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

Yungping J. Chiang, Hemanta K. Kole, Karen Brown, Mayumi Naramura, Shigetomo Fukuhara, Ren Ju Hu, Ihn Kyung Jang, J. Silvio Gutkind, Ethan Shevach, Hua Gu

Research output: Contribution to journalArticle

452 Scopus citations

Abstract

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 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/CDCA2, 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.

Original languageEnglish (US)
Pages (from-to)216-220
Number of pages5
JournalNature
Volume403
Issue number6766
DOIs
StatePublished - Jan 13 2000

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Cbl-b regulates the CD28 dependence of T-cell activation'. Together they form a unique fingerprint.

  • Cite this

    Chiang, Y. J., Kole, H. K., Brown, K., Naramura, M., Fukuhara, S., Hu, R. J., Jang, I. K., Gutkind, J. S., Shevach, E., & Gu, H. (2000). Cbl-b regulates the CD28 dependence of T-cell activation. Nature, 403(6766), 216-220. https://doi.org/10.1038/35003235