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

445 Citations (Scopus)

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

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T-Cell Antigen Receptor
T-Lymphocytes
Proto-Oncogene Proteins c-vav
Mutation
Autoimmune Experimental Encephalomyelitis
Type C Phospholipases
Mitogens
Protein-Tyrosine Kinases
Autoimmune Diseases
Multiple Sclerosis
Antibody Formation
Interleukin-2
Phosphotransferases

ASJC Scopus subject areas

  • General

Cite this

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

Cbl-b regulates the CD28 dependence of T-cell activation. / Chiang, Yungping J.; Kole, Hemanta K.; Brown, Karen; Naramura, Mayumi; Fukuhara, Shigetomo; Hu, Ren Ju; Jang, Ihn Kyung; Gutkind, J. Silvio; Shevach, Ethan; Gu, Hua.

In: Nature, Vol. 403, No. 6766, 13.01.2000, p. 216-220.

Research output: Contribution to journalArticle

Chiang, YJ, Kole, HK, Brown, K, Naramura, M, Fukuhara, S, Hu, RJ, Jang, IK, Gutkind, JS, Shevach, E & Gu, H 2000, 'Cbl-b regulates the CD28 dependence of T-cell activation', Nature, vol. 403, no. 6766, pp. 216-220. https://doi.org/10.1038/35003235
Chiang YJ, Kole HK, Brown K, Naramura M, Fukuhara S, Hu RJ et al. Cbl-b regulates the CD28 dependence of T-cell activation. Nature. 2000 Jan 13;403(6766):216-220. https://doi.org/10.1038/35003235
Chiang, Yungping J. ; Kole, Hemanta K. ; Brown, Karen ; Naramura, Mayumi ; Fukuhara, Shigetomo ; Hu, Ren Ju ; Jang, Ihn Kyung ; Gutkind, J. Silvio ; Shevach, Ethan ; Gu, Hua. / Cbl-b regulates the CD28 dependence of T-cell activation. In: Nature. 2000 ; Vol. 403, No. 6766. pp. 216-220.
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