35 research outputs found

    Identification of Roquin-regulated mRNAs in T helper cells and molecular characterization of the Roquin-RNA interaction

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    Vitamin A controls the allergic response through T follicular helper cell as well as plasmablast differentiation

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    Background Vitamin A regulates the adaptive immune response and a modulatory impact on type I allergy is discussed. The cellular mechanisms are largely unknown. Objective To determine the vitamin A-responding specific lymphocyte reaction in vivo. Methods Antigen-specific B and T lymphocytes were analyzed in an adoptive transfer airway inflammation mouse model in response to 9-cis retinoic acid (9cRA) and after lymphocyte-specific genetic targeting of the receptor RAR alpha. Flow cytometry, quantitative PCR, next-generation sequencing, and specific Ig-ELISA were used to characterize the cells functionally. Results Systemic 9cRA profoundly enhanced the specific IgA-secreting B-cell frequencies in the lung tissue and serum IgA while reducing serum IgE concentrations. RAR alpha overexpression in antigen-specific B cells promoted differentiation into plasmablasts at the expense of germinal center B cells. In antigen-specific T cells, RAR alpha strongly promoted the differentiation of T follicular helper cells followed by an enhanced germinal center response. Conclusions 9cRA signaling via RAR alpha impacts the allergen-specific immunoglobulin response directly by the differentiation of B cells and indirectly by promoting T follicular helper cells

    Who are Leibniz PostDocs and what is it like to work at a Leibniz institute? Report of the first Leibniz PostDoc Survey 2020

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    Postdoctoral researchers play a critical role in scientific research. This is the case not only for the Leibniz Association but for research worldwide. However, postdoctoral researchers are often overlooked or misrepresented as a homogeneous group of researchers. The principal aim of the Leibniz PostDoc Survey was to understand who Leibniz PostDocs are and to provide some insight into their experiences, interests, and needs. This report summarizes the results of the first Leibniz PostDoc Survey, which was open for submission from July to October 2020. The report includes a summary of the key findings and recommendations as well as a comprehensive description of all results from each survey question

    Stable lines and clones of long-term proliferating normal, genetically unmodified murine common lymphoid progenitors.

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    Common lymphoid progenitors (CLPs) differentiate to T and B lymphocytes, dendritic cells, natural killer cells, and innate lymphoid cells. Here, we describe culture conditions that, for the first time, allow the establishment of lymphoid-restricted, but uncommitted, long-term proliferating CLP cell lines and clones from a small pool of these cells from normal mouse bone marrow, without any genetic manipulation. Cells from more than half of the cultured CLP clones could be induced to differentiate to T, B, natural killer, dendritic, and myeloid cells in vitro. Cultured, transplanted CLPs transiently populate the host and differentiate to all lymphoid subsets, and to myeloid cells in vivo. This simple method to obtain robust numbers of cultured noncommitted CLPs will allow studies of cell-intrinsic and environmentally controlled lymphoid differentiation programs. If this method can be applied to human CLPs, it will provide new opportunities for cell therapy of patients in need of myeloid-lymphoid reconstitution

    MicroRNA-223 Dampens Pulmonary Inflammation during Pneumococcal Pneumonia

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    Community-acquired pneumonia remains a major contributor to global communicable disease-mediated mortality. Neutrophils play a leading role in trying to contain bacterial lung infection, but they also drive detrimental pulmonary inflammation, when dysregulated. Here we aimed at understanding the role of microRNA-223 in orchestrating pulmonary inflammation during pneumococcal pneumonia. Serum microRNA-223 was measured in patients with pneumococcal pneumonia and in healthy subjects. Pulmonary inflammation in wild-type and microRNA-223-knockout mice was assessed in terms of disease course, histopathology, cellular recruitment and evaluation of inflammatory protein and gene signatures following pneumococcal infection. Low levels of serum microRNA-223 correlated with increased disease severity in pneumococcal pneumonia patients. Prolonged neutrophilic influx into the lungs and alveolar spaces was detected in pneumococci-infected microRNA-223-knockout mice, possibly accounting for aggravated histopathology and acute lung injury. Expression of microRNA-223 in wild-type mice was induced by pneumococcal infection in a time-dependent manner in whole lungs and lung neutrophils. Single-cell transcriptome analyses of murine lungs revealed a unique profile of antimicrobial and cellular maturation genes that are dysregulated in neutrophils lacking microRNA-223. Taken together, low levels of microRNA-223 in human pneumonia patient serum were associated with increased disease severity, whilst its absence provoked dysregulation of the neutrophil transcriptome in murine pneumococcal pneumonia

