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

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 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.

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Figure 1: Generation of Cbl-b-/- mice by gene targeting.
Figure 2: Comparison of T-cell proliferation and IL-2 secretion between Cbl-b-/- and wild-type T cells.
Figure 3: Biochemical analyses of signal transduction pathways in T cells from wild-type and Cbl-b-/- mice.
Figure 4: Analysis of Vav activation in Cbl-b-/- T cells.

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Acknowledgements

We thank L. X. Zheng, Y. C. Liu and Y. Pewzner-Jung for the reagents, and K. Druey, D. Garboczi, R. N. Germain, W. E. Paul and R. H. Schwartz for critical comments on the manuscript.

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Correspondence to Hua Gu.

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Chiang, Y., Kole, H., Brown, K. et al. Cbl-b regulates the CD28 dependence of T-cell activation. Nature 403, 216–220 (2000). https://doi.org/10.1038/35003235

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