title: CD4 T cells contribute to virus control and pathology following central nervous system infection with neurotropic mouse hepatitis virus.
abstract: 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.
authors: Department of Neurosciences NC30, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. stohlms2@ccf.org
authors: Stephen A
authors: SA
authors: Stohlman
authors: David R
authors: DR
authors: Hinton
authors: Beatriz
authors: B
authors: Parra
authors: Roscoe
authors: R
authors: Atkinson
authors: Cornelia C
authors: CC
authors: Bergmann
mesh_terms: 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
chemical_list: D054353:Perforin; D007371:Interferon-gamma