Interferon alpha/beta mediates early virus-induced expression of H-2D and H-2K in the central nervous system.
Cells of the central nervous system (CNS) normally do not express detectable levels of major histocompatibility complex (MHC) Class I antigens. However, MHC Class I expression can be induced after virus infection. We tested the hypothesis that virus-induced Class I expression is mediated by lymphocytes or cytokines using lymphocyte- and cytokine-deficient mice. We used Theiler's murine encephalomyelitis virus (TMEV), which induces CNS demyelination that maps genetically to the D region of MHC Class I and is associated with high levels of Class I products. TMEV infection of severe combined immunodeficiency (SCID) and recombination activation gene-1-deficient mice, which lack B and T lymphocytes, resulted in equivalent H-2D and H-2K expression in brain and spinal cord, according to analysis of the area and intensity of immunoperoxidase 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 factor. 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-alpha (TNFRp55(-/-)). TMEV-infected IFN-gamma R(-/-) and TN-FRp55(-/-) mice expressed Class I antigens in the CNS, whereas IFN-alpha/beta R(-/-) mice did not, establishing that IFN-alpha/beta mediated the expression. In contrast to the equivalent expression in SCID mice, we observed greater area and higher intensity of H-2D versus H-2K antigens in infected SCID mice reconstituted with normal spleen cells. Collectively, the data indicate that after TMEV infection, early generalized MHC Class I expression is mediated by IFN-alpha/beta independently of lymphocytes, but the differential regulation of H-2D over H-2K may be controlled by B and/or T lymphocytes.
Njenga
M K
MK
Department of Immunology, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.
Pease
L R
LR
Wettstein
P
P
Mak
T
T
Rodriguez
M
M
D000818:Animals; D001921:Brain / Q000378:metabolism; D002490:Central Nervous System / Q000276:immunology*; D002831:Choroid Plexus / Q000276:immunology; D004268:DNA-Binding Proteins / Q000276:immunology / Q000502:physiology; D005434:Flow Cytometry; D006183:H-2 Antigens / Q000096:biosynthesis*; D018398:Homeodomain Proteins; D007091:Image Processing, Computer-Assisted; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D016898:Interferon-alpha / Q000378:metabolism*; D016899:Interferon-beta / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D011051:Poliomyelitis / Q000276:immunology*; D012367:RNA, Viral / Q000378:metabolism; D016511:Severe Combined Immunodeficiency / Q000276:immunology; D013116:Spinal Cord / Q000378:metabolism; D017945:Theilovirus / Q000472:pathogenicity; D015854:Up-Regulation
D004268:DNA-Binding Proteins; D006183:H-2 Antigens; D018398:Homeodomain Proteins; D016898:Interferon-alpha; D012367:RNA, Viral; C064658:RAG-1 protein; D016899:Interferon-beta