(original) (raw)

TY - JOUR AU - Chiang, Yungping J. AU - Kole, Hemanta K. AU - Brown, Karen AU - Naramura, Mayumi AU - Fukuhara, Shigetomo AU - Hu, Ren-Ju AU - Jang, Ihn Kyung AU - Gutkind, J. Silvio AU - Shevach, Ethan AU - Gu, Hua PY - 2000 DA - 2000/01/01 TI - Cbl-b regulates the CD28 dependence of T-cell activation JO - Nature SP - 216 EP - 220 VL - 403 IS - 6766 AB - 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 induction1,2. 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 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 Cγ-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. SN - 1476-4687 UR - https://doi.org/10.1038/35003235 DO - 10.1038/35003235 ID - Chiang2000 ER -