    Roquin Paralogs 1 and 2 Redundantly Repress the Icos and Ox40 Costimulator mRNAs and Control Follicular Helper T Cell Differentiation

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    SummaryThe Roquin-1 protein binds to messenger RNAs (mRNAs) and regulates gene expression posttranscriptionally. A single point mutation in Roquin-1, but not gene ablation, increases follicular helper T (Tfh) cell numbers and causes lupus-like autoimmune disease in mice. In T cells, we did not identify a unique role for the much lower expressed paralog Roquin-2. However, combined ablation of both genes induced accumulation of T cells with an effector and follicular helper phenotype. We showed that Roquin-1 and Roquin-2 proteins redundantly repressed the mRNA of inducible costimulator (Icos) and identified the Ox40 costimulatory receptor as another shared mRNA target. Combined acute deletion increased Ox40 signaling, as well as Irf4 expression, and imposed Tfh differentiation on CD4+ T cells. These data imply that both proteins maintain tolerance by preventing inappropriate T cell activation and Tfh cell differentiation, and that Roquin-2 compensates in the absence of Roquin-1, but not in the presence of its mutated form

    MicroRNA-31 Reduces the Motility of Proinflammatory T Helper 1 Lymphocytes

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    Proinflammatory type 1 T helper (Th1) cells are enriched in inflamed tissues and contribute to the maintenance of chronic inflammation in rheumatic diseases. Here we show that the microRNA- (miR-) 31 is upregulated in murine Th1 cells with a history of repeated reactivation and in memory Th cells isolated from the synovial fluid of patients with rheumatic joint disease. Knock-down of miR-31 resulted in the upregulation of genes associated with cytoskeletal rearrangement and motility and induced the expression of target genes involved in T cell activation, chemokine receptor– and integrin-signaling. Accordingly, inhibition of miR-31 resulted in increased migratory activity of repeatedly activated Th1 cells. The transcription factors T-bet and FOXO1 act as positive and negative regulators of T cell receptor (TCR)–mediated miR-31 expression, respectively. Taken together, our data show that a gene regulatory network involving miR-31, T-bet, and FOXO1 controls the migratory behavior of proinflammatory Th1 cells

    Structural basis for RNA recognition in roquin-mediated post-transcriptional gene regulation

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    Roquin function in T cells is essential for the prevention of autoimmune disease. Roquin interacts with the 3′ untranslated regions (UTRs) of co-stimulatory receptors and controls T-cell activation and differentiation. Here we show that the N-terminal ROQ domain from mouse roquin adopts an extended winged-helix (WH) fold, which is sufficient for binding to the constitutive decay element (CDE) in the ​Tnf 3′ UTR. The crystal structure of the ROQ domain in complex with a prototypical CDE RNA stem-loop reveals tight recognition of the RNA stem and its triloop. Surprisingly, roquin uses mainly non-sequence-specific contacts to the RNA, thus suggesting a relaxed CDE consensus and implicating a broader spectrum of target mRNAs than previously anticipated. Consistently with this, NMR and binding experiments with CDE-like stem-loops together with cell-based assays confirm roquin-dependent regulation of relaxed CDE consensus motifs in natural 3′ UTRs
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