Perforin and Gamma Interferon-Mediated Control of Coronavirus Central Nervous System Infection by CD8 T Cells in the Absence of CD4 T Cells

Abstract

ABSTRACT Infection of the central nervous system (CNS) with the neurotropic JHM strain of mouse hepatitis virus produces acute and chronic demyelination. The contributions of perforin-mediated cytolysis and gamma interferon (IFN-γ) secretion by CD8 + T cells to the control of infection and the induction of demyelination were examined by adoptive transfer into infected SCID recipients. Untreated SCID mice exhibited uncontrolled virus replication in all CNS cell types but had little or no demyelination. Memory CD8 + T cells from syngeneic wild-type (wt), perforin-deficient, or IFN-γ-deficient (GKO) donors all trafficked into the infected CNS in the absence of CD4 + T cells and localized to similar areas. Although CD8 + T cells from all three donors suppressed virus replication in the CNS, GKO CD8 + T cells expressed the least antiviral activity. A distinct viral antigen distribution in specific CNS cell types revealed different mechanisms of viral control. While wt CD8 + T cells inhibited virus replication in all CNS cell types, cytolytic activity in the absence of IFN-γ suppressed the infection of astrocytes, but not oligodendroglia. In contrast, cells that secreted IFN-γ but lacked cytolytic activity inhibited replication in oligodendroglia, but not astrocytes. Demyelination was most severe following viral control by wt CD8 + T cells but was independent of macrophage infiltration. These data demonstrate the effective control of virus replication by CD8 + T cells in the absence of CD4 + T cells and support the necessity for the expression of distinct effector mechanisms in the control of viral replication in distinct CNS glial cell types.