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Berlin Brandenburg

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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: Proceedings of the National Academy of Sciences of the United States of America, 2012, Vol.109(4), pp.1210-1215
    Description: Infections with HIV, hepatitis B virus, and hepatitis C virus can turn into chronic infections, which currently affect more than 500 million patients worldwide. It is generally thought that virus-mediated T-cell exhaustion limits T-cell function, thus promoting chronic disease. Here we demonstrate that natural killer (NK) cells have a negative impact on the development of T-cell immunity by using the murine lymphocytic choriomeningitis virus. NK cell-deficient (Nfil3–/–, E4BP4–/–) mice exhibited a higher virus-specific T-cell response. In addition, NK cell depletion caused enhanced T-cell immunity in WT mice, which led to rapid virus control and prevented chronic infection in lymphocytic choriomeningitis virus clone 13- and reduced viral load in DOCILE-infected animals. Further experiments showed that NKG2D triggered regulatory NK cell functions, which were mediated by perforin, and limited T-cell responses. Therefore, we identified an important role of regulatory NK cells in limiting T-cell immunity during virus infection. ; p. 1210-1215.
    Keywords: Mice ; Lymphocytic Choriomeningitis Virus ; Hepatitis C Virus ; Hepatitis B Virus ; Hiv Infections ; Natural Killer Cells ; Cd8-Positive T-Lymphocytes ; Immunity ; Viruses ; Viral Load
    ISSN: 0027-8424
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  • 3
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 24 January 2012, Vol.109(4), pp.1210-5
    Description: Infections with HIV, hepatitis B virus, and hepatitis C virus can turn into chronic infections, which currently affect more than 500 million patients worldwide. It is generally thought that virus-mediated T-cell exhaustion limits T-cell function, thus promoting chronic disease. Here we demonstrate that natural killer (NK) cells have a negative impact on the development of T-cell immunity by using the murine lymphocytic choriomeningitis virus. NK cell-deficient (Nfil3(-/-), E4BP4(-/-)) mice exhibited a higher virus-specific T-cell response. In addition, NK cell depletion caused enhanced T-cell immunity in WT mice, which led to rapid virus control and prevented chronic infection in lymphocytic choriomeningitis virus clone 13- and reduced viral load in DOCILE-infected animals. Further experiments showed that NKG2D triggered regulatory NK cell functions, which were mediated by perforin, and limited T-cell responses. Therefore, we identified an important role of regulatory NK cells in limiting T-cell immunity during virus infection.
    Keywords: Chronic Disease ; Lymphocytic Choriomeningitis Virus ; Arenaviridae Infections -- Immunology ; Cd8-Positive T-Lymphocytes -- Immunology ; Communicable Diseases -- Immunology ; Immunity, Cellular -- Immunology ; Killer Cells, Natural -- Immunology ; Lymphocyte Activation -- Immunology
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 4
    Language: English
    In: Trends in cancer, February 2018, Vol.4(2), pp.138-150
    Description: Cells of the immune system display varying metabolic profiles to fulfill their functions. B lymphocytes overcome fluctuating energy challenges as they transition from the resting state and recirculation to activation, rapid proliferation, and massive antibody production. Only through a controlled interplay between metabolism, extracellular stimuli, and intracellular signaling can successful humoral responses be mounted. Alterations to this balance can promote malignant transformation of B cells. The metabolic control of B-cell fate is only partially understood. Here, we provide a compelling overview of the current state of the art and describe the main metabolic features of B cells during normal development and oncogenesis, with emphasis on the major B-cell transcriptional and metabolic regulators, including myelocytomatosis virus oncogene cellular homolog (Myc) and hypoxia-inducible factor 1-α (HIF-1α).
    Keywords: B Cell ; Hif-1α ; Myc ; Immunometabolism ; Lymphoma ; B-Lymphocytes -- Metabolism ; Neoplasms -- Metabolism
    ISSN: 24058033
    E-ISSN: 2405-8025
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  • 5
    Language: English
    In: PLoS ONE, 01 January 2014, Vol.9(9), p.e107990
    Description: The Interleukin (IL)-12 family contains several heterodimeric composite cytokines which share subunits among each other. IL-12 consists of the subunits p40 (shared with IL-23) and p35. p35 is shared with the composite cytokine IL-35 which comprises of the p35/EBI3 heterodimer (EBI3 shared with...
