title: Differential requirement for CD80 and CD80/CD86-dependent costimulation in the lung immune response to an influenza virus infection.
abstract: The CD28 costimulatory pathway is critical to T cell activation. Blockade of the interaction of CD28 with its ligands CD80 and CD86 using CTLA4-Ig has been proposed as a therapy for a number of immune-based disorders. We have used a murine model of influenza virus infection to study the role of CD28-dependent costimulation in the development of antiviral immune responses. In vivo treatment with CTLA4-Ig to block the interaction of CD28 with CD80 and CD86 reduced virus-specific cytotoxicity and IFN-gamma production by bronchoalveolar lavage fluid CD8+ T lymphocytes in vitro. It also resulted in decreased numbers of virus-specific CD8+ T lymphocytes in the bronchoalveolar lavage fluid, lung, and spleen and lowered virus-specific Ab titers. Mice treated with CTLA4-Ig were able to control and clear the virus infection, but this was delayed compared with controls. Treatment with Y100F-Ig, a mutant form of CTLA4-Ig which selectively binds to CD80 and blocks the CD28-CD80 interaction leaving CD28-CD86 binding intact, did not affect Ab production, spleen cytotoxic precursors, or clearance of virus. However, Y100F-Ig treatment had a clear effect on lung effector cell function. Secretion of IFN-gamma by bronchoalveolar lavage fluid CD8+ T lymphocytes in vitro was decreased, and the number of virus-specific CD8+ T lymphocytes in the bronchoalveolar lavage fluid and lungs of infected mice was reduced. These results indicate that CD28-dependent costimulation is important in the antiviral immune response to an influenza virus infection. The individual CD28 ligand, CD80, is important for some lung immune responses and cannot always be compensated for by CD86.
authors.affiliation: Malaghan Institute of Medical Research, Wellington School of Medicine, New Zealand.
authors.forename: J M
authors.initials: JM
authors.lastname: Lumsden
authors.forename: J M
authors.initials: JM
authors.lastname: Roberts
authors.forename: N L
authors.initials: NL
authors.lastname: Harris
authors.forename: R J
authors.initials: RJ
authors.lastname: Peach
authors.forename: F
authors.initials: F
authors.lastname: Ronchese
mesh_terms: D000069594:Abatacept; D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis; D015703:Antigens, CD / Q000502:physiology*; D000943:Antigens, Differentiation / Q000008:administration & dosage / Q000235:genetics; D018122:B7-1 Antigen / Q000502:physiology*; D051940:B7-2 Antigen; D060908:CTLA-4 Antigen; D002478:Cells, Cultured; D006801:Humans; D018796:Immunoconjugates; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D009980:Influenza A virus / Q000276:immunology*; D007251:Influenza, Human / Q000276:immunology* / Q000821:virology; D007274:Injections, Intraperitoneal; D008168:Lung / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016297:Mutagenesis, Site-Directed; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D000914:Antibodies, Viral; D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497964:CD86 protein, human; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C497965:Cd86 protein, mouse; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D008562:Membrane Glycoproteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011993:Recombinant Fusion Proteins; C075784:T cell receptor Vbeta8; D000069594:Abatacept