CD4 T cells contribute to virus control and pathology following central nervous system infection with neurotropic mouse hepatitis virus.
Replication of the neurotropic mouse hepatitis virus strain JHM (JHMV) is controlled primarily by CD8(+) T-cell effectors utilizing gamma interferon (IFN-gamma) and perforin-mediated cytotoxicity. CD4(+) T cells provide an auxiliary function(s) for CD8(+) T-cell survival; however, their direct contribution to control of virus replication and pathology is unclear. To examine a direct role of CD4(+) T cells in viral clearance and pathology, pathogenesis was compared in mice deficient in both perforin and IFN-gamma that were selectively reconstituted for these functions via transfer of virus-specific memory CD4(+) T cells. CD4(+) T cells from immunized wild-type, perforin-deficient, and IFN-gamma-deficient donors all initially reduced virus replication. However, prolonged viral control by IFN-gamma-competent donors suggested that IFN-gamma is important for sustained virus control. Local release of IFN-gamma was evident by up-regulation of class II molecules on microglia in recipients of IFN-gamma producing CD4(+) T cells. CD4(+) T-cell-mediated antiviral activity correlated with diminished clinical symptoms, pathology, and demyelination. Both wild-type donor CD90.1 and recipient CD90.2 CD4(+) T cells trafficked into the central nervous system (CNS) parenchyma and localized to infected white matter, correlating with decreased numbers of virus-infected oligodendrocytes in the CNS. These data support a direct, if limited, antiviral role for CD4(+) T cells early during acute JHMV encephalomyelitis. Although the antiviral effector mechanism is initially independent of IFN-gamma secretion, sustained control of CNS virus replication by CD4(+) T cells requires IFN-gamma.
Stohlman
Stephen A
SA
Department of Neurosciences NC30, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. stohlms2@ccf.org
Hinton
David R
DR
Parra
Beatriz
B
Atkinson
Roscoe
R
Bergmann
Cornelia C
CC
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002494:Central Nervous System Infections / Q000276:immunology* / Q000473:pathology / Q000821:virology; D005434:Flow Cytometry; D006524:Hepatitis, Viral, Animal / Q000276:immunology* / Q000473:pathology / Q000821:virology; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D006517:Murine hepatitis virus / Q000276:immunology* / Q000502:physiology; D054353:Perforin / Q000378:metabolism; D014779:Virus Replication
D054353:Perforin; D007371:Interferon-gamma