Compromised Virus Control and Augmented Perforin-Mediated Immunopathology in IFN-γ-Deficient Mice Infected with Lymphocytic Choriomeningitis Virus

Abstract

Abstract To define the role of IFN-γ in the control of acute infection with a noncytopathogenic virus, mice with targeted defects of the genes encoding IFN-γ, perforin, or both were infected i.v. with two strains of lymphocytic choriomeningitis virus differing markedly in their capacity to spread in wild-type mice. Our results reveal that IFN-γ is pivotal to T cell-mediated control of a rapidly invasive stain, whereas it is less important in the acute elimination of a slowly invasive strain. Moreover, the majority of mice infected with the rapidly invasive strain succumb to a wasting syndrome mediated by CD8+ effector cells. The primary effector mechanism underlying this disease is perforin-dependent lysis, but other mechanisms are also involved. Wasting disease can be prevented if naive CD8+ cells from mice transgenic for an MHC class I-restricted lymphocytic choriomeningitis virus-specific TCR are adoptively transferred before virus challenge, indicating that the disease is the result of an unfortunate balance between virus replication in internal organs, e.g., liver and spleen, and the host response; resetting this balance by increasing host responsiveness will again lead to a rapidly controlled infection and limited tissue damage. Thus, the presence or absence of IFN-γ determines whether CTLs will clear infection with this noncytopathogenic virus or induce severe immunopathology.