| Stromal interaction molecules 1 and 2 are key regulators of autoreactive T cell activation in murine autoimmune central nervous system inflammation. | |
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MedLine Citation:
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PMID: 20028655 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Calcium (Ca(2+)) signaling in T lymphocytes is essential for a variety of functions, including the regulation of differentiation, gene transcription, and effector functions. A major Ca(2+) entry pathway in nonexcitable cells, including T cells, is store-operated Ca(2+) entry (SOCE), wherein depletion of intracellular Ca(2+) stores upon receptor stimulation causes subsequent influx of extracellular Ca(2+) across the plasma membrane. Stromal interaction molecule (STIM) 1 is the Ca(2+) sensor in the endoplasmic reticulum, which controls this process, whereas the other STIM isoform, STIM2, coregulates SOCE. Although the contribution of STIM molecules and SOCE to T lymphocyte function is well studied in vitro, their significance for immune processes in vivo has remained largely elusive. In this study, we studied T cell function in mice lacking STIM1 or STIM2 in a model of myelin-oligodendrocyte glycoprotein (MOG(35-55))-induced experimental autoimmune encephalomyelitis (EAE). We found that STIM1 deficiency significantly impaired the generation of neuroantigen-specific T cell responses in vivo with reduced Th1/Th17 responses, resulting in complete protection from EAE. Mice lacking STIM2 developed EAE, but the disease course was ameliorated. This was associated with a reduced clinical peak of disease. Deficiency of STIM2 was associated with an overall reduced proliferative capacity of lymphocytes and a reduction of IFN-gamma/IL-17 production by neuroantigen-specific T cells. Neither STIM1 nor STIM2 deficiency altered the phenotype or function of APCs. These findings reveal a crucial role of STIM-dependent pathways for T cell function and activation under autoimmune inflammatory conditions, establishing them as attractive new molecular therapeutic targets for the treatment of inflammatory and autoimmune disorders. |
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Authors:
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Michael K Schuhmann; David Stegner; Alejandro Berna-Erro; Stefan Bittner; Attila Braun; Christoph Kleinschnitz; Guido Stoll; Heinz Wiendl; Sven G Meuth; Bernhard Nieswandt |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2009-12-18 |
Journal Detail:
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Title: Journal of immunology (Baltimore, Md. : 1950) Volume: 184 ISSN: 1550-6606 ISO Abbreviation: J. Immunol. Publication Date: 2010 Feb |
Date Detail:
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Created Date: 2010-01-21 Completed Date: 2010-03-12 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 2985117R Medline TA: J Immunol Country: United States |
Other Details:
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Languages: eng Pagination: 1536-42 Citation Subset: AIM; IM |
Affiliation:
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Department of Neurology, University of W?rzburg, W?rzburg, Germany. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Calcium Signaling / genetics, immunology Drug Delivery Systems Encephalomyelitis, Autoimmune, Experimental / immunology*, mortality, pathology*, prevention & control Female Glycoproteins / administration & dosage, toxicity Immunity, Innate / genetics Inflammation Mediators / physiology* Lymphocyte Activation / genetics, immunology* Membrane Glycoproteins / deficiency, physiology* Mice Mice, Knockout Mice, Mutant Strains Peptide Fragments / administration & dosage, toxicity Protein Isoforms / deficiency, genetics, physiology T-Lymphocyte Subsets / immunology*, metabolism, pathology |
| Chemical | |
Reg. No./Substance:
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0/Glycoproteins; 0/Inflammation Mediators; 0/Membrane Glycoproteins; 0/Peptide Fragments; 0/Protein Isoforms; 0/Stim1 protein, mouse; 0/Stim2 protein, mouse; 0/myelin oligodendrocyte glycoprotein (35-55) |
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