IRF4-regulated transcriptional heterogeneity of lung resident CD11b+ cDC2 subsets during influenza virus infection
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PROVIDER: PRJNA1207077 | ENA |
REPOSITORIES: ENA
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Project description:Lung-resident conventional dendritic cells (cDCs) coordinate immune responses to respiratory viruses in the respiratory tract or after migration to mediastinal lymph nodes (mLN). Migratory DCs include cDC1s (CD103+XCR1+CD24hi) expressing IRF8 or cDC2s (CD11b+SIRPa+CD24+) expressing IRF4. IRF4+ cDC2s are divided into a CD24hi subset that requires IRF4 for differentiation and a CD24int subset that is present in the absence of IRF4. During influenza A virus (IAV) infection of mice, we characterized the kinetics of cDC2 subset accumulation in the lung and mLN and their differences in IRF4-dependent gene expression and function. We found that the two IRF4-expressing cDC2 subsets upregulated CD86 to high levels, produced IL-12p40 and the chemokines CCL17 and CCL2, and were capable of acquiring antigen in vivo and activating antigen-specific CD8+ T cells. Notably, the CD11b+CD24int cDC2 subset expressed canonical cDC markers and transcription factors and expanded to high numbers in the lung and mLN by day 6 post-infection. Transcriptome analyses on day 5 post-infection revealed that the CD11b+CD24int cDC2 subset expressed both IRF4 and IRF8 and harbored an elevated interferon response signature compared to the CD11b+CD24hi subset. Analyses of mice lacking Irf4 in CD11c+ cells showed that IRF4 promoted the function of CD11b+CD24int cDC2s, including the capacity to migrate to mLN and to produce CCL17 and CCL22, consistent with their altered gene expression profile in the absence of IRF4. In sum, our data show that the two lung-resident CD11b+ cDC2 subsets present in naïve mice elaborated distinct and common functional responses regulated by IRF4 during IAV infection.
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Project description:We performed ChIP-seq to analyze chromatin bindings of IRF4 transcription factor in cDC2.
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Project description:Mouse lung CD11c+ dendritic cells are composed of 2 major DC subsets, the CD103+CD11b-low/intermediate DC (CD103+ DC) and the CD11b-highCD103- DC (CD11b-high DC). These 2 subsets are functionally distinct. Comparison of their functions showed CD103+ DC Microarray analysis was performed to compare the gene expression profiles of the 2 lung DC subsets in naïve mice.
2010-03-15 | GSE17322 | GEO
Project description:Mouse lung CD11c+ dendritic cells are composed of 2 major DC subsets, the CD103+CD11b-low/intermediate DC (CD103+ DC) and the CD11b-highCD103- DC (CD11b-high DC). These 2 subsets are functionally distinct. Comparison of their functions showed CD103+ DC Microarray analysis was performed to compare the gene expression profiles of the 2 lung DC subsets in naïve mice. Perfused lungs from 6-8-week naïve BALB/cByJ mice were pooled and digested with collagenase D. CD11c+ cells were selected by anti-CD11c magnetic microbeads (Miltenyi) and stained by fluorochrome-conjugated mAb against I-A, CD103, CD11b, and CD11c plus 7-
2010-03-24 | E-GEOD-17322 | biostudies-arrayexpress
Project description:Previous reports have defined three subsets of mouse NK cells on the basis of the expression of CD27 and CD11b. The developmental relationship between these subsets was unclear. To address this issue, we evaluated the overall proximity between mouse NK cell subsets defined by CD27 and CD11b expression using pangenomic gene expression profiling. The results suggest that CD27+CD11b-, CD27+CD11b+ and CD27-CD11b+ correspond to three different intermediates stages of NK cell development.
2009-03-15 | GSE13229 | GEO
Project description:T follicular helper (Tfh) cells are a subset of CD4+ T cells that promote antibody production during vaccination. Conventional dendritic cells (cDCs) efficiently prime Tfh cells; however, conclusions regarding the nature of the cDC responsible for instructing Tfh cell differentiation have differed between recent studies. We found that these discrepancies might exist, in part, due to the unusual sites used for immunization in murine models, which differentially bias which DC subsets access antigen. We used intranasal immunization as a physiologically relevant route of exposure that we show delivers antigen to all tissue DC subsets. Using a combination of mice in which the function of individual DC subsets is impaired and different formulations of antigen delivery, we determined that CD11b+ migratory type 2 conventional DCs (cDC2s) are necessary and sufficient for Tfh induction. DC-specific deletion of the guanine nucleotide exchange factor DOCK8 resulted in an isolated loss of CD11b+ cDC2 but not CD103+ cDC1 migration to lung-draining lymph nodes. Impaired cDC2 migration or development in DC-specific Dock8 or Irf4 knockout mice, respectively, led to reduced Tfh cell and antibody development, whereas loss of CD103+ cDC1s in Batf3-/- mice did not. Loss of cDC2-mediated Tfh responses was associated with impaired antibody-mediated protection from live influenza virus challenge. We show that migratory cDC2s uniquely carry antigen into the sub-anatomic regions of the lymph node where Tfh cell priming occurs, the T-B border. This work identifies the DC responsible for Tfh cell-dependent antibody responses, in particular when antigen dose is limiting or is encountered at a mucosal site, which could ultimately inform the formulation and delivery of vaccines.
