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

被引:497
作者
Chiang, YPJ
Kole, HK
Brown, K
Naramura, M
Fukuhara, S
Hu, RJ
Jang, IK
Gutkind, JS
Shevach, E
Gu, H
机构
[1] NIAID, Immunol Lab, NIH, Rockville, MD 20852 USA
[2] NIH, Bethesda, MD 20892 USA
[3] NIDCR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA
关键词
D O I
10.1038/35003235
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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(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-dependent antibody responses in CD28(-/-) mice. The main TCR signalling pathways, 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 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.
引用
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页码:216 / 220
页数:5
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