Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b
- 1 January 2000
- journal article
- letter
- Published by Springer Science and Business Media LLC in Nature
- Vol. 403 (6766), 211-216
- https://doi.org/10.1038/35003228
Abstract
The signalling thresholds of antigen receptors and co-stimulatory receptors determine immunity or tolerance to self molecules1. Changes in co-stimulatory pathways can lead to enhanced activation of lymphocytes and autoimmunity, or the induction of clonal anergy2. 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 receptors3,4,5. 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-γ or tumour necrosis factor-α. 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.Keywords
This publication has 23 references indexed in Scilit:
- Tyrosine phosphorylation and complex formation of Cbl-b upon T cell receptor stimulationOncogene, 1999
- Dendritic Cells Induce Autoimmune Diabetes and Maintain Disease via De Novo Formation of Local Lymphoid TissueThe Journal of Experimental Medicine, 1998
- Vav is a regulator of cytoskeletal reorganization mediated by the T-cell receptorCurrent Biology, 1998
- POSITIVE VERSUS NEGATIVE SIGNALING BY LYMPHOCYTE ANTIGEN RECEPTORSAnnual Review of Immunology, 1998
- Chronic inflammation caused by lymphotoxin is lymphoid neogenesis.The Journal of Experimental Medicine, 1996
- The protein product of the c-cbl protooncogene is phosphorylated after B cell receptor stimulation and binds the SH3 domain of Bruton's tyrosine kinase.The Journal of Experimental Medicine, 1995
- Differential T Cell Costimulatory Requirements in CD28-Deficient MiceScience, 1993
- CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clonesNature, 1992
- B lymphocytes express and lose syndecan at specific stages of differentiation.Cell Regulation, 1989
- Thymic major histocompatibility complex antigens and the αβ T-cell receptor determine the CD4/CD8 phenotype of T cellsNature, 1988