Memory CD4+ T-cell-mediated protection from lethal coronavirus encephalomyelitis.
The antiviral role of CD4(+) T cells in virus-induced pathologies of the central nervous system (CNS) has not been explored extensively. Control of neurotropic mouse hepatitis virus (JHMV) requires the collaboration of CD4(+) and CD8(+) T cells, with CD8(+) T cells providing direct perforin and gamma interferon (IFN-gamma)-mediated antiviral activity. To distinguish bystander from direct antiviral contributions of CD4(+) T cells in virus clearance and pathology, memory CD4(+) T cells purified from wild type (wt), perforin-deficient (PKO), and IFN-gamma-deficient (GKO) immune donors were transferred to immunodeficient SCID mice prior to CNS challenge. All three donor CD4(+) T-cell populations controlled CNS virus replication at 8 days postinfection, indicating IFN-gamma- and perforin-independent antiviral function. Recipients of GKO CD4(+) T cells succumbed more rapidly to fatal disease than untreated control infected mice. In contrast, wt and PKO donor CD4(+) T cells cleared infectious virus to undetectable levels and protected from fatal disease. Recipients of all CD4(+) T-cell populations exhibited demyelination. However, it was more severe in wt CD4(+) T-cell recipients. These data support a role of CD4(+) T cells in virus clearance and demyelination. Despite substantial IFN-gamma-independent antiviral activity, IFN-gamma was crucial in providing protection from death. IFN-gamma reduced neutrophil accumulation and directed macrophages to white matter but did not ameliorate myelin loss.
Department of Neurosciences, NC30, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
Carine
C
Savarin
Cornelia C
CC
Bergmann
David R
DR
Hinton
Richard M
RM
Ransohoff
Stephen A
SA
Stohlman
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D017934:Coronavirus / Q000276:immunology*; D004679:Encephalomyelitis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D007156:Immunologic Memory / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D009186:Myelin Sheath / Q000378:metabolism
D007371:Interferon-gamma