In vivo overexpression of CTLA-4 suppresses lymphoproliferative diseases and thymic negative selection

Shigekazu Takahashi, Hiroshi Kataoka, Satoru Hara, Tadashi Yokosuka, Kan Takase, Shou Yamasaki, Wakana Kobayashi, Yasushi Saito, Takashi Saito

    Research output: Contribution to journalArticle

    30 Citations (Scopus)

    Abstract

    Cytotoxic T lymphocyte antigen-4 (CTLA-4) induces major inhibitory signals for T cell activation. From analyses of TCR-transgenic (Tg) CTLA-4-deficient mice, it has been believed that CTLA-4 does not affect thymocyte development. To focus upon the in vivo function of CTLA-4 in thymocyte development from a different aspect, we have established Tg mice expressing either full-length CTLA-4 (FL-Tg) or a mutant CTLA-4 lacking the cytoplasmic region (truncated, TR-Tg), and analyzed thymocyte development. TR-T cells express much higher CTLA-4 on the cell surface than FL-T cells, in which most CTLA-4 was localized in intracellular vesicles. While CTLA-4-/- mice exhibit lymphoproliferative disease, neither of the Tg mice with CTLA-4-/- background developed the disorder. Although the development of thymocytes appeared normal in both Tg mice, in vivo depletion of double-positive thymocytes by injection of anti-CD3 Ab as well as the elimination of minor lymphocyte-stimulating antigen-reactive thymocytes were impaired in FL-Tg mice but not in TR-Tg mice. Functionally, cross-linking of CTLA-4 on thymocytes from FL-Tg mice, but not from TR-Tg mice, inhibited proliferation. These results reveal a potential role of CTLA-4, through its cytoplasmic domain, in the negative selection of thymocytes and in the prevention of lymphoproliferative disease.

    Original languageEnglish
    Pages (from-to)399-407
    Number of pages9
    JournalEuropean Journal of Immunology
    Volume35
    Issue number2
    DOIs
    Publication statusPublished - Feb 1 2005

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    CTLA-4 Antigen
    Thymocytes
    Transgenic Mice
    T-Lymphocytes
    Minor Lymphocyte Stimulatory Antigens

    All Science Journal Classification (ASJC) codes

    • Immunology and Allergy
    • Immunology

    Cite this

    Takahashi, S., Kataoka, H., Hara, S., Yokosuka, T., Takase, K., Yamasaki, S., ... Saito, T. (2005). In vivo overexpression of CTLA-4 suppresses lymphoproliferative diseases and thymic negative selection. European Journal of Immunology, 35(2), 399-407. https://doi.org/10.1002/eji.200324746

    In vivo overexpression of CTLA-4 suppresses lymphoproliferative diseases and thymic negative selection. / Takahashi, Shigekazu; Kataoka, Hiroshi; Hara, Satoru; Yokosuka, Tadashi; Takase, Kan; Yamasaki, Shou; Kobayashi, Wakana; Saito, Yasushi; Saito, Takashi.

    In: European Journal of Immunology, Vol. 35, No. 2, 01.02.2005, p. 399-407.

    Research output: Contribution to journalArticle

    Takahashi, S, Kataoka, H, Hara, S, Yokosuka, T, Takase, K, Yamasaki, S, Kobayashi, W, Saito, Y & Saito, T 2005, 'In vivo overexpression of CTLA-4 suppresses lymphoproliferative diseases and thymic negative selection', European Journal of Immunology, vol. 35, no. 2, pp. 399-407. https://doi.org/10.1002/eji.200324746
    Takahashi, Shigekazu ; Kataoka, Hiroshi ; Hara, Satoru ; Yokosuka, Tadashi ; Takase, Kan ; Yamasaki, Shou ; Kobayashi, Wakana ; Saito, Yasushi ; Saito, Takashi. / In vivo overexpression of CTLA-4 suppresses lymphoproliferative diseases and thymic negative selection. In: European Journal of Immunology. 2005 ; Vol. 35, No. 2. pp. 399-407.
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