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  • American Association for the Advancement of Science (AAAS)  (2)
  • 1
    Online Resource
    Online Resource
    TSLP signaling in CD4 + T cells programs a pathogenic T helper 2 cell state
    American Association for the Advancement of Science (AAAS) ; 2018
    In:  Science Signaling Vol. 11, No. 521 ( 2018-03-13)
    Details
    In: Science Signaling, American Association for the Advancement of Science (AAAS), Vol. 11, No. 521 ( 2018-03-13)
    Abstract: Pathogenic T helper 2 (T H 2) cells, which produce increased amounts of the cytokines interleukin-5 (IL-5) and IL-13, promote allergic disorders, including asthma. Thymic stromal lymphopoietin (TSLP), a cytokine secreted by epithelial and innate immune cells, stimulates such pathogenic T H 2 cell responses. We found that TSLP signaling in mouse CD4 + T cells initiated transcriptional changes associated with T H 2 cell programming. IL-4 signaling amplified and stabilized the genomic response of T cells to TSLP, which increased the frequency of T cells producing IL-4, IL-5, and IL-13. Furthermore, the TSLP- and IL-4–programmed T H 2 cells had a pathogenic phenotype, producing greater amounts of IL-5 and IL-13 and other proinflammatory cytokines than did T H 2 cells stimulated with IL-4 alone. TSLP-mediated T H 2 cell induction involved distinct molecular pathways, including activation of the transcription factor STAT5 through the kinase JAK2 and repression of the transcription factor BCL6. Mice that received wild-type CD4 + T cells had exacerbated pathogenic T H 2 cell responses upon exposure to house dust mites compared to mice that received TSLP receptor–deficient CD4 + T cells. Transient TSLP signaling stably programmed pathogenic potential in memory T H 2 cells. In human CD4 + T cells, TSLP and IL-4 promoted the generation of T H 2 cells that produced greater amounts of IL-5 and IL-13. Compared to healthy controls, asthmatic children showed enhancement of such T cell responses in peripheral blood. Our data support a sequential cytokine model for pathogenic T H 2 cell differentiation and provide a mechanistic basis for the therapeutic targeting of TSLP signaling in human allergic diseases.
    Type of Medium: Online Resource
    ISSN: 1945-0877 , 1937-9145
    URL: Article
    DOI: 10.1126/scisignal.aam8858
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2018
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  • 2
    Online Resource
    Online Resource
    The antiprotease SPINK7 serves as an inhibitory checkpoint for esophageal epithelial inflammatory responses
    American Association for the Advancement of Science (AAAS) ; 2018
    In:  Science Translational Medicine Vol. 10, No. 444 ( 2018-06-06)
    Details
    In: Science Translational Medicine, American Association for the Advancement of Science (AAAS), Vol. 10, No. 444 ( 2018-06-06)
    Abstract: Loss of barrier integrity has an important role in eliciting type 2 immune responses, yet the molecular events that initiate and connect this with allergic inflammation remain unclear. We reveal an endogenous, homeostatic mechanism that controls barrier function and inflammatory responses in esophageal allergic inflammation. We show that a serine protease inhibitor, SPINK7 (serine peptidase inhibitor, kazal type 7), is part of the differentiation program of human esophageal epithelium and that SPINK7 depletion occurs in a human allergic, esophageal condition termed eosinophilic esophagitis. Experimental manipulation strategies reducing SPINK7 in an esophageal epithelial progenitor cell line and primary esophageal epithelial cells were sufficient to induce barrier dysfunction and transcriptional changes characterized by loss of cellular differentiation and altered gene expression known to stimulate allergic responses (for example, FLG and SPINK5 ). Epithelial silencing of SPINK7 promoted production of proinflammatory cytokines including thymic stromal lymphopoietin (TSLP). Loss of SPINK7 increased the activity of urokinase plasminogen-type activator (uPA), which in turn had the capacity to promote uPA receptor–dependent eosinophil activation. Treatment of epithelial cells with the broad-spectrum antiserine protease, α1 antitrypsin, reversed the pathologic features associated with SPINK7 silencing. The relevance of this pathway in vivo was supported by finding genetic epistasis between variants in TSLP and the uPA-encoding gene, PLAU . We propose that the endogenous balance between SPINK7 and its target proteases is a key checkpoint in regulating mucosal differentiation, barrier function, and inflammatory responses and that protein replacement with antiproteases may be therapeutic for select allergic diseases.
    Type of Medium: Online Resource
    ISSN: 1946-6234 , 1946-6242
    URL: Article
    DOI: 10.1126/scitranslmed.aap9736
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2018
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