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 and Hua Gu ()
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Yungping J. Chiang: Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Hemanta K. Kole: Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Karen Brown: National Institutes of Health
Mayumi Naramura: Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Shigetomo Fukuhara: Oral and Pharyngeal Cancer Branch, NIDCR, National Institutes of Health
Ren-Ju Hu: Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Ihn Kyung Jang: Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health
J. Silvio Gutkind: Oral and Pharyngeal Cancer Branch, NIDCR, National Institutes of Health
Ethan Shevach: National Institutes of Health
Hua Gu: Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health

Nature, 2000, vol. 403, issue 6766, 216-220

Abstract: 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.

Date: 2000
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DOI: 10.1038/35003235

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