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

Nature | Jan 13, 2000

http://www.ncbi.nlm.nih.gov/pubmed/10646609

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 RIS Download

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