1. Comparison of the TCR zeta-chain with the FcR gamma-chain in chimeric TCR constructs for T cell activation and apoptosis.
- Author
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Ren-Heidenreich L, Mordini R, Hayman GT, Siebenlist R, and LeFever A
- Subjects
- Amino Acid Motifs, Cytokines biosynthesis, DNA metabolism, Genetic Vectors, Humans, Models, Genetic, Phenotype, Polymerase Chain Reaction, Recombinant Fusion Proteins metabolism, Retroviridae genetics, Tumor Cells, Cultured, Apoptosis, Genetic Therapy methods, Immunotherapy methods, Lymphocyte Activation, Membrane Proteins chemistry, Neoplasms therapy, Receptors, Antigen, T-Cell chemistry, Receptors, Antigen, T-Cell metabolism, Receptors, IgG chemistry, Recombinant Fusion Proteins chemistry
- Abstract
A promising strategy for cancer treatment is adoptive gene therapy/immunotherapy by genetically modifying T cells with a chimeric T cell receptor (cTCR). When transduced T cells (T-bodies) specifically bind to tumor antigens through cTCR, they will become cytotoxic T lymphocytes (CTL) and lyse the tumor cells in a non-major histocompatibility complex (MHC)-restricted manner. Both the FcR gamma-chain and the TCR zeta-chain have been used to construct such cTCR, and both have shown specific cytolytic functions against tumor cells. However, most researchers believe that the zeta-chain generates stronger cytolytic activities against tumor than the gamma-chain and therefore would be a better candidate for cTCR construction. On the other hand, because of the lack of costimulation signaling in such constructs, the T-body might cause activation-induced T cell death (AICD) when bound to tumor antigens. Therefore, one can argue that the gamma-chain might generate less AICD than the zeta-chain because the gamma-chain has only one immunoreceptor tyrosine-based activation motif (ITAM), and the cytolytic activities can be therefore recycled. Two cTCR, GAHgamma and GAHzeta, were constructed and evaluated for cytokine production, specific cytolytic function and AICD in T-bodies after exposure to tumor cells. Using EGP-2-positive LS174T colorectal carcinoma cells as targets, there was no substantial difference observed between a gamma-chain or zeta-chain as the T-body signaling moiety in terms of specific cytolytic functions and induced cytokine production. This paper also demonstrates that, in the absence of a costimulation system, tumor antigen may not trigger apoptosis of T cells transduced with a cTCR carrying either an FcR gamma-chain or a TCR zeta-chain. These observations challenge current ideas about the role of ITAM in T cell activation.
- Published
- 2002
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