Comparison of the TCR zeta-chain with the FcR gamma-chain in chimeric TCR constructs for T cell activation and apoptosis.
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.
Cancer Immunotherapy Program, G01, Roger Williams Medical Center, 825 Chalkstone Ave, Providence, RI 02908, USA. lrenheidenreich@rwmc.org
Lifen
L
Ren-Heidenreich
Ryan
R
Mordini
G Thomas
GT
Hayman
Ruth
R
Siebenlist
Ann
A
LeFever
D020816:Amino Acid Motifs; D017209:Apoptosis; D016207:Cytokines / Q000096:biosynthesis; D004247:DNA / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000737:chemistry*; D008957:Models, Genetic; D009369:Neoplasms / Q000628:therapy*; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry* / Q000378:metabolism*; D017452:Receptors, IgG / Q000737:chemistry*; D011993:Recombinant Fusion Proteins / Q000737:chemistry* / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D014407:Tumor Cells, Cultured
D016207:Cytokines; D008565:Membrane Proteins; D011948:Receptors, Antigen, T-Cell; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins; C054979:antigen T cell receptor, zeta chain; D004247:DNA