Murine cytomegalovirus inhibits interferon gamma-induced antigen presentation to CD4 T cells by macrophages via regulation of expression of major histocompatibility complex class II-associated genes.
CD4 T cells and interferon gamma (IFN-gamma) are required for clearance of murine cytomegalovirus (MCMV) infection from the salivary gland in a process taking weeks to months. To explain the inefficiency of salivary gland clearance we hypothesized that MCMV interferes with IFN-gamma induced antigen presentation to CD4 T cells. MCMV infection inhibited IFN-gamma-induced presentation of major histocompatibility complex (MHC) class II associated peptide antigen by differentiated bone marrow macrophages (BMMphis) to a T cell hybridoma via impairment of MHC class II cell surface expression. This effect was independent of IFN-alpha/beta induction by MCMV infection, and required direct infection of the BMMphis with live virus. Inhibition of MHC class II cell surface expression was associated with a six- to eightfold reduction in IFN-gamma induced IAb mRNA levels, and comparable decreases in IFN-gamma induced expression of invariant chain (Ii), H-2Ma, and H-2Mb mRNAs. Steady state levels of several constitutive host mRNAs, including beta-actin, cyclophilin, and CD45 were not significantly decreased by MCMV infection, ruling out a general effect of MCMV infection on mRNA levels. MCMV effects were specific to certain MHC genes since IFN-gamma-induced transporter associated with antigen presentation (TAP)2 mRNA levels were minimally altered in infected cells. Analysis of early upstream events in the IFN-gamma signaling pathway revealed that MCMV did not affect activation and nuclear translocation of STAT1alpha, and had minor effects on the early induction of IRF-1 mRNA and protein. We conclude that MCMV infection interferes with IFN-gamma-mediated induction of specific MHC genes and the Ii at a stage subsequent to STAT1alpha activation and nuclear translocation. This impairs antigen presentation to CD4 T cells, and may contribute to the capacity of MCMV to spread and persist within the infected host.
Heise
M T
MT
Center for Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Connick
M
M
Virgin
H W
HW
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects; D005802:Genes, MHC Class II / Q000235:genetics*; D006651:Histocytochemistry; D007371:Interferon-gamma / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D008285:Major Histocompatibility Complex / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D018146:Muromegalovirus / Q000378:metabolism*; D012333:RNA, Messenger / Q000187:drug effects; D012469:Salivary Glands / Q000821:virology; D015398:Signal Transduction / Q000502:physiology
D018528:ATP-Binding Cassette Transporters; D012333:RNA, Messenger; D007371:Interferon-gamma