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 6
    Language: English
    In: European Journal of Immunology, Feb, 2015, Vol.45(2), p.418(10)
    Description: To purchase or authenticate to the full-text of this article, please visit this link: http://onlinelibrary.wiley.com/doi/10.1002/eji.201445060/abstract Byline: , , Vitaly I. Pozdeev, Haifeng C. Xu, Prashant Shinde, Colin Reardon, Zhenyue Hao, Marc Beyer, Andreas Bergthaler, Dieter Haussinger, Dieter Haussinger, Dieter Haussinger, Philipp A. Lang Keywords: Chronic infection; Humoral immunity; LCMV; STAT3; T follicular helper cells STAT3 is a critical transcription factor activated downstream of cytokine signaling and is integral for the function of multiple immune cell types. Human mutations in STAT3 cause primary immunodeficiency resulting in impaired control of a variety of infections, including reactivation of latent viruses. In this study, we investigate how T-cell functions of STAT3 contribute to responses to viral infection by inducing chronic lymphocytic choriomeningitis virus (LCMV) infection in mice lacking STAT3 specifically in T cells. Although mice with conditional disruption of STAT3 in T cells were able to mount early responses to viral infection similar to control animals, including expansion of effector T cells, we found generation of T-follicular helper (Tfh) cells to be impaired. As a result, STAT3 T cell deficient mice produced attenuated germinal center reactions, and did not accumulate bone marrow virus specific IgG-secreting cells, resulting in failure to maintain levels of virus-specific IgG or mount neutralizing responses to LCMV in the serum. These effects were associated with reduced control of viral replication and prolonged infection. Our results demonstrate the importance of STAT3 in T cells for the generation of functional long-term humoral immunity to viral infections. Article Note: These authors contributed equally to this work as first authors. These authors contributed equally to this work as senior authors. Supporting information: Additional Supporting Information may be found in the online version of this article As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re-organized for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors. CAPTION(S): Figure 1. Thymic T-cell populations and survival are similar between naive control and T-cell STAT3 deficient mice. (A) Survival of naive uninfected Lck-Cre- Stat3fl/fl vs. Lck-Cre+ Stat3fl/fl mice was monitored over time (mean [+ or -] SEM; n = 155-175 mice/group). (B) CD4+, CD8+, CD4+CD8+, and CD4-CD8- T-cells were measured in naive thymus samples from Lck-Cre- Stat3fl/fl vs. Lck-Cre+ Stat3fl/fl mice (mean [+ or -] SEM; n = 5-6 mice, data pooled from two independent experiments). (C) CD44 and CD25 expression were analyzed on double negative (CD4-CD8-) T cells in naive thymus from Lck-Cre- Stat3fl/fl vs. Lck-Cre+ Stat3fl/fl (mean [+ or -] SEM; n = 5-6 mice). Data shown in (C and D) are pooled from two independent experiments. Statistical significance between groups was determined by Student's t-test or Kaplan-Meier log rank test for survival data. Figure 2. Representative flow cytometry gating strategy. (A) Pregaiting strategy used to identify T cells, including tetramer positive or IFN-[gamma] positive T cells as shown in Figure 1. (B) Pregating strategy used to identify B cells as shown in Figure 2. Figure 3. B-Cell proliferation is unaffected by the absence of STAT3 in T cells. Percentage of cells in each division cycle for positively selected (B220+), CFSE labeled Lck-Cre- Stat3fl/fl vs. Lck-Cre+ Stat3fl/fl B cells, stimulated with (A) 1 I1/4g/mL LPS or (B) 2 I1/4g/mL CD40-L and 10 ng/mL Il-4 for 72 h as measured by flow cytometry (mean [+ or -] SEM; n = 4-6 mice). Data is pooled from two independent experiments. Statistical significance between groups was determined by Student's t-test.
