Interferon regulatory factor 8 regulates pathways for antigen presentation in myeloid cells and during tuberculosis

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...

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Bibliographic Details
Published in:PLoS genetics 2011-06, Vol.7 (6), p.e1002097-e1002097
Main Authors: Marquis, Jean-François, Kapoustina, Oxana, Langlais, David, Ruddy, Rebecca, Dufour, Catherine Rosa, Kim, Bae-Hoon, MacMicking, John D, Giguère, Vincent, Gros, Philippe
Format: Article
Language:English
Subjects:
Alleles
Animals
Antigen Presentation
Binding Sites
Biology
Blotting, Western
Cell Line
Chromatin Immunoprecipitation
Dendritic Cells - immunology
Dendritic Cells - metabolism
Female
Gene Expression Profiling
Gene Expression Regulation
Gene mutations
Genes
Genetic aspects
Genotype
Health aspects
Immunology
Interferon gamma
Interferon Regulatory Factors - genetics
Interferon Regulatory Factors - immunology
Interferon Regulatory Factors - metabolism
Interferon-gamma - immunology
Lung - immunology
Lung - metabolism
Lung - microbiology
Major Histocompatibility Complex
Male
Medicine
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mutation
Mycobacterium tuberculosis - immunology
Myeloid Cells - immunology
Myeloid Cells - metabolism
Oligonucleotide Array Sequence Analysis
Prevention
Promoter Regions, Genetic
Proteins
Risk factors
Tuberculosis
Tuberculosis, Pulmonary - genetics
Tuberculosis, Pulmonary - immunology
Tuberculosis, Pulmonary - microbiology
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Summary: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.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1002097