title: T cell retargeting with MHC class I-restricted antibodies: the CD28 costimulatory domain enhances antigen-specific cytotoxicity and cytokine production.
abstract: T cells require both primary and costimulatory signals for optimal activation. The primary Ag-specific signal is delivered by engagement of the TCR. The second Ag-independent costimulatory signal is mediated by engagement of the T cell surface costimulatory molecule CD28 with its target cell ligand B7. However, many tumor cells do not express these costimulatory molecules. We previously constructed phage display derived F(AB), G8, and Hyb3, Ab-based receptors with identical specificity but distinct affinities for HLA-A1/MAGE-A1, i.e., "TCR-like" specificity. These chimeric receptors comprised the FcepsilonRI-gamma signaling element. We analyzed whether linking the CD28 costimulation structure to it (gamma + CD28) could affect the levels of MHC-restricted cytolysis and/or cytokine production. Human scFv-G8(POS) T lymphocytes comprising the gamma + CD28 vs the gamma signaling element alone produced substantially more IL-2, TNF-alpha, and IFN-gamma in response to HLA-A1/MAGE-A1(POS) melanoma cells. Also a drastic increase in cytolytic capacity of scFv-G8(POS) T cells, equipped with gamma + CD28 vs the gamma-chain alone was observed.
authors.affiliation: Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus Medisch Centrum Daniel den hoed, Rotterdam, The Netherlands. r.a.willemsen@erasmusmc.nl
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Willemsen
authors.forename: Cees
authors.initials: C
authors.lastname: Ronteltap
authors.forename: Patrick
authors.initials: P
authors.lastname: Chames
authors.forename: Reno
authors.initials: R
authors.lastname: Debets
authors.forename: Reinder L H
authors.initials: RL
authors.lastname: Bolhuis
mesh_terms: D000276:Adjuvants, Immunologic / Q000235:genetics / Q000378:metabolism / Q000633:toxicity; D000951:Antigens, Neoplasm; D001666:Binding Sites, Antibody / Q000235:genetics; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000096:biosynthesis*; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology / Q000633:toxicity*; D015788:HLA-A1 Antigen / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000235:genetics / Q000378:metabolism / Q000633:toxicity; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000378:metabolism; D020014:K562 Cells; D008213:Lymphocyte Activation / Q000235:genetics; D008545:Melanoma / Q000276:immunology / Q000473:pathology; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D017455:Receptors, IgE / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D014161:Transduction, Genetic / Q000379:methods
chemical_list: D000276:Adjuvants, Immunologic; D000951:Antigens, Neoplasm; D018106:CD28 Antigens; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D015788:HLA-A1 Antigen; D007140:Immunoglobulin Fab Fragments; D007135:Immunoglobulin Variable Region; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins; D011948:Receptors, Antigen, T-Cell; D017455:Receptors, IgE