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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, 11 May 2010, Vol.107(19), pp.8742-7
    Description: Genetic and epigenetic programming of T helper (Th) cell subsets during their polarization from naive Th cells establishes long-lived memory Th cells that stably maintain their lineage signatures. However, whether memory Th cells can be redifferentiated into another Th lineage is unclear. In this study, we show that Ag-specific memory Th cells were redifferentiated into Foxp3(+) T cells by TGF-beta when stimulated in the presence of all-trans retinoic acid and rapamycin. The "converted" Foxp3(+) T cells that were derived from Th2 memory cells down-regulated GATA-3 and IRF4 and produced little IL-4, IL-5, and IL-13. Instead, the converted Foxp3(+) T cells suppressed the proliferation and cytokine production of Th2 memory cells. More importantly, the converted Foxp3(+) T cells efficiently accumulated in the airways and significantly suppressed Th2 memory cell-mediated airway hyperreactivity, eosinophilia, and allergen-specific IgE production. Our findings reveal the plasticity of Th2 memory cells and provide a strategy for adoptive immunotherapy for the treatment of allergic diseases.
    Keywords: Asthma -- Immunology ; Forkhead Transcription Factors -- Immunology ; Immunologic Memory -- Immunology ; T-Lymphocytes, Regulatory -- Immunology ; Th2 Cells -- Immunology
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 2
    Language: English
    In: Nature, 6/2016, Vol.534(7608), pp.553-557
    ISSN: 0028-0836
    E-ISSN: 1476-4687
    Source: Nature Publishing Group (via CrossRef)
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  • 3
    In: Nature, 2016
    Description: Autophagy is a highly conserved self-digestion process, which is essential for maintaining homeostasis and viability in response to nutrient starvation (1-4). Although the components of autophagy in the cytoplasm have been well studied (5,6), the molecular basis for the transcriptional and epigenetic regulation of autophagy is poorly understood. Here we identify co-activator-associated arginine methyltransferase 1 (CARM1) as a crucial component of autophagy in mammals. Notably, CARM1 stability is regulated by the SKP2-containing SCF (SKP1-cullin1-F-box protein) E3 ubiquitin ligase in the nucleus, but not in the cytoplasm, under nutrient-rich conditions. Furthermore, we show that nutrient starvation results in AMP-activated protein kinase (AMPK)-dependent phosphorylation of FOXO3a in the nucleus, which in turn transcriptionally represses SKP2. This repression leads to increased levels of CARM1 protein and subsequent increases in histone H3 Arg17 dimethylation. Genome-wide analyses reveal that CARM1 exerts transcriptional co-activator function on autophagy-related and lysosomal genes through transcription factor EB (TFEB). Our findings demonstrate that CARMl-dependent histone arginine methylation is a crucial nuclear event in autophagy, and identify a new signalling axis of AMPK-SKP2-CARM1 in the regulation of autophagy induction after nutrient starvation.
    Keywords: Autophagy (Cytology) -- Analysis ; Genetic Regulation -- Analysis ; Methyltransferases -- Properties ; Methyltransferases -- Analysis ; Transcription (Genetics) -- Analysis;
    ISSN: 0028-0836
    E-ISSN: 1476-4687
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  • 4
    Language: English
    In: Biochemical and Biophysical Research Communications, 2010, Vol.401(4), pp.554-560
    Description: 5a M90T invades 7-day-old BALB/c mice but not 14-day-old mice. ► 7-day-old BALB/c mice, but not 14-day-old mice, show low levels of cryptdin expression. ► 14-day-old defensin-deficient mice have increased bacterial colonization in the intestine. ► Defensin has a critical role against infection in these mice. An earlier study revealed that 4-day-old mice, but not older mice, were infected with invasive strains. Here we attempted to determine the underlying mechanism that induces inflammation in the intestines of neonate mice after oral infection. Wild-type BALB/c mice of different ages (7, 14, and 35 days old) were orally administered GFP-expressing 5a M90T strain (5 × 10 CFU) and analyzed for colonization 6 h following infection. We found that localized in the epithelium, lamina propria, and crypt regions of the small intestines of 7-day-old BALB/c mice. Microarray analysis revealed that expression levels of cryptdin and various types of cryptdin-related mRNA (e.g., cryptrs-2, -5, -7, -12 and lysozyme) in the small intestines were significantly lower in 7-day-old than in older mice regardless of infection status. Interestingly, matrix metalloprotease-7 (matrilysin)-deficient (MAT ) mice of B6 background had more colonies and more severe symptoms of inflammation in the intestines than did wild-type B6 mice after oral challenge. This suggests that cryptdin-related antimicrobial molecules are indispensable for efficient protection against oral infection.
