MURINE CYTOMEGALOVIRUS INHIBITS INTERFERON-GAMMA-INDUCED ANTIGEN PRESENTATION TO CD4 T-CELLS BY MACROPHAGES VIA REGULATION OF EXPRESSION OFMAJOR HISTOCOMPATIBILITY COMPLEX CLASS-II ASSOCIATED GENES

CD4 T cells and interferon gamma (IFN-gamma) are required for clearanc e of murine cytomegalovirus (MCMV) infection from the salivary gland i n a process taking weeks to months. To explain the inefficiency of sal ivary gland clearance we hypothesized that MCMW interferes with IFN-ga mma induced antigen presentation to CD4 T cells. MCMV infection inhibi ted IFN-gamma-induced presentation of major histocompatibility complex (MHC) class II associated peptide antigen by differentiated bone marr ow macrophages (BMM phi s) 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 BMM phi s with live virus. Inhibition of MHC class II cell surf ace expression was associated with a six- to eightfold reduction in IF N-gamma induced IA(b) mRNA levels, and comparable decreases in IFN-gam ma induced expression of invariant chain (Ii), H-2Ma, and H-2Mb mRNAs. Steady state levels of several constitutive host mRNAs, including bet a-actin, cyclophilin, and CD-45 were not significantly decreased by MC MV infection, ruling out a general effect of MCMV infection on mRNA le vels. MCMV effects were specific to certain MHC genes since IFN-gamma- induced transporter associated with antigen presentation (TAP)2 mRNA l evels were minimally altered in infected cells. Analysis of early upst ream stream events in the IFN-gamma signaling pathway revealed that MC MV did not affect activation and nuclear translocation or STAT1 alpha, and had minor effects on the early induction of IRF-1 mRNA and protei n. We conclude that MCMV infection interferes with IFN-gamma-mediated induction of specific MHC genes and the Ii at a stage subsequent to ST AT1 alpha activation and nuclear translocation. This impairs antigen p resentation to CD4 T cells, and may contribute to the capacity of MCMV to spread and persist within the infected host.