Type II but not type I interferon signaling is indispensable for TLR7-promoted development of autoreactive B cells and systemic autoimmunity
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE141433 | GEO | 2019/12/05
REPOSITORIES: GEO
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Project description:TLR7 is associated with development of systemic lupus erythematosus (SLE), but the underlying mechanisms are incompletely understood. Although TLRs are known to activate type I IFN (T1IFN) signaling, the role of T1IFN and IFN-? signaling in differential regulation of TLR7-mediated Ab-forming cell (AFC) and germinal center (GC) responses, and SLE development has never been directly investigated. Using TLR7-induced and TLR7 overexpression models of SLE, we report in this study a previously unrecognized indispensable role of TLR7-induced IFN-? signaling in promoting AFC and GC responses, leading to autoreactive B cell and SLE development. T1IFN signaling in contrast, only modestly contributed to autoimmune responses and the disease process in these mice. TLR7 ligand imiquimod treated IFN-? reporter mice show that CD4+ effector T cells including follicular helper T (Tfh) cells are the major producers of TLR7-induced IFN-?. Transcriptomic analysis of splenic tissues from imiquimod-treated autoimmune-prone B6.Sle1b mice sufficient and deficient for IFN-?R indicates that TLR7-induced IFN-? activates multiple signaling pathways to regulate TLR7-promoted SLE. Conditional deletion of Ifngr1 gene in peripheral B cells further demonstrates that TLR7-driven autoimmune AFC, GC and Tfh responses and SLE development are dependent on IFN-? signaling in B cells. Finally, we show crucial B cell-intrinsic roles of STAT1 and T-bet in TLR7-driven GC, Tfh and plasma cell differentiation. Altogether, we uncover a nonredundant role for IFN-? and its downstream signaling molecules STAT1 and T-bet in B cells in promoting TLR7-driven AFC, GC, and SLE development whereas T1IFN signaling moderately contributes to these processes.
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Project description:Type II but not type I interferon signaling is indispensable for TLR7-promoted development of autoreactive B cells and systemic autoimmunity
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Project description:The y-linked autoimmune accelerating (yaa) locus is a potent autoimmune disease allele. Transcription profiling of yaa-bearing B cells revealed the overexpression of a cluster of X-linked genes that included Tlr7. FISH analysis demonstrated the translocation of this segment onto the yaa chromosome. The resulting overexpression of Tlr7 increased in vitro responses to Toll-like receptor (TLR) 7 signaling in all yaa-bearing males. B6.yaa mice are not overtly autoimmune, but the addition of Sle1, which contains the autoimmune-predisposing Slam/Cd2 haplotype, causes the development of fatal lupus with numerous immunological aberrations. B6.Sle1yaa CD4 T cells develop the molecular signature for T(FH) cells and also show expression changes in numerous cytokines and chemokines. Disease development and all component autoimmune phenotypes were inhibited by Sles1, a potent suppressor locus. Sles1 had no effect on yaa-enhanced TLR7 signaling in vitro, and these data place Sles1 downstream from the lesion in innate immune responses mediated by TLR7, suggesting that Sles1 modulates the activation of adaptive immunity in response to innate immune signaling.
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Project description:Western lifestyle is linked to autoimmune and metabolic diseases, driven by changes in diet and gut microbiota composition. Using Toll-like receptor 7 (TLR7)-dependent mouse models of systemic lupus erythematosus (SLE), we dissect dietary effects on the gut microbiota and find that Lactobacillus reuteri can drive autoimmunity but is ameliorated by dietary resistant starch (RS). Culture of internal organs and 16S rDNA sequencing revealed TLR7-dependent translocation of L. reuteri in mice and fecal enrichment of Lactobacillus in a subset of SLE patients. L. reuteri colonization worsened autoimmune manifestations under specific-pathogen-free and gnotobiotic conditions, notably increasing plasmacytoid dendritic cells (pDCs) and interferon signaling. However, RS suppressed the abundance and translocation of L. reuteri via short-chain fatty acids, which inhibited its growth. Additionally, RS decreased pDCs, interferon pathways, organ involvement, and mortality. Thus, RS exerts beneficial effects in lupus-prone hosts through suppressing a pathobiont that promotes interferon pathways implicated in the pathogenesis of human autoimmunity.
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Project description:Exploratory study to identify genome-wide changes in expression between conventional NK cells isolated from B6 WT and NK1.1+ cells from TLR7tg mice Isolated splenic NK1.1+ cells are compared between B6 WT and TLR7tg mice
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Project description:Although STAT1 tyrosine-701 phosphorylation (designated STAT1-pY701) is indispensable for STAT1 function, the requirement for STAT1 serine-727 phosphorylation (designated STAT1-pS727) during systemic autoimmune and antipathogen responses remains unclear. Using autoimmune-prone B6.Sle1b mice expressing a STAT1-S727A mutant in which serine is replaced by alanine, we report in this study that STAT1-pS727 promotes autoimmune Ab-forming cell (AFC) and germinal center (GC) responses, driving autoantibody production and systemic lupus erythematosus (SLE) development. In contrast, STAT1-pS727 is not required for GC, T follicular helper cell (Tfh), and Ab responses to various foreign Ags, including pathogens. STAT1-pS727 is also not required for gut microbiota and dietary Ag-driven GC and Tfh responses in B6.Sle1b mice. By generating B cell-specific bone marrow chimeras, we demonstrate that STAT1-pS727 plays an important B cell-intrinsic role in promoting autoimmune AFC, GC, and Tfh responses, leading to SLE-associated autoantibody production. Our analysis of the TLR7-accelerated B6.Sle1b.Yaa SLE disease model expressing a STAT1-S727A mutant reveals STAT1-pS727-mediated regulation of autoimmune AFC and GC responses and lupus nephritis development. Together, we identify previously unrecognized differential regulation of systemic autoimmune and antipathogen responses by STAT1-pS727. Our data implicate STAT1-pS727 as a therapeutic target for SLE without overtly affecting STAT1-mediated protection against pathogenic infections.