    Keywords: Shigella ; Inflammation ; Mucosa ; Neonate ; Defensin ; Biology ; Chemistry ; Anatomy & Physiology
    ISSN: 0006-291X
    E-ISSN: 1090-2104
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  • 5
    Language: English
    In: Vaccine, 27 February 2013, Vol.31(10), pp.1377-1384
    Description: ► Attenuated Salmonella vaccine (RASV) significantly inhibited tumor growth. ► RASV significantly increased TNF-α-secreting CD11b Gr-1 myeloid cells. ► RASV significantly reduced CD4 CD25 Foxp3 Tregs. ► RASV can induce a tumor microenvironmental shift from suppressive to immunogenic. Attenuated vaccines show therapeutic anti-cancer effects, but the underlying mechanism has not been well investigated. In the current study, intratumoral ( ) injection of recombinant attenuated serovar Typhimurium vaccine (RASV) significantly inhibited Her-2/neu-expressing tumor growth. Although depletion of CD8 cells in RASV-treated mice significantly restored tumor growth, the induction of Her-2/neu-specific cytotoxic T lymphocytes (CTLs) was not well correlated with the generation of the anti-tumor effect. Therefore, we hypothesized that RASV might induce a tumor microenvironmental shift, from immune suppressive to immunogenic, to reduce the suppressive force and finally elicit a successful anti-tumor response. We found that injection of RASV significantly increased the level of CD11b Gr-1 myeloid cells identified as myeloid-derived suppressor cell (MDSC), but a significant portion of these cells were TNF-α-secreting Ly6-G subsets, which can function as antitumor effector cells. We further investigated whether RASV can modulate immunosuppressive Treg cells, and CD4 CD25 Foxp3 Tregs was significantly reduced in RASV-treated mice. Thus, injection of RASV may offer a novel anti-cancer approach by eliciting transformation of immunosuppressive MDSCs into TNF-α-secreting neutrophils and reducing the generation of Treg cells, especially in the presence of tumor-specific CTLs. Collectively, these data will provide us an insight for the development of new anti-tumor approaches to overcome the immunosuppressive environment generated by tumors.
    Keywords: Salmonella ; Tumor ; Mdsc ; Treg ; Ctl ; Medicine ; Biology ; Veterinary Medicine ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 0264-410X
    E-ISSN: 1873-2518
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  • 6
    Language: English
    In: International Journal of Cancer, 15 June 2013, Vol.132(12), pp.2839-2848
    Description: Myd88 is an important adaptor molecule for the activation of NADPH oxidase and arginase‐1, which are responsible for the suppressive function of myeloid‐derived suppressor cells (MDSCs). When wild‐type and Myd88 mice were subcutaneously injected with CT26 colon cancer cells expressing human Her‐2/neu, tumor growth was retarded in Myd88 mice than in wild‐type mice. Although the generation of CD11bGr‐1 MDSCs was less in Myd88 mice than in wild‐type mice, Myd88 mice having tumor masses still had significant quantities of MDSCs, suggesting that MDSC generation might be independent of Myd88 signaling. However, MDSCs obtained from tumor‐bearing Myd88 mice failed to suppress antigen‐specific proliferation of CD8 T cells and CD4 T cells, whereas MDSCs from wild‐type mice significantly suppressed both types of T cells. Consistent with this, we found that the levels of costimulatory molecules and MHC class II were significantly increased in MDSCs obtained from Myd88 mice compared with wild‐type mice after tumor challenge. Furthermore, CD4 T cells residing in tumor‐draining lymph nodes of Myd88 mice secreted more TNF‐α than those of wild‐type mice. Finally, the blockade of Myd88 signaling by treatment with Myd88 inhibitory peptide, during later tumor stages, significantly inhibited the growth of immunogenic tumors. Overall, these data suggest that signaling through the Myd88 adaptor molecule is critical for the direct suppressive function of MDSCs and approaches to block Myd88‐mediated signaling in MDSCs might be effective to inhibit the immunosuppressive function of MDSCs. What's new? A promising avenue of cancer research involves the use of molecules that increase the innate immune response against tumor cells. One such immunostimulatory molecule is Myd88. Paradoxically, however, Myd88 also appears to play a role in suppressing this immune response, via cells called “myeloid derived suppressor cells” (MDSCs). In this study, the authors examined Myd88′s role in MDSC activation, and found that a peptide that inhibits Myd88′s function in MDSCs can slow tumor growth. These results suggest a new strategy for increasing immunity against established tumors.
    Keywords: Myd88 ; Mdsc ; Cytotoxic T Lymphocyte ; Tnf‐Α ; Peptide Inhibitor
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 7
    Language: English
    In: Cytokine, April 2011, Vol.54(1), pp.1-5
    Description: Needle-free vaccine delivery has become a global priority, both to eliminate the risk of improper and unsafe needle use and to simplify vaccination procedures. In pursuit of greater ease of vaccination, a number of needle-free delivery routes have been explored, with mucosal routes being perhaps the most prominent. Since the vaccine administration route significantly affects immune responses, numerous researchers are attempting to develop alternative vaccine delivery methods including a mucosal route. My group’s recent studies demonstrate the potential of the sublingual (s.l.) route for delivering vaccines capable of inducing mucosal as well as systemic immune responses. Sublingual administration conferred effective protection against a lethal challenge with influenza virus (H1N1) or genital papillomavirus. Moreover, CCR7-CCL19/CCL21-regulated dendritic cells are responsible for activation of T and B cells following s.l. administration. This review highlights current knowledge about the safety and effectiveness of s.l. vaccination and describes how s.l. vaccination can induce both systemic and mucosal immunity.
