In vivo overexpression of CTLA-4 suppresses lymphoproliferative diseases and thymic negative selection.
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.
Takahashi
Shigekazu
S
Department of Molecular Genetics, Graduate School of Medicine, Chiba University, Chiba, Japan.
Kataoka
Hiroshi
H
Hara
Satoru
S
Yokosuka
Tadashi
T
Takase
Kan
K
Yamasaki
Sho
S
Kobayashi
Wakana
W
Saito
Yasushi
Y
Saito
Takashi
T
D000818:Animals; D000906:Antibodies / Q000276:immunology; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D017252:CD3 Complex / Q000276:immunology; D060908:CTLA-4 Antigen; D002454:Cell Differentiation / Q000276:immunology; D008232:Lymphoproliferative Disorders / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D014443:Tyrosine / Q000235:genetics / Q000276:immunology / Q000378:metabolism
D000906:Antibodies; D015703:Antigens, CD; D000943:Antigens, Differentiation; D017252:CD3 Complex; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D014443:Tyrosine