title: Activation of resting human primary T cells with chimeric receptors: costimulation from CD28, inducible costimulator, CD134, and CD137 in series with signals from the TCR zeta chain.
abstract: Chimeric receptors that include CD28 signaling in series with TCRzeta in the same receptor have been demonstrated to activate prestimulated human primary T cells more efficiently than a receptor providing TCRzeta signaling alone. We examined whether this type of receptor can also activate resting human primary T cells, and whether molecules other than CD28 could be included in a single chimeric receptor in series with TCRzeta to mediate the activation of resting human primary T cells. Human CD33-specific chimeric receptors were generated with CD28, inducible costimulator, CD134, or CD137 signaling regions in series with TCRzeta signaling region and transfected by electroporation into resting human primary T cells. Their ability to mediate Ag-specific activation was analyzed in comparison with a receptor providing TCRzeta signaling alone. Inclusion of any of the costimulatory signaling regions in series with TCRzeta enhanced the level of specific Ag-induced IL-2, IFN-gamma, TNF-alpha, and GM-CSF cytokine production and enabled resting primary T cells to survive and proliferate in response to Ag in the absence of any exogenous factors. Inclusion of CD28, inducible costimulator, or CD134 enhanced TCRzeta-mediated, Ag-specific target cell lysis. Chimeric receptors providing B7 and TNFR family costimulatory signals in series with TCRzeta in the same receptor can confer self-sufficient clonal expansion and enhanced effector function to resting human T cells. This type of chimeric receptor may now be used to discover the most potent combination of costimulatory signals that will improve current immunotherapeutic strategies.
authors.affiliation: Celltech R&D, 208 Bath Road, Slough, Berkshire SL1 3WE, United Kingdom. hfinney@celltech.co.uk
authors.forename: Helene M
authors.initials: HM
authors.lastname: Finney
authors.forename: Arne N
authors.initials: AN
authors.lastname: Akbar
authors.forename: Alastair D G
authors.initials: AD
authors.lastname: Lawson
mesh_terms: D000818:Animals; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D018106:CD28 Antigens / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D003601:Cytotoxicity Tests, Immunologic / Q000379:methods; D006801:Humans; D060889:Inducible T-Cell Co-Stimulator Protein; D007399:Interphase / Q000276:immunology; D007424:Intracellular Fluid / Q000201:enzymology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D016254:Mutagenesis, Insertional / Q000379:methods; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017475:Receptors, Nerve Growth Factor / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D014162:Transfection; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D014443:Tyrosine / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D018106:CD28 Antigens; D016207:Cytokines; C556692:ICOS protein, human; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011948:Receptors, Antigen, T-Cell; D017475:Receptors, Nerve Growth Factor; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; C505716:TNFRSF4 protein, human; C505714:TNFRSF9 protein, human; C505717:Tnfrsf4 protein, mouse; C505715:Tnfrsf9 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; C054979:antigen T cell receptor, zeta chain; D014443:Tyrosine; D019869:Phosphatidylinositol 3-Kinases