2017-12-01 | GSE103956 | GEO
Project description:Previous reports have defined three subsets of mouse NK cells on the basis of the expression of CD27 and CD11b. The developmental relationship between these subsets was unclear. To address this issue, we evaluated the overall proximity between mouse NK cell subsets defined by CD27 and CD11b expression using pangenomic gene expression profiling. The results suggest that CD27+CD11b-, CD27+CD11b+ and CD27-CD11b+ correspond to three different intermediates stages of NK cell development. Experiment Overall Design: Spleen cells from RAG-/- mice have been isolated and stained with anti-NK1.1, anti CD27 and anti CD11b antibodies. NK1.1+ cells were sorted into CD27+ CD11b-, CD27+ CD11b+ and CD27- CD11b+ subsets by flow cytometry. There are two independent replicates for each sample. Total RNA was extracted with the RNeasy microkit (Qiagen) and gene expression profiles were performed according to manufacturer instructions (Affymetrix mouse 430 2.0).
2009-03-21 | E-GEOD-13229 | biostudies-arrayexpress
Project description:We have identified the dendritic cell (DC) populations that are sufficient for the induction of T helper 2 (Th2) cell responses in the intestine against both live Trichuris muris worms, and inert Schistosoma mansoni eggs. Antigen-specific Th2 responses did not develop after deletion of IRF4 in DCs, yet IRF4-deficient DCs were not functionally affected. Instead, IRF4flox/flox CD11c-cre mice had fewer CD11b+ migrating DCs, and fewer DCs carrying parasite antigen from the intestine. Adoptive transfer of purified DCs from infected animals directly into intestinal afferent lymphatics enabled us to identify that CD11b+CD103+ DCs were central to the induction of Th2 responses in the small intestine, whereas CD11b+CD103- DCs were more important in the colon. Similarly, after pulsing with Schistosome egg antigen (SEA) in vitro, adoptively-transferred small intestinal or colonic DCs acquired the ability to induce SEA-specific Th2 responses. These data demonstrate a functional specialisation among intestinal DC populations in inducing Th2 responses, and elucidate the roles of IRF4 in this process.
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Project description:Conventional dendritic cells (cDC) consist of two functionally and phenotypically distinct subsets, cDC1 and cDC2, whose development is dependent on distinct sets of transcription factors. Interferon regulatory factor 8 (IRF8) is required at multiple stages of cDC1 development, but its role in mature cDC1 remains unclear. Here we used XCR1-cre to delete Irf8 in committed cDC1 and demonstrate that Irf8 is required for maintaining the identify of cDC1 but not their survival. In the absence of Irf8, committed cDC1 (“ex-cDC1”) acquired the transcriptional, functional and chromatin accessibility properties of cDC2. This conversion was independent on Irf4 and was associated with decreased accessibility in putative IRF8, Batf3 and composite AP-1-IRF (AICE) binding elements, together with increased accessibility of cDC2 associated transcription factor binding elements. Thus, IRF8 expression by committed cDC1 is required for preventing their conversion into cDC2.
2022-06-21 | GSE168477 | GEO
Project description:Dendritic cell (DC) are critical initiators and regulators of immunity to pathogens, vaccines, tumors and tolerance to self. Mouse and human dendritic cells (DCs) are comprised of functionally specialized subsets, but precise interspecies correlation is currently incomplete and hampers the full translation of murine findings to human DC-based clinical therapies. In this study, we show that murine lung and gut lamina propria CD11b+ DC populations are comprised of two subsets: FLT3- and IRF4-dependent CD24+CD64- DCs and contaminating CSF-1R-dependent CD24-CD64+ macrophages. CD11b+CD24+CD64- DCs are instrumental in inducing Th17 cell immune response in the steady state and upon Aspergillus fumigatus challenge. We also identified human CD1c+CD11b+ DCs as the functional homologue of mouse mucosal CD11b+ DCs. Our findings highlight the conservation of key immune functions across species and aid the translation of murine studies to human DC immunobiology. The data for the associated human studies have been stored within GSE35459. Gene Expression from total RNA from specific mouse dendritic cell subsets purified by FACS
2013-05-29 | E-GEOD-46680 | biostudies-arrayexpress