5 results on '"Strobl B."'
Search Results
2. Sustained Post-Developmental T-Bet Expression Is Critical for the Maintenance of Type One Innate Lymphoid Cells In Vivo .
- Author
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Schroeder JH, Roberts LB, Meissl K, Lo JW, Hromadová D, Hayes K, Zabinski T, Read E, Moreira Heliodoro C, Reis R, Howard JK, Grencis RK, Neves JF, Strobl B, and Lord GM
- Subjects
- Animals, Citrobacter rodentium, Colitis chemically induced, Colitis immunology, Dextran Sulfate, Enterobacteriaceae Infections immunology, Female, Immunity, Innate, Male, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Transgenic, STAT1 Transcription Factor genetics, STAT1 Transcription Factor immunology, STAT4 Transcription Factor genetics, STAT4 Transcription Factor immunology, Tamoxifen pharmacology, Trichinella spiralis, Trichinellosis immunology, Mice, Intestinal Mucosa immunology, Lymphocytes immunology, T-Box Domain Proteins immunology
- Abstract
Innate lymphoid cells (ILC) play a significant role in the intestinal immune response and T-bet
+ CD127+ group 1 cells (ILC1) have been linked to the pathogenesis of human inflammatory bowel disease (IBD). However, the functional importance of ILC1 in the context of an intact adaptive immune response has been controversial. In this report we demonstrate that induced depletion of T-bet using a Rosa26-Cre-ERT2 model resulted in the loss of intestinal ILC1, pointing to a post-developmental requirement of T-bet expression for these cells. In contrast, neither colonic lamina propria (cLP) ILC2 nor cLP ILC3 abundance were altered upon induced deletion of T-bet. Mechanistically, we report that STAT1 or STAT4 are not required for intestinal ILC1 development and maintenance. Mice with induced deletion of T-bet and subsequent loss of ILC1 were protected from the induction of severe colitis in vivo . Hence, this study provides support for the clinical development of an IBD treatment based on ILC1 depletion via targeting T-bet or its downstream transcriptional targets., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Schroeder, Roberts, Meissl, Lo, Hromadová, Hayes, Zabinski, Read, Moreira Heliodoro, Reis, Howard, Grencis, Neves, Strobl and Lord.)- Published
- 2021
- Full Text
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3. T-Bet Controls Cellularity of Intestinal Group 3 Innate Lymphoid Cells.
- Author
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Schroeder JH, Meissl K, Hromadová D, Lo JW, Neves JF, Howard JK, Helmby H, Powell N, Strobl B, and Lord GM
- Subjects
- Animals, Colitis genetics, Colitis immunology, Colitis pathology, Inflammatory Bowel Diseases genetics, Inflammatory Bowel Diseases immunology, Inflammatory Bowel Diseases pathology, Intestinal Mucosa pathology, Lymphocytes pathology, Mice, Mice, Knockout, Nuclear Receptor Subfamily 1, Group F, Member 3 genetics, Nuclear Receptor Subfamily 1, Group F, Member 3 immunology, Receptors, Interleukin-7 genetics, Receptors, Interleukin-7 immunology, STAT1 Transcription Factor genetics, STAT1 Transcription Factor immunology, STAT4 Transcription Factor genetics, STAT4 Transcription Factor immunology, T-Box Domain Proteins genetics, Immunity, Innate, Intestinal Mucosa immunology, Lymphocytes immunology, T-Box Domain Proteins immunology
- Abstract
Innate lymphoid cells (ILC) play a significant immunological role at mucosal surfaces such as the intestine. T-bet-expressing group 1 innate lymphoid cells (ILC1) are believed to play a substantial role in inflammatory bowel disease (IBD). However, a role of T-bet-negative ILC3 in driving colitis has also been suggested in mouse models questioning T-bet as a critical factor for IBD. We report here that T-bet deficient mice had a greater cellularity of NKp46-negative ILC3 correlating with enhanced expression of RORγt and IL-7R, but independent of signaling through STAT1 or STAT4. We observed enhanced neutrophilia in the colonic lamina propria (cLP) of these animals, however, we did not detect a greater risk of T-bet-deficient mice to develop spontaneous colitis. Furthermore, by utilizing an in vivo fate-mapping approach, we identified a population of T-bet-positive precursors in NKp46-negative ILC3s. These data suggest that T-bet controls ILC3 cellularity, but does do not drive a pathogenic role of ILC3 in mice with a conventional specific pathogen-free microbiota., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Schroeder, Meissl, Hromadová, Lo, Neves, Howard, Helmby, Powell, Strobl and Lord.)
- Published
- 2021
- Full Text
- View/download PDF
4. STAT1 Isoforms Differentially Regulate NK Cell Maturation and Anti-tumor Activity.
- Author
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Meissl K, Simonović N, Amenitsch L, Witalisz-Siepracka A, Klein K, Lassnig C, Puga A, Vogl C, Poelzl A, Bosmann M, Dohnal A, Sexl V, Müller M, and Strobl B
- Subjects
- Animals, Bone Marrow Transplantation, Cell Line, Tumor, Cytotoxicity, Immunologic, Immunologic Surveillance drug effects, Immunologic Surveillance immunology, Interferon-Stimulated Gene Factor 3 deficiency, Interferon-Stimulated Gene Factor 3 genetics, Interferon-Stimulated Gene Factor 3 immunology, Interleukin-15 pharmacology, Interleukin-15 Receptor alpha Subunit, Killer Cells, Natural drug effects, Killer Cells, Natural immunology, Lymphocyte Depletion, Lymphoid Tissue cytology, Lymphoma immunology, Lymphoma pathology, Lymphopoiesis drug effects, Mice, Mice, Inbred C57BL, Mice, Knockout, Organ Specificity, Protein Isoforms genetics, Protein Isoforms immunology, Receptors, Interferon deficiency, STAT1 Transcription Factor deficiency, STAT1 Transcription Factor genetics, Specific Pathogen-Free Organisms, Spleen cytology, Interferon gamma Receptor, Killer Cells, Natural cytology, Lymphopoiesis physiology, STAT1 Transcription Factor immunology
- Abstract
Natural killer (NK) cells are important components of the innate immune defense against infections and cancers. Signal transducer and activator of transcription 1 (STAT1) is a transcription factor that is essential for NK cell maturation and NK cell-dependent tumor surveillance. Two alternatively spliced isoforms of STAT1 exist: a full-length STAT1α and a C-terminally truncated STAT1β isoform. Aberrant splicing is frequently observed in cancer cells and several anti-cancer drugs interfere with the cellular splicing machinery. To investigate whether NK cell-mediated tumor surveillance is affected by a switch in STAT1 splicing, we made use of knock-in mice expressing either only the STAT1α ( Stat1
α/α ) or the STAT1β ( Stat1β / β ) isoform. NK cells from Stat1α/α mice matured normally and controlled transplanted tumor cells as efficiently as NK cells from wild-type mice. In contrast, NK cells from Stat1β/β mice showed impaired maturation and effector functions, albeit less severe than NK cells from mice that completely lack STAT1 ( Stat1-/- ). Mechanistically, we show that NK cell maturation requires the presence of STAT1α in the niche rather than in NK cells themselves and that NK cell maturation depends on IFNγ signaling under homeostatic conditions. The impaired NK cell maturation in Stat1β/β mice was paralleled by decreased IL-15 receptor alpha (IL-15Rα) surface levels on dendritic cells, macrophages and monocytes. Treatment of Stat1β/β mice with exogenous IL-15/IL-15Rα complexes rescued NK cell maturation but not their effector functions. Collectively, our findings provide evidence that STAT1 isoforms are not functionally redundant in regulating NK cell activity and that the absence of STAT1α severely impairs, but does not abolish, NK cell-dependent tumor surveillance., (Copyright © 2020 Meissl, Simonović, Amenitsch, Witalisz-Siepracka, Klein, Lassnig, Puga, Vogl, Poelzl, Bosmann, Dohnal, Sexl, Müller and Strobl.)- Published
- 2020
- Full Text
- View/download PDF
5. The C-Terminal Transactivation Domain of STAT1 Has a Gene-Specific Role in Transactivation and Cofactor Recruitment.
- Author
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Parrini M, Meissl K, Ola MJ, Lederer T, Puga A, Wienerroither S, Kovarik P, Decker T, Müller M, and Strobl B
- Subjects
- Animals, Cells, Cultured, GTP-Binding Proteins genetics, GTP-Binding Proteins metabolism, Histone Code, Interferon-Stimulated Gene Factor 3, gamma Subunit genetics, Interferon-Stimulated Gene Factor 3, gamma Subunit metabolism, Macrophages, Mice, Mice, Inbred C57BL, Mice, Knockout, Nuclear Proteins metabolism, Primary Cell Culture, Promoter Regions, Genetic genetics, Protein Isoforms genetics, Protein Isoforms immunology, Protein Isoforms metabolism, STAT1 Transcription Factor genetics, STAT1 Transcription Factor immunology, STAT2 Transcription Factor genetics, STAT2 Transcription Factor metabolism, Trans-Activators metabolism, Nuclear Proteins genetics, Protein Domains immunology, RNA Polymerase II metabolism, STAT1 Transcription Factor metabolism, Trans-Activators genetics, Transcriptional Activation immunology
- Abstract
STAT1 has a key role in the regulation of innate and adaptive immunity by inducing transcriptional changes in response to cytokines, such as all types of interferons (IFN). STAT1 exist as two splice isoforms, which differ in regard to the C-terminal transactivation domain (TAD). STAT1β lacks the C-terminal TAD and has been previously reported to be a weaker transcriptional activator than STAT1α, although this was strongly dependent on the target gene. The mechanism of this context-dependent effects remained unclear. By using macrophages from mice that only express STAT1β, we investigated the role of the C-terminal TAD during the distinct steps of transcriptional activation of selected target genes in response to IFNγ. We show that the STAT1 C-terminal TAD is absolutely required for the recruitment of RNA polymerase II (Pol II) and for the establishment of active histone marks at the class II major histocompatibility complex transactivator ( CIIta ) promoter IV, whereas it is dispensable for histone acetylation at the guanylate binding protein 2 ( Gbp2 ) promoter but required for an efficient recruitment of Pol II, which correlated with a strongly reduced, but not absent, transcriptional activity. IFNγ-induced expression of Irf7 , which is mediated by STAT1 in complex with STAT2 and IRF9, did not rely on the presence of the C-terminal TAD of STAT1. Moreover, we show for the first time that the STAT1 C-terminal TAD is required for an efficient recruitment of components of the core Mediator complex to the IFN regulatory factor ( Irf ) 1 and Irf8 promoters, which both harbor an open chromatin state under basal conditions. Our study identified novel functions of the STAT1 C-terminal TAD in transcriptional activation and provides mechanistic explanations for the gene-specific transcriptional activity of STAT1β.
- Published
- 2018
- Full Text
- View/download PDF
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