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  • 1
    Abstract: Tissue osmolarity varies among different organs and can be considerably increased under pathologic conditions. Hyperosmolarity has been associated with altered stimulatory properties of immune cells, especially macrophages and dendritic cells. We have recently reported that dendritic cells upon exposure to hypertonic stimuli shift their profile towards a macrophage-M2-like phenotype, resulting in attenuated local alloreactivity during acute kidney graft rejection. Here, we examined how hyperosmotic microenvironment affects the cross-priming capacity of dendritic cells. Using ovalbumin as model antigen, we showed that exposure of dendritic cells to hyperosmolarity strongly inhibits activation of antigen-specific T cells despite enhancement of antigen uptake, processing and presentation. We identified TRIF as key mediator of this phenomenon. Moreover, we detected a hyperosmolarity-triggered, TRIF-dependent clustering of MHCI loaded with the ovalbumin-derived epitope, but not of overall MHCI molecules, providing a possible explanation for a reduced T cell activation. Our findings identify dendritic cells as important players in hyperosmolarity-mediated immune imbalance and provide evidence for a novel pathway of inhibition of antigen specific CD8+ T cell response in a hypertonic micromilieu.
    Type of Publication: Journal article published
    PubMed ID: 28331179
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  • 2
    Abstract: Immune checkpoint inhibitors have significantly improved the treatment of several cancers. T-cell infiltration and the number of neoantigens caused by tumor-specific mutations are correlated to favorable responses in cancers with a high mutation load. Accordingly, checkpoint immunotherapy is thought to be less effective in tumors with low mutation frequencies such as neuroblastoma, a neuroendocrine tumor of early childhood with poor outcome of the high-risk disease group. However, spontaneous regressions and paraneoplastic syndromes seen in neuroblastoma patients suggest substantial immunogenicity. Using an integrative transcriptomic approach, we investigated the molecular characteristics of T-cell infiltration in primary neuroblastomas as an indicator of pre-existing immune responses and potential responsiveness to checkpoint inhibition. Here, we report that a T-cell-poor microenvironment in primary metastatic neuroblastomas is associated with genomic amplification of the MYCN (N-Myc) proto-oncogene. These tumors exhibited lower interferon pathway activity and chemokine expression in line with reduced immune cell infiltration. Importantly, we identified a global role for N-Myc in the suppression of interferon and pro-inflammatory pathways in human and murine neuroblastoma cell lines. N-Myc depletion potently enhanced targeted interferon pathway activation by a small molecule agonist of the cGAS-STING innate immune pathway. This promoted chemokine expression including Cxcl10 and T-cell recruitment in microfluidics migration assays. Hence, our data suggest N-Myc inhibition plus targeted IFN activation as adjuvant strategy to enforce cytotoxic T-cell recruitment in MYCN-amplified neuroblastomas.
    Type of Publication: Journal article published
    PubMed ID: 28680756
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  • 3
    Keywords: RECEPTOR ; CELLS ; CELL ; Germany ; human ; DISTINCT ; MOLECULES ; TIME ; ACTIVATION ; COMPLEX ; MECHANISM ; DENDRITIC CELLS ; mechanisms ; T cell ; T cells ; T-CELL ; T-CELLS ; SIGNAL ; MOLECULE ; cytokines ; RECOGNITION ; STIMULATION ; ACID ; ACQUISITION ; EFFICIENT ; LYMPHOCYTES ; EXCHANGE ; NATURAL-KILLER-CELLS ; ANTIGEN-PRESENTING CELLS ; CD8(+) ; specificity ; LIVE CELLS ; RECEPTORS ; CYTOKINE ; T-CELL-ACTIVATION ; interaction ; dendritic cell ; PHASE ; EVENTS ; USA ; SIGNALS ; immunology ; exosomes ; detachment ; INTERCELLULAR TRANSFER ; PEPTIDE-MHC COMPLEXES
    Abstract: Activation of CD4(+) T cells by APCs occurs by multiple Ag recognition events including the exchange of costimulatory signals and cytokines. Additionally, the T cells acquire APC-derived surface molecules. Herein, we describe for the first time the transfer of human and murine T cell surface receptors to APCs after Ag-specific interaction. This transfer occurs in two qualitatively different phases. The first group of molecules (e.g., CD2) derived from the T cell surface was transferred rapidly after 2 h of interaction, was strongly bound on the DC surface (acid wash-resistant), was strictly dependent on dendritic cell-T cell contact, and transferred independently of T cell activation. The second group, including the CD3/TCR complex, CD27, and OX40, was of intracellular origin, transferred later after 10-16 h in a cell-cell contact-independent fashion, was noncovalently bound, and was strictly dependent on Ag-specific T cell