Thymic tolerance to only one viral protein reduces lymphocytic choriomeningitis virus-induced immunopathology and increases survival in perforin-deficient mice

The outcome of viral infections is dependent on the amount of tissue destru ction caused either by direct lysis of infected cells and/or by immunopatho logy resulting from the immune response to the virus. We investigated wheth er induction of tolerance to only one viral protein could reduce immunopath ology caused by nonlytic lymphocytic choriomeningitis virus (LCMV) in perfo rin-deficient hosts. Earlier studies had shown that LCMV infection results in aplastic anemia and death in most of these mice and that this is associa ted with bone marrow infiltration by antiviral cytotoxic T lymphocytes (CTL ) that secrete inflammatory cytokines. We report here that perforin-deficie nt mice exhibit severe immunopathology in multiple organs that is character ized by infiltration of anti-LCMV CTL that secrete large amounts of gamma i nterferon (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha). importan tly, this immunopathology is significantly reduced and long-term survival o f LCMV infection is increased in perforin-deficient mice expressing LCMV nu cleoprotein (NP) in the thymus land therefore deleting most of their LCMV-N P CTL) compared to the situation in thymus nonexpressors. This is due to th e selective reduction of NP-specific CTL responses and their inflammatory-c ytokine (IFN-gamma and TNF-alpha) secretion and to a lack of pathogenetical ly relevant compensatory responses to other viral proteins. Thus, "selectiv e reduction" of the antiviral immune response to only one viral protein can significantly reduce inflammatory immunopathology and might be a therapeut ic possibility for certain nonlytic infections.