J. Exp. Med., Volume 187, Number 7, April 6, 1998 1037-1046

Murine Cytomegalovirus Inhibits Interferon -induced Antigen Presentation to CD4 T Cells by Macrophages Via Regulation of Expression of Major Histocompatibility Complex Class II-associated Genes

By Mark T. Heise, Megan Connick, and Herbert W. Virgin IV

From the Center for Immunology and Departments of Pathology and Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110

CD4 T cells and interferon  (IFN-) 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- induced antigen presentation to CD4 T cells. MCMV infection inhibited IFN--induced presentation of major histocompatibility complex (MHC) class II associated peptide antigen by differentiated bone marrow macrophages (BMMs) to a T cell hybridoma via impairment of MHC class II cell surface expression. This effect was independent of IFN-/ induction by MCMV infection, and required direct infection of the BMMs with live virus. Inhibition of MHC class II cell surface expression was associated with a six- to eightfold reduction in IFN- induced IA^b mRNA levels, and comparable decreases in IFN- induced expression of invariant chain (Ii), H-2Ma, and H-2Mb mRNAs. Steady state levels of several constitutive host mRNAs, including -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--induced transporter associated with antigen presentation (TAP)2 mRNA levels were minimally altered in infected cells. Analysis of early upstream events in the IFN- signaling pathway revealed that MCMV did not affect activation and nuclear translocation of STAT1, and had minor effects on the early induction of IRF-1 mRNA and protein. We conclude that MCMV infection interferes with IFN--mediated induction of specific MHC genes and the Ii at a stage subsequent to STAT1 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.

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