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-γ 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-γ 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.

Nuclear factor of activated T (NFAT) cells activity within CD4+ T cells is influenced by activation status and tissue localisation

“…The A/HKx31 (H3N2) influenza A virus was maintained as described [25]. For Flu infection, mice were anaesthetised by intraperitoneal injection (i.p.)…”

Lower GrB+ CD62Lhigh CD8 TCM effector lymphocyte response to influenza virus in older adults is associated with increased CD28null CD8 T lymphocytes

“…Low antibody response to influenza vaccination in older adults is correlated with high frequencies of CD28 null T cells (Goronzy et al, 2001;Saurwein-Teissl et al, 2002). The lack of CD28 potentially diminishes T cell responses to influenza vaccination and suggests that CD28 plays a critical role in the subsequent response to infection (Lumsden et al, 2000).…”

A critical role for ICOS co‐stimulation in immune containment of pulmonary influenza virus infection

“…We previously demonstrated that inhibiting the proliferation and survival of antigen-activated T cells by targeting OX40 co-stimulation reduces influenza-induced pulmonary inflammation and associated disease without impairing viral clearance [16], similar to mice genetically deficient in this molecule [17,18]. In contrast, inhibition of constitutively expressed CD28 delays the clearance of influenza from the lung [19].…”