Down-regulation of major histocompatibility complex class I synthesis by murine cytomegalovirus early gene expression.
Murine cytomegalovirus (MCMV) infection of C57BL/6 (H-2b) mice prevents priming of antigen-specific helper and cytotoxic T lymphocytes (CTL) (J. S. Slater, W. S. Futch, V. J. Cavanaugh, and A. E. Campbell, Virology 185:132-139, 1991). In vitro, MCMV infection alters presentation of antigens to antigen-specific, MHC class I-restricted CTL (A. E. Campbell, J. S. Slater, V. J. Cavanaugh, and R. M. Stenberg, J. Virol. 66:3011-3017, 1992). This is accompanied by a significant decrease in surface expression of H-2Kb and H-2Db. We therefore examined the effects of MCMV infection on the intracellular expression of H-2Kb and H-2Db by immunoprecipitation with conformation-independent antibodies. MCMV early-gene products severely repressed synthesis of H-2Kb and H-2Db. This down-regulation was not restored by gamma interferon treatment. The MCMV-induced suppression of MHC class I protein synthesis resulted in a retarded rate of accumulation of these molecules within the cell. In addition, MCMV infection prevented maturation of class I heavy chains to the fully glycosylated forms and inhibited transport of H-2Db from the endoplasmic reticulum-cis Golgi. Virus infection had no effect on the rate of degradation of the class I molecules. These results demonstrate that MCMV early-gene products down-regulate synthesis and posttranslational events in MHC class I expression, thereby limiting the number of antigen-presenting molecules within infected cells. This limitation defines a potential mechanism for regulation of MHC class I-restricted antigen presentation by MCMV.
Campbell
A E
AE
Department of Microbiology and Immunology, Eastern Virginia Medical School, Norfolk 23507.
Slater
J S
JS
D000818:Animals; D000956:Antigens, Viral / Q000378:metabolism*; D001692:Biological Transport; D002461:Cell Line, Transformed; D015536:Down-Regulation; D015870:Gene Expression; D006183:H-2 Antigens / Q000235:genetics / Q000378:metabolism*; D064532:Histocompatibility Antigen H-2D; D017874:Immediate-Early Proteins / Q000378:metabolism*; D007371:Interferon-gamma / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018146:Muromegalovirus / Q000378:metabolism*
D000956:Antigens, Viral; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D064532:Histocompatibility Antigen H-2D; D017874:Immediate-Early Proteins; C044582:immediate-early proteins, cytomegalovirus; D007371:Interferon-gamma