INTERFERON-ALPHA BETA MEDIATES EARLY VIRUS-INDUCED EXPRESSION OF H-2DAND H-2K IN THE CENTRAL-NERVOUS-SYSTEM/

Cells of the central nervous system (CNS) normally do not express dete ctable levels of major histocompatibility complex (MHC) Class I antige ns. However, MHC Class I expression can be induced after Virus infecti on. We tested the hypothesis that virus-induced Class I expression is mediated by lymphocytes or cytokines using lymphocyte- and cytokine-de ficient mice. We used Theiler's murine encephalomyelitis virus (TMEV), which induces GNS demyelination that maps genetically to the D region of MHC Class I and is associated with high levels of Glass I products . TMEV infection of severe combined immunodeficiency (SCID) and recomb ination activation gene-1-deficient mice, which lack B and T lymphocyt es, resulted in equivalent H-2D and H-2K expression in brain and spina l cord, according to analysis of the area and intensity of immunoperox idase staining. Class I antigens were demonstrated as early as 6 hours after infection, and they were more widely distributed than viral RNA , indicating that expression was induced indirectly via a soluble fact or. To determine whether cytokines induced the expression, we infected mice lacking receptors for interferon-alpha/beta (IFN-alpha/beta R(-/ -)), interferon-gamma (IFN-gamma R(-/-)), and tumor necrosis factor-al pha (TNFRp55(-/-)). TMEV-infected IFN-gamma R(-/-) and TNFRp55(-/-) mi ce expressed Class I antigens in the CNS, whereas IFN-alpha/beta R(-/- ) mice did not, establishing that IFN-alpha/beta mediated the expressi on. In contrast to the equivalent expression in SCID mice, we observed greater area and higher intensity of H-2D Versus H-2K antigens in inf ected SCID mice reconstituted with normal spleen cells. Collectively, the data indicate that after TMEV infection, early generalized MHC Cla ss I expression is mediated by IFN-alpha/beta independently of lymphoc ytes, but the differential regulation of H-2D over H-2K may be control led by B and/or T lymphocytes.