Structural Mutations of the T Cell Receptor ζ Chain and Its Role in T Cell Activation

Abstract

T cell hybridomas that express zeta zeta, but not zeta eta, dimers in their T cell receptors (TCRs) produce interleukin-2 (IL-2) and undergo an inhibition of spontaneous growth when activated by antigen, antibodies to the receptor, or antibodies to Thy-1. Hybridomas without zeta and eta were reconstituted with mutated zeta chains. Cytoplasmic truncations of up to 40% of the zeta molecule reconstituted normal surface assembly of TCRs, but antigen-induced IL-2 secretion and growth inhibition were lost. In contrast, cross-linking antibodies to the TCR activated these cells. A point mutation conferred the same signaling phenotype as did the truncations and caused defective antigen-induced tyrosine kinase activation. Thus zeta allows the binding of antigen/major histocompatibility complex (MHC) to alpha beta to effect TCR signaling.

Grafting primary human T lymphocytes with cancer-specific chimeric single chain and two chain TCR

“…14 Based on knowledge that antibodymediated cross-linking of proteins, expressed at the cell surface, and linked to CD3-, induces T cell activation, 7,[20][21][22] the sc-TCR V␣V␤C␤, and the tc-TCR V␣C␣ and V␤C␤ genes were ligated to the gene that was cloned from a cytotoxic T cell clone, as previously described. 23 Chimeric tc-TCR V␣C␣-and V␤C␤-genes were formatted to exclude pairing with endogenous TCR ␣␤ chains on T lymphocytes.…”

A Splice Variant of the TCR ζ mRNA Lacking Exon 7 Leads to the Down-Regulation of TCR ζ, the TCR/CD3 Complex, and IL-2 Production in Systemic Lupus Erythematosus T Cells

“…In contrast, we and other groups have reported alterations in the mRNA open reading frame (ORF) or the 3Ј-untranslated region of mRNA in T cells from SLE patients (18 -22). has crucial roles in signal transduction through the TCR/CD3 complex (23)(24)(25) and in the efficient transport of the assembled TCR complexes to the cell surface (26). is composed of three ITAM domains that are sufficient to couple chimeric receptors to early and late signaling events (24,25,(27)(28)(29)(30)(31)(32).…”

“…has crucial roles in signal transduction through the TCR/CD3 complex (23)(24)(25) and in the efficient transport of the assembled TCR complexes to the cell surface (26). is composed of three ITAM domains that are sufficient to couple chimeric receptors to early and late signaling events (24,25,(27)(28)(29)(30)(31)(32). The mutation of tyrosines within the ITAM or the nonphosphorylated and monophosphorylated motif abrogates the signal transduction ability (32,33), suggesting that these tyrosines and their phosphorylation have crucial roles in protein function.…”

Cytotoxic T lymphocytes with a grafted recognition specificity for ERBB2-expressing tumor cells.

“…The disulfide-linked Chomodimer is a transmembrane molecule and its cytoplasmic part plays a central role in TCR-mediated signal transduction and induction ofcytolysis (17)(18)(19). Fusion of the ; chain with an extracellular ligand-binding domain results in a molecule which can be activated by interaction with the ligand (17,20,21).…”

“…Fusion of the ; chain with an extracellular ligand-binding domain results in a molecule which can be activated by interaction with the ligand (17,20,21).…”