    Keywords: Sublingual ; Mucosa ; Influenza ; Dendritic Cells ; Ccr7 ; Medicine ; Biology
    ISSN: 1043-4666
    E-ISSN: 1096-0023
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  • 8
    In: Experimental & Molecular Medicine, 2014, Vol.46(3), p.e86
    Description: Mucosal surfaces are covered with specialized epithelial cells that serve as physical barriers to the environment and prevent exogenous challenges by pathogens and soluble antigens.1 Functionally independent of the systemic immune compartments, the mucosal immune system has developed its own highly organized lymphoid tissues. Mucosal tissues maintain homeostasis by mounting specialized anti-inflammatory immune defenses, such as the production of secretory IgA (SIgA) antibodies and the induction of tolerance against innocuous soluble substances and commensal bacteria. When antigens are administered with appropriate adjuvants or attenuated live vaccines via mucosal routes (oral, nasal, sublingual, ocular, genital or rectal), the mucosal immune system can trigger both humoral and cell-mediated immune protection not only in mucosal sites but also systemically.2 Furthermore, owing to mucosal homing properties, local mucosal immunization leads to antigen-specific T- and B-cell responses at both local and distal mucosal sites. Nevertheless, most pathogens can still effectively invade by crossing the host's mucosal membranes. Hence, effective vaccines that exert protective effects at mucosal surfaces are much needed.
    Keywords: Medicine;
    ISSN: 20926413
    E-ISSN: 20926413
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  • 9
    Language: English
    In: Gastroenterology, 2010, Vol.138(4), pp.1468-1478.e6
    Description: Retinoic acid (RA) is a crucial factor for maintaining homeostasis in the gut, including lymphocyte homing, immunoglobulin (Ig) A production, and T regulatory cells (Treg) and T helper cell 17 (T 17) generation. Until now, most attention has focused on the function of dendritic cells (DCs) to initiate adaptive immunity including T and B lymphocytes through RA. To investigate the effects of RA on DCs of gut-associated lymphoid tissue (GALT), we analyzed the phenotype and function of DC subsets from GALT of vitamin A-deficient (VAD) mice. VAD mice were prepared by feeding them a VAD diet over 12 weeks from gestational days 10–14. Here, we report that tremendous increase of langerin DCs occurred in the mesenteric lymph nodes (MLNs) and gut lamina propria of VAD mice dependent on CCR7 signaling. Langerin DCs have phenotypes more similar to those of bone marrow-derived dermal langerin DCs than epidermal Langerhans cells. Moreover, RA receptor antagonists enhance the differentiation of langerin DCs from mouse and human precursors of bone marrow and peripheral blood. Langerin DCs were highly differentiated but less inflammatory than langerin DCs of MLNs of VAD mice. Moreover, tolerance to orally delivered antigen was completely abrogated by depletion of langerin DCs in the VAD mice. These results suggest that generation of langerin DCs in the GALT is tightly regulated by RA and that the microenvironment of tissues determines the phenotype of DCs.
    Keywords: Dendritic Cells ; Langerin ; Retinoic Acid ; Gut ; Medicine
    ISSN: 0016-5085
    E-ISSN: 1528-0012
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  • 10
    Language: English
    In: PLoS ONE, 2010, Vol.5(9), p.e12925
    Description: Vitamin D 3 , the most physiologically relevant form of vitamin D, is an essential organic compound that has been shown to have a crucial effect on the immune responses. Vitamin D 3 ameliorates the onset of the experimental autoimmune encephalomyelitis (EAE); however, the direct effect of vitamin D 3 on T cells is largely unknown. ; In an system using cells from mice, the active form of vitamin D (1,25-dihydroxyvitamin D) suppresses both interleukin (IL)-17-producing T cells (T17) and regulatory T cells (Treg) differentiation via a vitamin D receptor signal. The ability of 1,25-dihydroxyvitamin D (1,25(OH)D) to reduce the amount of IL-2 regulates the generation of Treg cells, but not T17 cells. Under T17-polarizing conditions, 1,25(OH)D helps to increase the numbers of IL-10-producing T cells, but 1,25(OH)D's negative regulation of T17 development is still defined in the IL-10 T cells. Although the STAT1 signal reciprocally affects the secretion of IL-10 and IL-17, 1,25(OH)D inhibits IL-17 production in STAT1 T cells. Most interestingly, 1,25(OH)D negatively regulates CCR6 expression which might be essential for T17 cells to enter the central nervous system and initiate EAE. ; Our present results in an experimental murine model suggest that 1,25(OH)D can directly regulate T cell differentiation and could be applied in preventive and therapeutic strategies for T17-mediated autoimmune diseases.
    Keywords: Research Article ; Immunology -- Autoimmunity ; Immunology -- Immune Response ; Immunology -- Leukocyte Development
    E-ISSN: 1932-6203
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