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Project description:The transcriptomes of FACS-sorted B220+GL7+CD95+ germinal center B cells and B220+GL7-CD95- non-germinal center B cells from lupus-prone B6.Sle1b were compared to the same cell types in B6.Sle1b mice without the type 1 interferon receptor (B6.Sle1b.IFNaR1-/-).
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Project description:Plasmacytoid dendritic cells (pDCs) express Toll like receptors (TLRs) that modulate the immune response by production of type I interferons. Here, we report that sphingosine kinase 1 (SphK1) which produces the bioactive sphingolipid metabolite, sphingosine 1-phosphate (S1P), plays a critical role in the pDC functions and interferon production. Although dispensable for the pDC development, SphK1 is essential for the pDC activation and production of type I IFN and pro-inflammatory cytokines stimulated by TLR7/9 ligands. SphK1 interacts with TLRs and specific inhibition or deletion of SphK1 in pDCs mitigates uptake of CpG oligonucleotide ligands by TLR9 ligand. In the pristane-induced murine lupus model, pharmacological inhibition of SphK1 or its genetic deletion markedly decreased the IFN signature, pDC activation, and glomerulonephritis. Moreover, increases in the SphK1 expression and S1P levels were observed in human lupus patients. Taken together, our results indicate a pivotal regulatory role for the SphK1/S1P axis in maintaining the balance between immunosurveillance and immunopathology and suggest that specific SphK1 inhibitors might be a new therapeutic avenue for the treatment of type I IFN-linked autoimmune disorders.
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Project description:T cells from many patients with systemic lupus erythematosus are hypoproliferative in response to TCR ligation. This defect is mediated, at least in part, through down regulation of the TCR zeta chain. Investigation of this phenomenon in lupus-prone mice revealed that the hypoproliferative T cell phenotype apparent in BXSB males is mediated in part by the Yaa locus. The BXSB model of lupus is a recombinant inbred strain that was originally derived from a cross between a male SB/LE mouse and a female C57BL/6 mouse. BXSB is unique among lupus-prone mouse strains, in that males carry an autoimmune accelerating factor on the Y chromosome, termed Yaa, which accelerates disease onset in male BXSB mice so that fatal glomerulonephritis occurs around 6 months of age. It was recently reported that the Yaa locus is a translocation of a short stretch of genes including that encoding Toll-like receptor 7 (Tlr-7) from the X to the Y chromosome, leading to a two-fold over expression of a subset of these genes, including Tlr-7, and hypersensitivity of Yaa+ cells to TLR-7 agonists. To more fully understand the functional significance of the Yaa gene and how it plays a part in the modulation of CD4+ T cell responses, we performed microarray analysis using Affymetrix 430 2.0 arrays on spleens from B6 male B6.Yaa male samples. The analysis revealed an enhanced signature of innate immunity, including increased expression not only of Tlr7 and Tlr8, in line with reports that the Yaa locus leads to a duplication of the murine Tlr7 and Tlr8 genes , but also of Tlr2, Tlr5, Cd14, Lbp, C2, C3 and genes for several heat-shock proteins. T cells from B6.Yaa mice also displayed decreased TCRζ expression. Interestingly, cell surface levels of the inhibitory molecule B7-H1 were increased on B6.Yaa B cells and monocytes/macrophages. In line with increased TLR-7 expression reported in B6.Yaa mice, the TLR-7 agonist imiquimod increased B7-H1 expression on normal B cells. Restoration of proliferation in co-cultures of B6 T cells and B6.Yaa APC with B7-H1 blocking Ab demonstrated a mechanistic contribution of B7-H1 up-regulation to Yaa-mediated APC-dependent T cell hypoproliferation. In addition, T cell hypoproliferation was induced in normal B6 T cells in vitro by the application of imiquimod. However, this defect was not mediated by B7-H1 or secreted factors but was independent of APC and mediated through direct imiquimod stimulation of T cells themselves. We postulate that excessive TLR-7 stimulation in Yaa+ mice mediates T cell hypoproliferation in part through up-regulation of B7-H1 and possibly also through direct T cell-mediated effects. Keywords: differential gene expression, RNA, spleen, C57Bl/6J, B6.SB-Yaa/J, male, wild type, Yaa
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Project description:The purpose of this experiment was to assess the genes upregulated when pDCs were stimulated with TLR7 agonist imiquimod and TLR9 agonist CpG C. pDCs were isolated from six healthy donors by FACS sorting, and were stimulated with CpG and imiquimod for 18 hours, after which RNA was extracted for next generation sequencing on the Illumina HiSeq platform. Unstimulated samples were included as controls.
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