Involvement of Rap-1 activation and early termination of immune synapse in CTLA-4-mediated negative signal

Satoru Hara, Chiaki Nakaseko, Sho Yamasaki, Masakazu Hattori, Johannes L. Bos, Yasushi Saito, Nagahiro Minato, Takashi Saito

    Research output: Contribution to journalArticle

    10 Citations (Scopus)

    Abstract

    Netherlands Cytotoxic T lymphocyte antigen 4 (CTLA-4) is a T cell co-stimulation receptor that delivers inhibitory signals upon activation. This inhibitory effect by CTLA-4 requires activation of small GTPase Rap-1. However, the precise mechanism underlying these negative signals remains unclear. Here, we show that CTLA-4-induced suppression of IL-2 production correlates with rapid destabilization of immunological synapse (IS) formation in murine normal T cell clones. Overexpression of Spa-1, a Rap-1-specific GTPase activating protein (GAP), abolished both Rap-1 activation and IL-2 suppression induced by CTLA-4. Although we failed to find any specific inhibition of activation of early signals upon CTLA-4 engagement, we found that CTLA-4 specifically up-regulates cell motility and suppresses prolonged accumulation of Talin at the contact area with antigen presenting cells upon antigen stimulation. These results suggest that Rap-1 is activated upon CTLA-4 ligation and mediates inhibitory signals through prevention of IS formation.

    Original languageEnglish
    Pages (from-to)150-158
    Number of pages9
    JournalHematology
    Volume14
    Issue number3
    DOIs
    Publication statusPublished - Jun 1 2009

    All Science Journal Classification (ASJC) codes

    • Hematology

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