Vaccination against persistent viral infection exacerbates CD4(+) T-cell-mediated immunopathological disease

Lymphocytic choriomeningitis virus (LCMV) infection of normal mice results in a fatal immunopathologic meningitis mediated by CD8(+) cytotoxic T lymphocytes (CTL). We have previously shown that female beta(2)-microglobulin-deficient (beta(2)m-/-) mice, which are also deficient in CD8(+) T cells, are susceptible to LCMV-induced immune-mediated meningitis, characterized by significant weight loss and mortality. This LCMV disease in beta(2)m-/- mice is mediated by CD4(+) T lymphocytes. Our previous studies have also demonstrated that male beta(2)m-/- mice are less susceptible than female beta(2)m-/- mice to LCMV-induced, immune-mediated mortality and weight loss. In this report, we show that vaccination of male beta(2)m-/- mice enhances immunopathology following intracranial infection with LCMV. We observed increased production of gamma interferon (IFN-gamma), an increase in CD4(+) CTL precursor frequency, and an increased frequency of IFN-gamma-producing cells from spleen cells of vaccinated male beta(2)m-/- mice. Vaccinated male beta(2)m-/- mice also had significantly increased inflammation in the cerebrospinal fluid (CSF), characterized by a large CD4(+) T-cell infiltrate. CSF cells from vaccinated mice showed increased production of IFN-gamma on day 7 postchallenge. Neither vaccinated nor control beta(2)m-/- mice were able to clear virus, and the two groups had similarly high levels of virus early after infection. These results suggest that the magnitude of the early immune response is more important than the level of virus in the brain in determining the outcome of immunopathology in beta(2)m-/- mice. We show here that vaccination can increase CD4(+) T-cell-dependent immunopathology to a persistent viral infection.