Virus-induced type I IFN stimulates generation of immunoproteasomes at the site of infection.
IFN-gamma is known as the initial and primary inducer of immunoproteasomes during viral infections. We now report that type I IFN induced the transcription and translation of immunoproteasome subunits, their incorporation into the proteasome complex, and the generation of an immunoproteasome-dependent CD8 T cell epitope in vitro and provide in vivo evidence that this mechanism occurs prior to IFN-gamma responses at the site of viral infection. Type I IFN-mediated generation of immunoproteasomes was initiated by either poly(I:C) or HCV RNA in human hepatoma cells and was inhibited by neutralization of type I IFN. In serial liver biopsies of chimpanzees with acute HCV infection, increases in immunoproteasome subunit mRNA preceded intrahepatic IFN-gamma responses by several weeks, instead coinciding with intrahepatic type I IFN responses. Thus, viral RNA-induced innate immune responses regulate the antigen-processing machinery, which occurs prior to the detection of IFN-gamma at the site of infection. This mechanism may contribute to the high effectiveness (95%) of type I IFN-based therapies if administered early during HCV infection.
Shin
Eui-Cheol
EC
Immunology Section and Liver Diseases Branch, NIDDK, NIH, Department of Health and Human Services, Bethesda, Maryland 20892, USA.
Seifert
Ulrike
U
Kato
Takanobu
T
Rice
Charles M
CM
Feinstone
Stephen M
SM
Kloetzel
Peter-M
PM
Rehermann
Barbara
B
D000208:Acute Disease; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D008099:Liver / Q000276:immunology / Q000378:metabolism; D002679:Pan troglodytes; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D021122:Protein Subunits / Q000276:immunology / Q000378:metabolism; D012330:RNA, Double-Stranded / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics
D007370:Interferon Type I; D021122:Protein Subunits; D012330:RNA, Double-Stranded; D012333:RNA, Messenger; D007371:Interferon-gamma; D046988:Proteasome Endopeptidase Complex