CD160Ig fusion protein targets a novel costimulatory pathway and prolongs allograft survival

• Published in: PloS one 2013-04, Vol.8 (4), p.e60391
• Main Authors: D'Addio, Francesca, Ueno, Takuya, Clarkson, Michael, Zhu, Baogong, Vergani, Andrea, Freeman, Gordon J, Sayegh, Mohamed H, Ansari, Mohammed Javeed I, Fiorina, Paolo, Habicht, Antje
• Format: Article
• Language: English
• Subjects: Animals; Antigen-Presenting Cells - immunology; Antigen-Presenting Cells - metabolism; Antigens; Antigens, CD - genetics; Antigens, CD - immunology; Biology; CD28 antigen; CD28 Antigens - deficiency; CD28 Antigens - immunology; CD4 antigen; CD4 Antigens - genetics; CD4 Antigens - immunology; CD8 antigen; Cell activation; Cell growth; Cell proliferation; Cell surface; Cell survival; CTLA-4 protein; Cytokines; Cytokines - biosynthesis; Cytotoxicity; Cytotoxicity, Immunologic - genetics; Cytotoxicity, Immunologic - immunology; Development and progression; Diabetes; Fusion protein; Gene Expression; Genetic aspects; GPI-Linked Proteins - genetics; GPI-Linked Proteins - immunology; Graft rejection; Graft Survival - drug effects; Graft Survival - genetics; Graft Survival - immunology; Heart diseases; Heart Transplantation - immunology; Heart Transplantation - mortality; Histocompatibility Antigens Class I - genetics; Histocompatibility Antigens Class I - immunology; Homografts; Hospitals; Immunoglobulin G - genetics; Immunoglobulin G - immunology; Immunologic Memory - genetics; Immunologic Memory - immunology; Immunological memory; Interferon; Interferon-gamma - biosynthesis; Internal medicine; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Laboratory animals; Ligands; Lymphocyte Activation - immunology; Lymphocytes; Lymphocytes T; Major histocompatibility complex; Medical schools; Medicine; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Ostomy; Physiological aspects; Proteins; Receptors, Immunologic - genetics; Receptors, Immunologic - immunology; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - immunology; Recombinant Fusion Proteins - pharmacology; Rejection; Signal Transduction - drug effects; Signaling; Skin Transplantation - immunology; Skin Transplantation - mortality; Survival; T cell receptors; T cells; T-cell receptor; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; Transplantation, Homologous; Transplants & implants; Viral infections; Womens health; γ-Interferon
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0060391

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.