    Keywords: Virus Diseases -- Health Aspects ; Virus Diseases -- Analysis ; T Cells -- Health Aspects ; T Cells -- Analysis
    ISSN: 0014-2980
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  • 7
    In: European Journal of Immunology, February 2015, Vol.45(2), pp.418-427
    Description: STAT3 is a critical transcription factor activated downstream of cytokine signaling and is integral for the function of multiple immune cell types. Human mutations in STAT3 cause primary immunodeficiency resulting in impaired control of a variety of infections, including reactivation of latent viruses. In this study, we investigate how T‐cell functions of STAT3 contribute to responses to viral infection by inducing chronic lymphocytic choriomeningitis virus (LCMV) infection in mice lacking STAT3 specifically in T cells. Although mice with conditional disruption of STAT3 in T cells were able to mount early responses to viral infection similar to control animals, including expansion of effector T cells, we found generation of T‐follicular helper (Tfh) cells to be impaired. As a result, STAT3 T cell deficient mice produced attenuated germinal center reactions, and did not accumulate bone marrow virus specific IgG‐secreting cells, resulting in failure to maintain levels of virus‐specific IgG or mount neutralizing responses to LCMV in the serum. These effects were associated with reduced control of viral replication and prolonged infection. Our results demonstrate the importance of STAT3 in T cells for the generation of functional long‐term humoral immunity to viral infections.
    Keywords: Chronic Infection ; Humoral Immunity ; Lcmv ; Stat3 ; T Follicular Helper Cells
    ISSN: 0014-2980
    E-ISSN: 1521-4141
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  • 8
    In: Nature Immunology, 2011, Vol.13(1), p.51
    Description: The innate immune system limits viral replication via type I interferon and also induces the presentation of viral antigens to cells of the adaptive immune response. Using infection of mice with vesicular stomatitis virus, we analyzed how the innate immune system inhibits viral propagation but still allows the presentation of antigen to cells of the adaptive immune response. We found that expression of the gene encoding the inhibitory protein Usp18 in metallophilic macrophages led to lower type I interferon responsiveness, thereby allowing locally restricted replication of virus. This was essential for the induction of adaptive antiviral immune responses and, therefore, for preventing the fatal outcome of infection. In conclusion, we found that enforced viral replication in marginal zone macrophages was an immunological mechanism that ensured the production of sufficient antigen for effective activation of the adaptive immune response.
    Keywords: Immune System – Research ; Polymerase Chain Reaction – Usage ; Viral Antigens – Physiological Aspects ; Viral Antigens – Research ; Virus Replication – Physiological Aspects ; Virus Replication – Research;
    ISSN: 1529-2908
    E-ISSN: 15292916
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  • 9
    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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  • 10
    Language: English
    In: Immunity, 18 April 2017, Vol.46(4), pp.675-689
    Description: Activated T cells produce reactive oxygen species (ROS), which trigger the antioxidative glutathione (GSH) response necessary to buffer rising ROS and prevent cellular damage. We report that GSH is essential for T cell effector functions through its regulation of metabolic activity. Conditional gene targeting of the catalytic subunit of glutamate cysteine ligase ( blocked GSH production specifically in murine T cells. Gclc-deficient T cells initially underwent normal activation but could not meet their increased energy and biosynthetic requirements. GSH deficiency compromised the activation of mammalian target of rapamycin-1 (mTOR) and expression of NFAT and Myc transcription factors, abrogating the energy utilization and Myc-dependent metabolic reprogramming that allows activated T cells to switch to glycolysis and glutaminolysis. In vivo, T-cell-specific ablation of murine prevented autoimmune disease but blocked antiviral defense. The antioxidative GSH pathway thus plays an unexpected role in metabolic integration and reprogramming during inflammatory T cell responses. Upon activation, T cells adapt their metabolism to meet their increased bioenergetic and biosynthetic needs. Activated T cells produce ROS, which trigger the antioxidative GSH response to prevent cellular damage. Mak et al. report that the GSH pathway plays an unexpected role in metabolic integration during inflammatory T cell responses.
    Keywords: Metabolic Reprogramming ; Metabolism ; Glycolysis ; Glutathione ; Gsh ; Gclc ; Reactive Oxygen Species ; Ros ; Nfat ; Mtor ; Myc ; T Cells ; Medicine ; Biology
    ISSN: 1074-7613
    E-ISSN: 1097-4180
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