Abstract
CD160 is a cell surface molecule expressed by most NK cells and approximately 50% of CD8(+) cytotoxic T lymphocytes. Engagement of CD160 by MHC class-I directly triggers a costimulatory signal to TCR-induced proliferation, cytokine production and cytotoxic effector functions. The role of CD160 in alloimmunity is unknown. Using a newly generated CD160 fusion protein (CD160Ig) we examined the role of the novel costimulatory molecule CD160 in mediating CD4(+) or CD8(+) T cell driven allograft rejection. CD160Ig inhibits alloreactive CD8(+) T cell proliferation and IFN-γ production in vitro, in particular in the absence of CD28 costimulation. Consequently CD160Ig prolongs fully mismatched cardiac allograft survival in CD4(-/-), CD28(-/-) knockout and CTLA4Ig treated WT recipients, but not in WT or CD8(-/-) knockout recipients. The prolonged cardiac allograft survival is associated with reduced alloreactive CD8(+) T cell proliferation, effector/memory responses and alloreactive IFN-γ production. Thus, CD160 signaling is particularly important in CD28-independent effector/memory CD8(+) alloreactive T cell activation in vivo and therefore may serve as a novel target for prevention of allograft rejection.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigen-Presenting Cells / immunology
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Antigen-Presenting Cells / metabolism
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Antigens, CD / genetics
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Antigens, CD / immunology*
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CD28 Antigens / deficiency
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CD28 Antigens / immunology
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CD4 Antigens / genetics
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CD4 Antigens / immunology
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Cytokines / biosynthesis
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Cytotoxicity, Immunologic / genetics
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Cytotoxicity, Immunologic / immunology
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GPI-Linked Proteins / genetics
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GPI-Linked Proteins / immunology
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Gene Expression
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Graft Survival / drug effects*
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Graft Survival / genetics
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Graft Survival / immunology*
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Heart Transplantation / immunology
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Heart Transplantation / mortality
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Histocompatibility Antigens Class I / genetics
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Histocompatibility Antigens Class I / immunology
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Immunoglobulin G / genetics
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Immunoglobulin G / immunology*
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Immunologic Memory / genetics
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Immunologic Memory / immunology
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Interferon-gamma / biosynthesis
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Killer Cells, Natural / immunology
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Killer Cells, Natural / metabolism
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Lymphocyte Activation / immunology
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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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Receptors, Immunologic / genetics
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Receptors, Immunologic / immunology*
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / immunology
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Recombinant Fusion Proteins / pharmacology*
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Signal Transduction / drug effects*
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Skin Transplantation / immunology
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Skin Transplantation / mortality
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T-Lymphocyte Subsets / immunology
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T-Lymphocyte Subsets / metabolism
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Transplantation, Homologous
Substances
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Antigens, CD
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CD160 protein, human
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CD28 Antigens
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CD4 Antigens
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Cytokines
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GPI-Linked Proteins
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Histocompatibility Antigens Class I
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Immunoglobulin G
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Receptors, Immunologic
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Recombinant Fusion Proteins
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Interferon-gamma