title: Interferon regulatory factor 8 regulates pathways for antigen presentation in myeloid cells and during tuberculosis.
abstract: IRF8 (Interferon Regulatory Factor 8) plays an important role in defenses against intracellular pathogens, including several aspects of myeloid cells function. It is required for ontogeny and maturation of macrophages and dendritic cells, for activation of anti-microbial defenses, and for production of the Th1-polarizing cytokine interleukin-12 (IL-12) in response to interferon gamma (IFNγ) and protection against infection with Mycobacterium tuberculosis. The transcriptional programs and cellular pathways that are regulated by IRF8 in response to IFNγ and that are important for defenses against M. tuberculosis are poorly understood. These were investigated by transcript profiling and chromatin immunoprecipitation on microarrays (ChIP-chip). Studies in primary macrophages identified 368 genes that are regulated by IRF8 in response to IFNγ/CpG and that behave as stably segregating expression signatures (eQTLs) in F2 mice fixed for a wild-type or mutant allele at IRF8. A total of 319 IRF8 binding sites were identified on promoters genome-wide (ChIP-chip) in macrophages treated with IFNγ/CpG, defining a functional G/AGAAnTGAAA motif. An analysis of the genes bearing a functional IRF8 binding site, and showing regulation by IFNγ/CpG in macrophages and/or in M. tuberculosis-infected lungs, revealed a striking enrichment for the pathways of antigen processing and presentation, including multiple structural and enzymatic components of the Class I and Class II MHC (major histocompatibility complex) antigen presentation machinery. Also significantly enriched as IRF8 targets are the group of endomembrane- and phagosome-associated small GTPases of the IRG (immunity-related GTPases) and GBP (guanylate binding proteins) families. These results identify IRF8 as a key regulator of early response pathways in myeloid cells, including phagosome maturation, antigen processing, and antigen presentation by myeloid cells.
authors: Department of Biochemistry, McGill University, Montréal, Canada.
authors: Jean-François
authors: JF
authors: Marquis
authors: Oxana
authors: O
authors: Kapoustina
authors: David
authors: D
authors: Langlais
authors: Rebecca
authors: R
authors: Ruddy
authors: Catherine Rosa
authors: CR
authors: Dufour
authors: Bae-Hoon
authors: BH
authors: Kim
authors: John D
authors: JD
authors: MacMicking
authors: Vincent
authors: V
authors: Giguère
authors: Philippe
authors: P
authors: Gros
mesh_terms: D000483:Alleles; D000818:Animals; D017951:Antigen Presentation; D001665:Binding Sites; D015153:Blotting, Western; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005838:Genotype; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000382:microbiology*; D008285:Major Histocompatibility Complex; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000276:immunology; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D014397:Tuberculosis, Pulmonary / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D000099185:Interferon Regulatory Factor-8
chemical_list: D050835:Interferon Regulatory Factors; D007371:Interferon-gamma; D000099185:Interferon Regulatory Factor-8