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

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  • Chiaki Nakaseko
    aDepartment of Molecular Genetics, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
  • Shoichiro Miyatake
    bDepartment of Molecular and Developmental Biology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
  • Tomohiko Iida
    aDepartment of Molecular Genetics, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
  • Satoru Hara
    aDepartment of Molecular Genetics, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
  • Ryo Abe
    cDivision of Immunobiology, Research Institute for Biological Science, Science University of Tokyo, Chiba 278-8510, Japan
  • Hiroshi Ohno
    aDepartment of Molecular Genetics, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
  • Takashi Saito
    aDepartment of Molecular Genetics, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan

抄録

<jats:p>Cytotoxic T lymphocyte antigen 4 (CTLA-4) is a T cell costimulation receptor that delivers inhibitory signals upon activation. Although the tyrosine-based motif (165YVKM) 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.</jats:p>

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