title: Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b.
abstract: 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.
authors.affiliation: Amgen Institute, Department of Medical Biophysics, University of Toronto, Ontario, Canada.
authors.forename: K
authors.initials: K
authors.lastname: Bachmaier
authors.forename: C
authors.initials: C
authors.lastname: Krawczyk
authors.forename: I
authors.initials: I
authors.lastname: Kozieradzki
authors.forename: Y Y
authors.initials: YY
authors.lastname: Kong
authors.forename: T
authors.initials: T
authors.lastname: Sasaki
authors.forename: A
authors.initials: A
authors.lastname: Oliveira-dos-Santos
authors.forename: S
authors.initials: S
authors.lastname: Mariathasan
authors.forename: D
authors.initials: D
authors.lastname: Bouchard
authors.forename: A
authors.initials: A
authors.lastname: Wakeham
authors.forename: A
authors.initials: A
authors.lastname: Itie
authors.forename: J
authors.initials: J
authors.lastname: Le
authors.forename: P S
authors.initials: PS
authors.lastname: Ohashi
authors.forename: I
authors.initials: I
authors.lastname: Sarosi
authors.forename: H
authors.initials: H
authors.lastname: Nishina
authors.forename: S
authors.initials: S
authors.lastname: Lipkowitz
authors.forename: J M
authors.initials: JM
authors.lastname: Penninger
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D001323:Autoantibodies / Q000096:biosynthesis; D015551:Autoimmunity / Q000235:genetics; D001402:B-Lymphocytes / Q000276:immunology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005260:Female; D018390:Gene Targeting; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D050721:Proto-Oncogene Proteins c-cbl; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D017634:Self Tolerance; D013154:Spleen / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology*; D014443:Tyrosine / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D001323:Autoantibodies; D002352:Carrier Proteins; C118387:Cblb protein, mouse; D010750:Phosphoproteins; D011948:Receptors, Antigen, T-Cell; D014443:Tyrosine; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases