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  • 1
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 10 September 2013, Vol.110(37), pp.15019-24
    Description: Robust cytotoxic CD8(+) T-cell response is important for immunity to intracellular pathogens. Here, we show that the transcription factor IFN Regulatory Factor 4 (IRF4) is crucial for the protective CD8(+) T-cell response to the intracellular bacterium Listeria monocytogenes. IRF4-deficient (Irf4(-/-)) mice could not clear L. monocytogenes infection and generated decreased numbers of L. monocytogenes-specific CD8(+) T cells with impaired effector phenotype and function. Transfer of wild-type CD8(+) T cells into Irf4(-/-) mice improved bacterial clearance, suggesting an intrinsic defect of CD8(+) T cells in Irf4(-/-) mice. Following transfer into wild-type recipients, Irf4(-/-) CD8(+) T cells became activated and showed initial proliferation upon L. monocytogenes infection. However, these cells could not sustain proliferation, produced reduced amounts of IFN-γ and TNF-α, and failed to acquire cytotoxic function. Forced IRF4 expression in Irf4(-/-) CD8(+) T cells rescued the defect. During acute infection, Irf4(-/-) CD8(+) T cells demonstrated diminished expression of B lymphocyte-induced maturation protein-1 (Blimp-1), inhibitor of DNA binding (Id)2, and T-box expressed in T cells (T-bet), transcription factors programming effector-cell generation. IRF4 was essential for expression of Blimp-1, suggesting that altered regulation of Blimp-1 contributes to the defects of Irf4(-/-) CD8(+) T cells. Despite increased levels of B-cell lymphoma 6 (BCL-6), Eomesodermin, and Id3, Irf4(-/-) CD8(+) T cells showed impaired memory-cell formation, indicating additional functions for IRF4 in this process. As IRF4 governs B-cell and CD4(+) T-cell differentiation, the identification of its decisive role in peripheral CD8(+) T-cell differentiation, suggests a common regulatory function for IRF4 in adaptive lymphocytes fate decision.
    Keywords: Interferon Regulatory Factors -- Immunology ; T-Lymphocytes, Cytotoxic -- Immunology
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 2
    Language: English
    In: Cytokine, November 2015, Vol.76(1), pp.78-78
    Keywords: Medicine ; Biology
    ISSN: 1043-4666
    E-ISSN: 1096-0023
    Source: ScienceDirect Journals (Elsevier)
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  • 3
    Language: English
    In: Journal of virology, April 2015, Vol.89(7), pp.3859-69
    Description: The Middle East respiratory syndrome coronavirus (MERS-CoV) emerged in 2012 as the causative agent of a severe respiratory disease with a fatality rate of approximately 30%. The high virulence and mortality rate prompted us to analyze aspects of MERS-CoV pathogenesis, especially its interaction with innate immune cells such as antigen-presenting cells (APCs). Particularly, we analyzed secretion of type I and type III interferons (IFNs) by APCs, i.e., B cells, macrophages, monocyte-derived/myeloid dendritic cells (MDDCs/mDCs), and by plasmacytoid dendritic cells (pDCs) of human and murine origin after inoculation with MERS-CoV. Production of large amounts of type I and III IFNs was induced exclusively in human pDCs, which were significantly higher than IFN induction by severe acute respiratory syndrome (SARS)-CoV. Of note, IFNs were secreted in the absence of productive replication. However, receptor binding, endosomal uptake, and probably signaling via Toll-like receptor 7 (TLR7) were critical for sensing of MERS-CoV by pDCs. Furthermore, active transcription of MERS-CoV N RNA and subsequent N protein expression were evident in infected pDCs, indicating abortive infection. Taken together, our results point toward dipeptidyl peptidase 4 (DPP4)-dependent endosomal uptake and subsequent infection of human pDCs by MERS-CoV. However, the replication cycle is stopped after early gene expression. In parallel, human pDCs are potent IFN-producing cells upon MERS-CoV infection. Knowledge of such IFN responses supports our understanding of MERS-CoV pathogenesis and is critical for the choice of treatment options. MERS-CoV causes a severe respiratory disease with high fatality rates in human patients. Recently, confirmed human cases have increased dramatically in both number and geographic distribution. Understanding the pathogenesis of this highly pathogenic CoV is crucial for developing successful treatment strategies. This study elucidates the interaction of MERS-CoV with APCs and pDCs, particularly the induction of type I and III IFN secretion. Human pDCs are the immune cell population sensing MERS-CoV but secrete significantly larger amounts of IFNs, especially IFN-α, than in response to SARS-CoV. A model for molecular virus-host interactions is presented outlining IFN induction in pDCs. The massive IFN secretion upon contact suggests a critical role of this mechanism for the high degree of immune activation observed during MERS-CoV infection.
