title: Cytotoxic T lymphocyte antigen 4 (CTLA-4) engagement delivers an inhibitory signal through the membrane-proximal region in the absence of the tyrosine motif in the cytoplasmic tail.
abstract: Cytotoxic T lymphocyte antigen 4 (CTLA-4) is a T cell costimulation receptor that delivers inhibitory signals upon activation. Although the tyrosine-based motif ((165)YVKM) within its cytoplasmic tail has been shown to associate in vitro with Src homology 2 domain-containing tyrosine phosphatase (SHP-2) and phosphatidylinositol 3 kinase upon phosphorylation, the mechanism of negative signaling remains unclear. Here, we report a new mechanism of negative signaling based on the analysis of murine T cell clones transfected with various mutants of CTLA-4. Upon T cell activation by cross-linking with anti-CD3 and anti-CD28 antibodies, CTLA-4 engagement inhibited both proliferation and interleukin 2 production in tyrosine mutants as well as in wild-type CTLA-4 transfectants. Furthermore, the mutant CTLA-4 lacking most of the cytoplasmic region strongly suppressed interleukin 2 production as well. These data suggest that negative signals by CTLA-4 could be mediated through the membrane-proximal region of CTLA-4 but not through the YVKM motif and that the association of CTLA-4 with SHP-2 is not required for CTLA-4-mediated suppression of T cell activation.
authors.affiliation: Department of Molecular Genetics, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan.
authors.forename: C
authors.initials: C
authors.lastname: Nakaseko
authors.forename: S
authors.initials: S
authors.lastname: Miyatake
authors.forename: T
authors.initials: T
authors.lastname: Iida
authors.forename: S
authors.initials: S
authors.lastname: Hara
authors.forename: R
authors.initials: R
authors.lastname: Abe
authors.forename: H
authors.initials: H
authors.lastname: Ohno
authors.forename: Y
authors.initials: Y
authors.lastname: Saito
authors.forename: T
authors.initials: T
authors.lastname: Saito
mesh_terms: D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics / Q000276:immunology*; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D060908:CTLA-4 Antigen; D002999:Clone Cells; D003602:Cytotoxicity, Immunologic; D018796:Immunoconjugates; D007376:Interleukin-2 / Q000096:biosynthesis / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D009154:Mutation; D015398:Signal Transduction / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014443:Tyrosine / Q000276:immunology; D018909:src Homology Domains / Q000276:immunology
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D018106:CD28 Antigens; D017252:CD3 Complex; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D007376:Interleukin-2; D014443:Tyrosine; D000069594:Abatacept