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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.

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Acknowledgements

We thank M. Saunders for scientific editing, and T.W. Mak, J. Sasaki, N. Joza, M. Crackover, E. Griffith, M. Cheng, Q. Liu and P. Liu for comments. K.B. is supported by grants from the Heart and Stroke Foundation of Canada and by Amgen. J.M.P is supported by the Medical Research Council (MRC) and the National Cancer Institute (NCI) of Canada.

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Affiliations

  1. *Amgen Institute, Ontario Cancer Institute, Departments of Medical Biophysics and Immunology, University of Toronto, Toronto, Ontario M5G 2C1, Canada

    • Kurt Bachmaier
    • , Connie Krawczyk
    • , Ivona Kozieradzki
    • , Young-Yun Kong
    • , Takehiko Sasaki
    • , Antonio Oliveira-dos-Santos
    • , Dennis Bouchard
    • , Andrew Wakeham
    • , Annick Itie
    • , Jenny Le
    • , Hiroshi Nishina
    •  & Josef M. Penninger
  2. †Ontario Cancer Institute, Departments of Medical Biophysics and Immunology, University of Toronto, Toronto , Ontario M5G 2M9, Canada

    • Sanjeev Mariathasan
    •  & Pamela S. Ohashi
  3. ‡Department of Pathology, Amgen Inc. , Thousand Oaks, California 91320-1789, USA

    • Ildiko Sarosi
  4. §Genetics Department, Medicine Branch, National Cancer Institute, Bethesda Naval Hospital, Bethesda, Maryland 20889-5101, USA

    • Stan Lipkowitz

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https://doi.org/10.1038/35003228

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