Abstract
To examine whether B7 costimulation can be mediated by a molecule on T cells that is neither CD28 nor CTLA4, we generated mice lacking both of these receptors. CD28/CTLA4(-/-) mice resemble CD28(-/-) mice in having decreased expression of T-cell activation markers in vivo and decreased T-cell proliferation in vitro, as compared with wild-type mice. Using multiple approaches, we find B7-dependent costimulation in CD28/CTLA4(-/-) mice. The proliferation of CD28/CTLA4(-/-) T cells is inhibited by CTLA4-Ig and by the use of antigen-presenting cells lacking both B7-1 and B7-2. CD28/CTLA4(-/-) T-cell proliferation is increased by exposure to Chinese hamster ovary cells transfected with B7-1 or B7-2. Finally, administration of CTLA4-Ig to CD28/CTLA4(-/-) cardiac allograft recipients significantly prolongs graft survival. These data support the existence of an additional receptor for B7 molecules that is neither CD28 nor CTLA4.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Abatacept
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Animals
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Antigens, CD / genetics
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Antigens, CD / immunology*
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Antigens, CD / physiology
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Antigens, Differentiation / genetics
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Antigens, Differentiation / immunology*
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B7-1 Antigen / genetics
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B7-1 Antigen / immunology*
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B7-1 Antigen / physiology
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B7-2 Antigen
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CD28 Antigens / genetics
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CD28 Antigens / immunology*
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CHO Cells
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CTLA-4 Antigen
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Cell Division
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Cricetinae
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Graft Rejection / immunology
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Graft Survival / immunology
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Heart Transplantation
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Immunoconjugates*
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Immunophenotyping
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Interferon-gamma / biosynthesis
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / immunology*
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Membrane Glycoproteins / physiology
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Knockout
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T-Lymphocytes / cytology
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T-Lymphocytes / immunology*
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Th1 Cells / immunology
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Transplantation, Homologous / immunology
Substances
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Antigens, CD
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Antigens, Differentiation
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B7-1 Antigen
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B7-2 Antigen
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CD28 Antigens
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CTLA-4 Antigen
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Cd86 protein, mouse
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Ctla4 protein, mouse
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Immunoconjugates
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Membrane Glycoproteins
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Abatacept
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Interferon-gamma