Abstract
The structurally related TCR-zeta and Fc receptor for IgE (Fc epsilon RI)-gamma are critical signaling components of the TCR and Fc epsilon RI, respectively. Although chimeric Ab receptors containing zeta and gamma signaling chains have been used to redirect CTL to tumors, a direct comparison of their relative efficacy has not previously been undertaken. Here, in naive T lymphocytes, we compare the signaling capacities of the zeta and gamma subunits within single-chain variable domain (scFv) chimeric receptors recognizing the carcinoembryonic Ag (CEA). Using a very efficient retroviral gene delivery system, high and equivalent levels of scFv-zeta and scFv-gamma receptors were expressed in T cells. Despite similar levels of expression and Ag-specific binding to colon carcinoma target cells, ligation of scFv-anti-CEA-zeta chimeric receptors on T cells resulted in greater cytokine production and direct cytotoxicity than activation via scFv-anti-CEA-gamma receptors. T cells expressing scFv-zeta chimeric receptors had a greater capacity to control the growth of human colon carcinoma in scid/scid mice or mouse colon adenocarcinoma in syngeneic C57BL/6 mice. Overall, these data are the first to directly compare and definitively demonstrate the enhanced potency of T cells activated via the zeta signaling pathway.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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3T3 Cells
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Adenocarcinoma / immunology
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Adenocarcinoma / prevention & control
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Animals
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Antibodies, Monoclonal / biosynthesis
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Carcinoembryonic Antigen / immunology
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Colonic Neoplasms / immunology*
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Colonic Neoplasms / prevention & control
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Cytokines / metabolism
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Cytotoxicity, Immunologic / genetics*
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Epitopes, T-Lymphocyte / metabolism
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Graft Rejection / genetics
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Graft Rejection / immunology
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Humans
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Immunoglobulin Variable Region / genetics
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Immunoglobulin Variable Region / physiology*
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Immunotherapy, Adoptive
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Membrane Proteins / biosynthesis
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Membrane Proteins / genetics*
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Membrane Proteins / physiology
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, SCID
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Protein Structure, Tertiary / genetics
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Receptors, Antigen, T-Cell / biosynthesis
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Receptors, Antigen, T-Cell / genetics*
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Receptors, Antigen, T-Cell / physiology
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Receptors, IgE / biosynthesis
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Receptors, IgE / genetics*
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Receptors, IgE / physiology
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Recombinant Fusion Proteins / biosynthesis
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / physiology*
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Signal Transduction / genetics
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Signal Transduction / immunology*
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T-Lymphocytes, Cytotoxic / immunology*
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T-Lymphocytes, Cytotoxic / metabolism
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T-Lymphocytes, Cytotoxic / transplantation
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Transduction, Genetic
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Transplantation, Isogeneic
Substances
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Antibodies, Monoclonal
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Carcinoembryonic Antigen
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Cytokines
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Epitopes, T-Lymphocyte
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Immunoglobulin Variable Region
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Membrane Proteins
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Receptors, Antigen, T-Cell
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Receptors, IgE
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Recombinant Fusion Proteins
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antigen T cell receptor, zeta chain