Negative Regulation of Lymphocyte Activation and Autoimmunity by the Molecular Adaptor Cbl-b

Nature. 2000 Jan 13;403(6766):211-6. doi: 10.1038/35003228.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Animals
  • Antigens, CD / biosynthesis
  • Autoantibodies / biosynthesis
  • Autoimmunity / genetics
  • B-Lymphocytes / immunology
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Carrier Proteins / physiology*
  • Female
  • Gene Targeting
  • Lymph Nodes / immunology
  • Lymph Nodes / pathology
  • Lymphocyte Activation*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Phosphoproteins / physiology*
  • Phosphorylation
  • Proto-Oncogene Proteins c-cbl
  • Receptors, Antigen, T-Cell / immunology
  • Self Tolerance
  • Spleen / immunology
  • Spleen / pathology
  • T-Lymphocytes / immunology*
  • Tyrosine / metabolism
  • Ubiquitin-Protein Ligases*

Substances

  • Adaptor Proteins, Signal Transducing
  • Antigens, CD
  • Autoantibodies
  • Carrier Proteins
  • Cblb protein, mouse
  • Phosphoproteins
  • Receptors, Antigen, T-Cell
  • Tyrosine
  • Proto-Oncogene Proteins c-cbl
  • Ubiquitin-Protein Ligases