title: CD160Ig fusion protein targets a novel costimulatory pathway and prolongs allograft survival.
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.
authors.affiliation: Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Francesca
authors.initials: F
authors.lastname: D'Addio
authors.forename: Takuya
authors.initials: T
authors.lastname: Ueno
authors.forename: Michael
authors.initials: M
authors.lastname: Clarkson
authors.forename: Baogong
authors.initials: B
authors.lastname: Zhu
authors.forename: Andrea
authors.initials: A
authors.lastname: Vergani
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Sayegh
authors.forename: Mohammed Javeed I
authors.initials: MJ
authors.lastname: Ansari
authors.forename: Paolo
authors.initials: P
authors.lastname: Fiorina
authors.forename: Antje
authors.initials: A
authors.lastname: Habicht
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology*; D018106:CD28 Antigens / Q000172:deficiency / Q000276:immunology; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D003602:Cytotoxicity, Immunologic / Q000235:genetics / Q000276:immunology; D058851:GPI-Linked Proteins / Q000235:genetics / Q000276:immunology; D015870:Gene Expression; D006085:Graft Survival / Q000187:drug effects* / Q000235:genetics / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology / Q000401:mortality; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology*; D007156:Immunologic Memory / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D016038:Skin Transplantation / Q000276:immunology / Q000401:mortality; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D014184:Transplantation, Homologous
chemical_list: D015703:Antigens, CD; C114505:CD160 protein, human; D018106:CD28 Antigens; D015704:CD4 Antigens; D016207:Cytokines; D058851:GPI-Linked Proteins; D015395:Histocompatibility Antigens Class I; D007074:Immunoglobulin G; D011971:Receptors, Immunologic; D011993:Recombinant Fusion Proteins; D007371:Interferon-gamma