    Keywords: Dendritic Cells -- Immunology ; Interferons -- Metabolism ; Middle East Respiratory Syndrome Coronavirus -- Immunology
    ISSN: 0022538X
    E-ISSN: 1098-5514
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  • 4
    Language: English
    In: Immunity, 19 June 2014, Vol.40(6), pp.949-960
    Description: Despite development of new antiviral drugs, viral infections are still a major health problem. The most potent antiviral defense mechanism is the innate production of type I interferon (IFN-I), which not only limits virus replication but also promotes antiviral T cell immunity through mechanisms, which remain insufficiently studied. Using the murine lymphocytic choriomeningitis virus model system, we show here that IFN-I signaling on T cells prevented their rapid elimination in vivo. Microarray analyses uncovered that IFN-I triggered the expression of selected inhibitory NK-cell-receptor ligands. Consequently, T cell immunity of IFN-I receptor (IFNAR)-deficient T cells could be restored by NK cell depletion or in NK-cell-deficient hosts ( ). The elimination of T cells was dependent on NK-cell-mediated perforin expression. In summary, we identified IFN-I as a key player regulating the protection of T cells against regulatory NK cell function. Type I interferons (IFN-I) are important for promoting antiviral T cell immunity, but the mechanisms behind IFN-I action have been unclear. Xu et al. show that IFN-I protects antiviral T cells from regulatory cytotoxic effects of natural killer cells and promotes their expansion and antiviral effector functions.
    Keywords: Medicine ; Biology
    ISSN: 1074-7613
    E-ISSN: 1097-4180
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  • 5
    In: PLoS ONE, 2015, Vol.10(9)
    Description: Introduction Data on the efficacy and safety of everolimus in pediatric renal transplantation compared to other immunosuppressive regimens are scarce. Patients/Methods We therefore performed a multicenter, observational, matched cohort study over 4 years post-transplant in 35 patients on everolimus plus low-dose cyclosporine, who were matched (1:2) with a control group of 70 children receiving a standard-dose calcineurin-inhibitor- and mycophenolate mofetil-based regimen. Results Corticosteroids were withdrawn in 83% in the everolimus vs. 39% in the control group (p〈0.001). Patient and graft survival were comparable. The rate of biopsy-proven acute rejection episodes Banff score ≥ IA during the first year post-transplant was 6% in the everolimus vs. 13% in the control group (p = 0.23). The rate of de novo donor-specific HLA antibodies (11% in everolimus, 18% in controls) was comparable (p = 0.55). At 4 years post-transplant, mean eGFR in the everolimus group was 56±33 ml/min per 1.73 m² vs. 63±22 ml/min per 1.73 m² in the control group (p = 0.14). Everolimus therapy was associated with less BK polyomavirus replication (3% vs. 17% in controls; p = 0.04), but with a higher percentage of arterial hypertension and more hyperlipidemia (p〈0.001). Conclusion In pediatric renal transplantation, an everolimus-based regimen with low-dose cyclosporine yields comparable four year results as a standard regimen, but with a different side effect profile.
    Keywords: Research Article
    E-ISSN: 1932-6203
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