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

    Fingerprint

    CTLA-4 Antigen
    Synapses
    Immunological Synapses
    Interleukin-2
    Talin
    T-Lymphocytes
    GTPase-Activating Proteins
    Monomeric GTP-Binding Proteins
    Antigen-Presenting Cells
    Netherlands
    Cell Movement
    Ligation
    Up-Regulation
    Clone Cells
    Antigens

    All Science Journal Classification (ASJC) codes

    • Hematology

    Cite this

    Hara, S., Nakaseko, C., Yamasaki, S., Hattori, M., Bos, J. L., Saito, Y., ... Saito, T. (2009). Involvement of Rap-1 activation and early termination of immune synapse in CTLA-4-mediated negative signal. Hematology, 14(3), 150-158. https://doi.org/10.1179/102453309X402241

    Involvement of Rap-1 activation and early termination of immune synapse in CTLA-4-mediated negative signal. / Hara, Satoru; Nakaseko, Chiaki; Yamasaki, Sho; Hattori, Masakazu; Bos, Johannes L.; Saito, Yasushi; Minato, Nagahiro; Saito, Takashi.

    In: Hematology, Vol. 14, No. 3, 01.06.2009, p. 150-158.

    Research output: Contribution to journalArticle

    Hara, S, Nakaseko, C, Yamasaki, S, Hattori, M, Bos, JL, Saito, Y, Minato, N & Saito, T 2009, 'Involvement of Rap-1 activation and early termination of immune synapse in CTLA-4-mediated negative signal', Hematology, vol. 14, no. 3, pp. 150-158. https://doi.org/10.1179/102453309X402241
    Hara, Satoru ; Nakaseko, Chiaki ; Yamasaki, Sho ; Hattori, Masakazu ; Bos, Johannes L. ; Saito, Yasushi ; Minato, Nagahiro ; Saito, Takashi. / Involvement of Rap-1 activation and early termination of immune synapse in CTLA-4-mediated negative signal. In: Hematology. 2009 ; Vol. 14, No. 3. pp. 150-158.
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