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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
6766
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pubmed:dateCreated |
2000-2-10
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pubmed:abstractText |
The signalling thresholds of antigen receptors and co-stimulatory receptors determine immunity or tolerance to self molecules. Changes in co-stimulatory pathways can lead to enhanced activation of lymphocytes and autoimmunity, or the induction of clonal anergy. The molecular mechanisms that maintain immunotolerance in vivo and integrate co-stimulatory signals with antigen receptor signals in T and B lymphocytes are poorly understood. Members of the Cbl/Sli family of molecular adaptors function downstream from growth factor and antigen receptors. Here we show that gene-targeted mice lacking the adaptor Cbl-b develop spontaneous autoimmunity characterized by auto-antibody production, infiltration of activated T and B lymphocytes into multiple organs, and parenchymal damage. Resting cbl-b(-/-) lymphocytes hyperproliferate upon antigen receptor stimulation, and cbl-b(-/-) T cells display specific hyperproduction of the T-cell growth factor interleukin-2, but not interferon-gamma or tumour necrosis factor-alpha. Mutation of Cbl-b uncouples T-cell proliferation, interleukin-2 production and phosphorylation of the GDP/GTP exchange factor Vav1 from the requirement for CD28 co-stimulation. Cbl-b is thus a key regulator of activation thresholds in mature lymphocytes and immunological tolerance and autoimmunity.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Adaptor Proteins, Signal Transducing,
http://linkedlifedata.com/resource/pubmed/chemical/Antigens, CD,
http://linkedlifedata.com/resource/pubmed/chemical/Autoantibodies,
http://linkedlifedata.com/resource/pubmed/chemical/Carrier Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphoproteins,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-cbl,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Antigen, T-Cell,
http://linkedlifedata.com/resource/pubmed/chemical/Tyrosine,
http://linkedlifedata.com/resource/pubmed/chemical/Ubiquitin-Protein Ligases
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pubmed:status |
MEDLINE
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pubmed:month |
Jan
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pubmed:issn |
0028-0836
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pubmed:author |
pubmed-author:BachmaierKK,
pubmed-author:BouchardDD,
pubmed-author:DAYG HGH,
pubmed-author:ItieAA,
pubmed-author:KongY YYY,
pubmed-author:KozieradzkiII,
pubmed-author:KrawczykCC,
pubmed-author:LipkowitzSS,
pubmed-author:MariathasanSS,
pubmed-author:NishineTT,
pubmed-author:OhashiP SPS,
pubmed-author:Oliveira-dos-SantosAA,
pubmed-author:PenningerJ MJM,
pubmed-author:SarosiII,
pubmed-author:SasakiTT,
pubmed-author:WakehamAA
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pubmed:issnType |
Print
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pubmed:day |
13
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pubmed:volume |
403
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
211-6
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pubmed:dateRevised |
2006-11-15
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pubmed:meshHeading |
pubmed-meshheading:10646608-Adaptor Proteins, Signal Transducing,
pubmed-meshheading:10646608-Animals,
pubmed-meshheading:10646608-Antigens, CD,
pubmed-meshheading:10646608-Autoantibodies,
pubmed-meshheading:10646608-Autoimmunity,
pubmed-meshheading:10646608-B-Lymphocytes,
pubmed-meshheading:10646608-Carrier Proteins,
pubmed-meshheading:10646608-Female,
pubmed-meshheading:10646608-Gene Targeting,
pubmed-meshheading:10646608-Lymph Nodes,
pubmed-meshheading:10646608-Lymphocyte Activation,
pubmed-meshheading:10646608-Male,
pubmed-meshheading:10646608-Mice,
pubmed-meshheading:10646608-Mice, Inbred C57BL,
pubmed-meshheading:10646608-Phosphoproteins,
pubmed-meshheading:10646608-Phosphorylation,
pubmed-meshheading:10646608-Proto-Oncogene Proteins c-cbl,
pubmed-meshheading:10646608-Receptors, Antigen, T-Cell,
pubmed-meshheading:10646608-Self Tolerance,
pubmed-meshheading:10646608-Spleen,
pubmed-meshheading:10646608-T-Lymphocytes,
pubmed-meshheading:10646608-Tyrosine,
pubmed-meshheading:10646608-Ubiquitin-Protein Ligases
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pubmed:year |
2000
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pubmed:articleTitle |
Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b.
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pubmed:affiliation |
Amgen Institute, Department of Medical Biophysics, University of Toronto, Ontario, Canada.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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