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

Whereas co-stimulation of the T-cell antigen receptor (TCR) and CD28 trigge rs T-cell activation, stimulation of the TCR alone may result in an anergic state or T-cell deletion, both possible mechanisms of tolerance induction( 1,2), 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 res;tores T-cell-depe ndent antibody responses in CD28(-/-) mice. The main TCR signalling pathway s, such as tyrosine kinases Zap-70 and Lck, Ras/mitogen-activated kinases, phospholipase C gamma-1 and Ca2+ mobilization, were not affected in Cbl-b(- /-) T cells. In contrast, the activation of Vav, a guanine nucleotide excha nge factor for Rac1/Rho/CDC42, was significantly enhanced. Our findings ind icate 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, sugg esting that the dysregulation of signalling pathways modulated by Cbl-b may also contribute to human autoimmune diseases such as multiple sclerosis.