IRF8 Governs Expression of Genes Involved in Innate and Adaptive Immunity in Human and Mouse Germinal Center B Cells

Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America.
PLoS ONE (Impact Factor: 3.23). 11/2011; 6(11):e27384. DOI: 10.1371/journal.pone.0027384
Source: PubMed

ABSTRACT IRF8 (Interferon Regulatory Factor 8) is a transcription factor expressed throughout B cell differentiation except for mature plasma cells. Previous studies showed it is part of the transcriptional network governing B cell specification and commitment in the bone marrow, regulates the distribution of mature B cells into the splenic follicular and marginal zone compartments, and is expressed at highest levels in germinal center (GC) B cells. Here, we investigated the transcriptional programs and signaling pathways affected by IRF8 in human and mouse GC B cells as defined by ChIP-chip analyses and transcriptional profiling. We show that IRF8 binds a large number of genes by targeting two distinct motifs, half of which are also targeted by PU.1. Over 70% of the binding sites localized to proximal and distal promoter regions with ∼25% being intragenic. There was significant enrichment among targeted genes for those involved in innate and adaptive immunity with over 30% previously defined as interferon stimulated genes. We also showed that IRF8 target genes contributes to multiple aspects of the biology of mature B cells including critical components of the molecular crosstalk among GC B cells, T follicular helper cells, and follicular dendritic cells.

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Available from: Herbert C Morse, Sep 29, 2015
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    • "Single nucleotide polymorphisms in the genes for IRF5, IRF7 and IRF8 have also been associated with an increased risk for SLE and other autoimmune diseases [32]. While variants of IRF5 are thought to contribute to enhanced IFN-α production, little is known about the role of IRF7 and IRF8 in SLE [33], However, IRF4 and IRF8 are known regulators of B cell differentiation [34], [35]. Despite the many up-regulated IFN-inducible transcripts, a number of transcripts key to the induction of IFN or nucleic acid sensing pathways were not up-regulated in our studies or in the work by Li et al. [22]. "
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    ABSTRACT: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that is characterized by defective immune tolerance combined with immune cell hyperactivity resulting in the production of pathogenic autoantibodies. Previous gene expression studies employing whole blood or peripheral blood mononuclear cells (PBMC) have demonstrated that a majority of patients with active disease have increased expression of type I interferon (IFN) inducible transcripts known as the IFN signature. The goal of the current study was to assess the gene expression profiles of isolated leukocyte subsets obtained from SLE patients. Subsets including CD19(+) B lymphocytes, CD3(+)CD4(+) T lymphocytes and CD33(+) myeloid cells were simultaneously sorted from PBMC. The SLE transcriptomes were assessed for differentially expressed genes as compared to healthy controls. SLE CD33(+) myeloid cells exhibited the greatest number of differentially expressed genes at 208 transcripts, SLE B cells expressed 174 transcripts and SLE CD3(+)CD4(+) T cells expressed 92 transcripts. Only 4.4% (21) of the 474 total transcripts, many associated with the IFN signature, were shared by all three subsets. Transcriptional profiles translated into increased protein expression for CD38, CD63, CD107a and CD169. Moreover, these studies demonstrated that both SLE lymphoid and myeloid subsets expressed elevated transcripts for cytosolic RNA and DNA sensors and downstream effectors mediating IFN and cytokine production. Prolonged upregulation of nucleic acid sensing pathways could modulate immune effector functions and initiate or contribute to the systemic inflammation observed in SLE.
    PLoS ONE 06/2013; 8(6):e67003. DOI:10.1371/journal.pone.0067003 · 3.23 Impact Factor
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    • "IRF4 expression in follicular helper T (Tfh) cells is essential for germinal center formation [35]. IRF8 is expressed by germinal center B cells, but not plasma cells, where it participates in the regulation of more than 50 genes involved in B cell activation and maturation, and interaction with Tfh cells and follicular dendritic cells that present antigen in its native confirmation to germinal center B cells [38]. Runx3 is expressed by B cells and promotes proliferation, presumably during clonal expansion induced by Th1 cells [39]. "
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    ABSTRACT: Background Deer mice (Peromyscus maniculatus) are the principal reservoir hosts of Sin Nombre virus (SNV), the cause of the great majority of hantavirus cardiopulmonary syndrome (HCPS) cases in North America. SNV, like all hantaviruses with their reservoirs, causes persistent infection without pathology in deer mice and appear to elicit a regulatory T cell response. Deer mice are also susceptible to Andes virus (ANDV), which causes the great majority of HCPS cases in South America, but they clear infection by 56 days post infection without signs of disease. Results We examined lymph node cell responses of deer mice infected with ANDV to determine expression profiles upon in vitro recall challenge with viral antigen. Because the deer mouse genome is currently unannotated, we developed a bioinformatics pipeline to use known lab mouse (Mus musculus) cDNAs to predict genes within the deer mouse genome and design primers for quantitative PCR ( Of 94 genes examined, 20 were elevated, the plurality of which were Th2-specific, whereas 12 were downregulated. Other expressed genes represented Th1, regulatory T cells and follicular helper T cells, and B cells, but not Th17 cells, indicating that many cellular phenotypes participate in the host response to Andes virus. Conclusions The ability to examine expression levels of nearly any gene from deer mice should allow direct comparison of infection with SNV or ANDV to determine the immunological pathways used for clearance of hantavirus infection in a reservoir host species.
    BMC Immunology 04/2013; 14(1):18. DOI:10.1186/1471-2172-14-18 · 2.48 Impact Factor
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    • "IRF8 is at several levels connected to the TLRs. Independent of TLRs, IRF8 increases TLR gene expression in B-cells and myeloma cells.49 As a TLR signaling component, IRF8 interacts with TNF-receptor associated factor (TRAF) 6, a MyD88 recruited ubiquitin ligase, and regulates the production of type I IFNs and other inflammatory mediators. "
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    ABSTRACT: Atherosclerosis is characterized by early endothelial dysfunction and altered vascular smooth muscle cells (VSMCs) contractility. The forming atheroma is a site of excessive production of cytokines and inflammatory ligands by various cell types that mediate inflammation and immune responses. Key factors contributing to early stages of plaque development are IFNγ and TLR4. This review provides insight in the differential STAT1-dependent signal integration between IFNγ and TLR4 signals in vascular cells and atheroma interacting immune cells. This results in increased leukocyte attraction and adhesion and VSMC proliferation and migration, which are important characteristics of EC dysfunction and early triggers of atherosclerosis.
    10/2012; 1(4):241-249. DOI:10.4161/jkst.22469
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