Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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

Nature volume 403, pages 216–220 (2000)Cite this article

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.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Janeway, C. A. Jr & Bottomly, K. Signals and signs for lymphocyte responses. Cell 76, 275–285 (1994).

    Article  CAS  Google Scholar 

  2. Schwartz, R. H. Models of T-cell anergy: is there a common molecular mechanism? J. Exp. Med. 184, 1–8 (1996).

    Article  CAS  Google Scholar 

  3. Keane, M. M., Revero-Lezcano, O. M., Mitchell, J. A., Robbins, K. C. & Lipkowitz, S. Cloning and characterization of cbl-b: a SH3 binding protein with homology to the c-cbl proto-oncogene. Oncogene 10, 2367–2377 (1995).

    CAS  PubMed  Google Scholar 

  4. Miyake, S. et al. The Cbl proto-oncogene product: from an enigmatic oncogene to center stage of signal transduction. Crit. Rev. Oncol. 8, 189–219 (1997).

    Article  CAS  Google Scholar 

  5. Keane, M. M. et al. Cbl-3: A new mammalian cbl family protein. Oncogene 18, 3365–3375 (1999).

    Article  CAS  Google Scholar 

  6. Ota, Y. & Samelson, L. E. The product of the proto-oncogene c-cbl: a negative regulator of the Syk tyrosine kinase. Science 276, 418–420 (1997).

    Article  CAS  Google Scholar 

  7. Lupher, M. L. Jr, Songyang, Z., Shoelson, S. E., Cantley, L. C. & Band, H. The Cbl phosphotyrosine-binding domain selects a D(N/D)XPY motif and binds to the Tyr(292) negative regulatory phosphorylation site of Zap70. J. Biol. Chem. 272, 33140–33144 (1997).

    Article  CAS  Google Scholar 

  8. Murphy, M. A. et al. Tissue hyperplasia and enhanced T-cell signaling via Zap70 in c-Cbl-deficient mice. Mol. Cell. Biol. 18, 4872–4882 (1998).

    Article  CAS  Google Scholar 

  9. Naramura, M., Kole, H. K., Hu, R. J. & Gu, H. Altered thymic positive selection and intracellular signals in Cbl-deficient mice. Proc. Natl Acad. Sci. USA 95, 15547–15552 (1998).

    Article  ADS  CAS  Google Scholar 

  10. Zhang, Z., Elly, C., Qiu, L., Altman, A. & Liu, Y. C. A direct interaction between the adaptor protein Cbl-b and the kinase Zap-70 induces a positive signal in T cells. Curr. Biol. 9, 203–206 (1999).

    Article  CAS  Google Scholar 

  11. Kisielow, P., Bluthmann, H., Staerz, U. D., Steinmetz, M. & von Boehmer, H. Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4+CD8+ thymocytes. Nature 333, 742–746 (1988).

    Article  ADS  CAS  Google Scholar 

  12. Seder, R. A., Paul, W. E., Davis, M. M. & Fazekas de St Grath, B. The presence of interleukin 4 during in vitro priming determines the lymphokine-producing potential of CD4+ T cells from T cell receptor transgenic mice. J. Exp. Med. 176, 1091–1098 (1992).

    Article  CAS  Google Scholar 

  13. Shahinian, A. et al. Differential T cell costimulatory requirements in CD28-deficient mice. Science 261, 609–612 (1993).

    Article  ADS  CAS  Google Scholar 

  14. Weiss, A. & Littman, D. R. Signal transduction by lymphocyte antigen receptors. Cell 76, 263–274 (1994).

    Article  CAS  Google Scholar 

  15. Viola, A., Schroeder, S., Sakakibara, