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

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

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35 Citations (Scopus)


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
Issue number2
Publication statusPublished - Feb 2005
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology


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