Differential requirement for CD80 and CD80/CD86-dependent costimulation inthe lung immune response to an influenza virus infection

The CD28 costimulatory pathway is critical to T cell activation. Blockade o f 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 br onchoalveolar lavage fluid CD8(+) T lymphocytes in vitro. It also resulted in decreased numbers of virus-specific CD8+ T lymphocytes in the bronchoalv eolar lavage fluid, lung, and spleen and lowered virus-specific Ab titers, Mice treated with CTLA4-Ig mere able to control and clear the virus infecti on, 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 CD2 8-CD80 interaction leaving CD28-CD86 binding intact, did not affect Ab prod uction, spleen cytotoxic precursors, or clearance of virus, However, Y100F- Ig treatment had a clear effect on lung effector cell function. Secretion o f IFN-gamma by bronchoalveolar lavage fluid CD8(+) T lymphocytes in vitro w as 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 anti viral 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.