Perforin-mediated effector function within the central nervous system requires IFN-gamma-mediated MHC up-regulation.
CD8(+) T cells infiltrating the CNS control infection by the neurotropic JHM strain of mouse hepatitis virus. Differential susceptibility of infected cell types to clearance by perforin or IFN-gamma uncovered distinct, nonredundant roles for these antiviral mechanisms. To separately evaluate each effector function specifically in the context of CD8(+) T cells, pathogenesis was analyzed in mice deficient in both perforin and IFN-gamma (PKO/GKO) or selectively reconstituted for each function by transfer of CD8(+) T cells. Untreated PKO/GKO mice were unable to control the infection and died of lethal encephalomyelitis within 16 days, despite substantially higher CD8(+) T cell accumulation in the CNS compared with controls. Uncontrolled infection was associated with limited MHC class I up-regulation and an absence of class II expression on microglia, coinciding with decreased CD4(+) T cells in CNS infiltrates. CD8(+) T cells from perforin-deficient and wild-type donors reduced virus replication in PKO/GKO recipients. By contrast, IFN-gamma-deficient donor CD8(+) T cells did not affect virus replication. The inability of perforin-mediated mechanisms to control virus in the absence of IFN-gamma coincided with reduced class I expression. These data not only confirm direct antiviral activity of IFN-gamma within the CNS but also demonstrate IFN-gamma-dependent MHC surface expression to guarantee local T cell effector function in tissues inherently low in MHC expression. The data further imply that IFN-gamma plays a crucial role in pathogenesis by regulating the balance between virus replication in oligodendrocytes, CD8(+) T cell effector function, and demyelination.
Bergmann
Cornelia C
CC
Department of Neurology, Keck School of Medicine, University of California, Los Angeles, CA 90033, USA.
Parra
Beatriz
B
Hinton
David R
DR
Chandran
Ramakrishna
R
Morrison
Maureen
M
Stohlman
Stephen A
SA
D000208:Acute Disease; D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D020805:Central Nervous System Viral Diseases / Q000235:genetics / Q000276:immunology* / Q000401:mortality / Q000517:prevention & control; D018352:Coronavirus Infections / Q000235:genetics / Q000276:immunology / Q000401:mortality / Q000517:prevention & control; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D004679:Encephalomyelitis / Q000235:genetics / Q000276:immunology / Q000401:mortality / Q000517:prevention & control; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis* / Q000235:genetics; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis* / Q000235:genetics; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D006517:Murine hepatitis virus / Q000276:immunology / Q000472:pathogenicity; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D015854:Up-Regulation / Q000276:immunology*
D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin; D007371:Interferon-gamma