activation. Functionally, murine dendritic cells that received TCR molecules from OVA-specific CD4(+) T cells after Ag-specific interaction were less efficient in priming naive CD4(+) T cells of the same specificity without losing their ability for CD8(+) T cell stimulation, indicating that the transferred TCR molecules mask the Ag-bearing MHC II molecules, thereby reducing their accessibility to following Ag-specific CD4(+) T cells. While the first. group of transferred T cell surface molecules might facilitate the detachment of the CD4+ T cell from the dendritic cell during the early scanning phases, the second group could play an important immunomodulatory role in intraclonal competition of T cells for APC access, making the physical presence of CD4(+) T cells unnecessary
    Type of Publication: Journal article published
    PubMed ID: 18768851
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  • 4
    Keywords: DENDRITIC CELLS ; ESCHERICHIA-COLI ; NECROSIS-FACTOR-ALPHA ; EPITHELIAL-CELLS ; IMMUNE-RESPONSE ; MATRIX METALLOPROTEINASES ; CHEMOKINE RECEPTORS ; URINARY-TRACT-INFECTION ; BACTERIAL-INFECTION ; BASEMENT-MEMBRANES
    Abstract: The phagocytes of the innate immune system, macrophages and neutrophils, contribute to antibacterial defense, but their functional specialization and cooperation is unclear. Here, we report that three distinct phagocyte subsets play highly coordinated roles in bacterial urinary tract infection. Ly6C(-) macrophages acted as tissue-resident sentinels that attracted circulating neutrophils and Ly6C(+) macrophages. Such Ly6C(+) macrophages played a previously undescribed helper role: once recruited to the site of infection, they produced the cytokine TNF, which caused Ly6C(-) macrophages to secrete CXCL2. This chemokine activated matrix metalloproteinase-9 in neutrophils, allowing their entry into the uroepithelium to combat the bacteria. In summary, the sentinel macrophages elicit the powerful antibacterial functions of neutrophils only after confirmation by the helper macrophages, reminiscent of the licensing role of helper T cells in antiviral adaptive immunity. These findings identify helper macrophages and TNF as critical regulators in innate immunity against bacterial infections in epithelia.
    Type of Publication: Journal article published
    PubMed ID: 24485454
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  • 5
    ISSN: 1365-3083
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: To determine whether NK cells are involved in the regulation of the antibody response, we studied the effects of human NK clones on B-cell growth and differentiation and the mechanisms involved. We demonstrate that various human NK clones enhance the immunoglobulin production of SAC/rlL-2-activated B cells, e.g. IgG and IgM by up to 230% and anti-tetanus toxoid antibodies by up to 430%. Cell-cell interactions via cell-surface structures, e.g. the CD11a/CD18 molecule, were found to be critical. Subsequently the NK-mediated B-cell regulation involves cytokines, since cell-free supernatants obtained by 48-h cultures of NK clones exerted BCGF and BCDF activity. Neutralization studies and direct determination characterized these cytokines as IFN-γ and TNF-α. The cytokine production of NK clones could be triggered by activated B cells only. Northern blot analysis demonstrated that activated B cells in co-culture with NK clones were able to induce accumulation of mRNA transcripts for IFN-γ and TNF-α in NK cells.
    Type of Medium: Electronic Resource
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  • 6
    Publication Date: 2018-06-05
    Description: Type I IFN production of plasmacytoid dendritic cells (pDCs) triggered by TLR-signaling is an essential part of antiviral responses and autoimmune reactions. Although it was well-documented that members of the cytokine signaling (SOCS) family regulate TLR-signaling, the mechanism of how SOCS proteins regulate TLR7-mediated type I IFN production has not been elucidated yet. In this article, we show that TLR7 activation in human pDCs induced the expression of SOCS1 and SOCS3. SOCS1 and SOCS3 strongly suppressed TLR7-mediated type I IFN production. Furthermore, we demonstrated that SOCS1- and SOCS3-bound IFN regulatory factor 7, a pivotal transcription factor of the TLR7 pathway, through the SH2 domain to promote its proteasomal degradation by lysine 48-linked polyubiquitination. Together, our results demonstrate that SOCS1/3-mediated degradation of IFN regulatory factor 7 directly regulates TLR7 signaling and type I IFN production in pDCs. This mechanism might be targeted by therapeutic approaches to either enhance type I IFN production in antiviral treatment or decrease type I IFN production in the treatment of autoimmune diseases.
    Print ISSN: 0022-1767
    Electronic ISSN: 1550-6606
    Topics: Medicine
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