Memory CD4 + T-Cell-Mediated Protection from Lethal Coronavirus Encephalomyelitis

Abstract

ABSTRACT 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-γ)-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-γ-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-γ- 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-γ-independent antiviral activity, IFN-γ was crucial in providing protection from death. IFN-γ reduced neutrophil accumulation and directed macrophages to white matter but did not ameliorate myelin loss.