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Cbl-b regulates the CD28 dependence of T-cell activation.

Whereas co-stimulation of the T-cell antigen receptor (TCR) and CD28 triggers T-cell activation, stimulation of the TCR alone may result in an anergic state or T-cell deletion, both possible mechanisms of tolerance induction. Here we show that T cells that are deficient in the adaptor molecule Cbl-b (ref. 3) do not require CD28 engagement for interleukin-2 production, and that the Cbl-b-null mutation (Cbl-b(-/-)) fully restores T-cell-dependent antibody responses in CD28-/- mice. The main TCR signalling pathways, such as tyrosine kinases Zap-70 and Lck, Ras/mitogen-activated kinases, phospholipase Cgamma-1 and Ca2+ mobilization, were not affected in Cbl-b(-/-) T cells. In contrast, the activation of Vav, a guanine nucleotide exchange factor for Rac1/Rho/CDC42, was significantly enhanced. Our findings indicate that Cbl-b may influence the CD28 dependence of T-cell activation by selectively suppressing TCR-mediated Vav activation. Mice deficient in Cbl-b are highly susceptible to experimental autoimmune encephalomyelitis, suggesting that the dysregulation of signalling pathways modulated by Cbl-b may also contribute to human autoimmune diseases such as multiple sclerosis.

Pubmed ID: 10646609


  • Chiang YJ
  • Kole HK
  • Brown K
  • Naramura M
  • Fukuhara S
  • Hu RJ
  • Jang IK
  • Gutkind JS
  • Shevach E
  • Gu H



Publication Data

January 13, 2000

Associated Grants


Mesh Terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Antigens, CD28
  • Autoimmunity
  • Carrier Proteins
  • Cell Cycle Proteins
  • Cell Line
  • Gene Targeting
  • Guanine Nucleotide Exchange Factors
  • Immune Tolerance
  • Interleukin-2
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred C57BL
  • Phosphoproteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-cbl
  • Proto-Oncogene Proteins c-vav
  • Receptors, Antigen, T-Cell
  • Signal Transduction
  • T-Lymphocytes
  • Ubiquitin-Protein Ligases