Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b

Kurt Bachmaier, Connie Krawczyk, Ivona Kozieradzki, Young-Yun Kong, Takehiko Sasaki, Antonio Oliveira-dos-Santos, Sanjeev Mariathasan, Dennis Bouchard, Andrew Wakeham, Annick Itie, Jenny Le, Pamela S. Ohashi, Ildiko Sarosi, Hiroshi Nishina, Stan Lipkowitz and Josef M. Penninger ()
Additional contact information
Kurt Bachmaier: Amgen Institute, Ontario Cancer Institute, University of Toronto
Connie Krawczyk: Amgen Institute, Ontario Cancer Institute, University of Toronto
Ivona Kozieradzki: Amgen Institute, Ontario Cancer Institute, University of Toronto
Young-Yun Kong: Amgen Institute, Ontario Cancer Institute, University of Toronto
Takehiko Sasaki: Amgen Institute, Ontario Cancer Institute, University of Toronto
Antonio Oliveira-dos-Santos: Amgen Institute, Ontario Cancer Institute, University of Toronto
Sanjeev Mariathasan: Ontario Cancer Institute, University of Toronto
Dennis Bouchard: Amgen Institute, Ontario Cancer Institute, University of Toronto
Andrew Wakeham: Amgen Institute, Ontario Cancer Institute, University of Toronto
Annick Itie: Amgen Institute, Ontario Cancer Institute, University of Toronto
Jenny Le: Amgen Institute, Ontario Cancer Institute, University of Toronto
Pamela S. Ohashi: Ontario Cancer Institute, University of Toronto
Ildiko Sarosi: Amgen Inc.
Hiroshi Nishina: Amgen Institute, Ontario Cancer Institute, University of Toronto
Stan Lipkowitz: Medicine Branch National Cancer Institute, Bethesda Naval Hospital
Josef M. Penninger: Amgen Institute, Ontario Cancer Institute, University of Toronto

Nature, 2000, vol. 403, issue 6766, 211-216

Abstract: 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.

Date: 2000
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DOI: 10.1038/35003228

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