrane Glycoproteins - genetics; Membrane Glycoproteins - immunology; Mutagenesis, Insertional; Pharmacology. Drug treatments; Protein Structure, Tertiary; Receptors, Antigen, T-Cell - biosynthesis; Receptors, Antigen, T-Cell - blood; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - immunology; Receptors, Cell Surface; Recombinant Proteins - biosynthesis; Recombinant Proteins - genetics; Signal Transduction - immunology; T-Lymphocytes - immunology; T-Lymphocytes - secretion; Transfection
• ISSN: 0008-5472; 1538-7445

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.