Cytomegaloviruses (CMV) cause significant disease in immunosuppressed people, including patients that have had an organ transplant and people with human immunodeficiency virus. The murine CMV (MCMV) is an excellent model of the human virus, as the pathogenesis and immune response between the hosts and viruses are similar. T cells are critical in the response to MCMV. In the initial infection, CD4+ cells are needed to clear the infection from the salivary glands and CD8+ T cells are critical in clearing MCMV from the spleen and lungs. Following the acute infection, the virus becomes latent. Suppression of the immune system during latency causes the virus to reactivate. This suggests that the immune system has an important role in suppressing the virus and keeping it latent. There are three main aims of the work proposed here. First, to determine if MCMV infection decreases the ability of antigen presenting cells (APC) to stimulate CD4+ T cells and, if so, what APC functions are inhibited. This will be investigated using MCMV infection of macrophages and dendritic cells in vitro to stimulate CD4+ T cells with specific antigen. Second, to determine what T cell subsets, if any, are required to maintain MCMV latency, and to determine if lyrically competent CD8+ CTL are generated during MCMV latency. This will be determined by depleting mice that have latent MCMV of T cell subsets (CD4+, CD8+ or both) and testing for reactivation of the virus. The role of lyrically competent CD8+ CTL will be investigated by generating a mouse in which cells expressing the perforin gene can be detected by flow cytometry or immunofluorescence. This will allow detection of lytic CD8+ cells during acute or latent infection. Third, to characterize the mechanisms by which CD4+ cells can eliminate acute MCMV infection from salivary glands. The functional capability of CD4+ cells (cytokine production, lytic ability) purified from salivary glands will be determined. These studies will make important contributions to our understanding of the host response to CMV infections, particularly latent infection.
| McAdam, A J; Chang, T T; Lumelsky, A E et al. (2000) Mouse inducible costimulatory molecule (ICOS) expression is enhanced by CD28 costimulation and regulates differentiation of CD4+ T cells. J Immunol 165:5035-40 |
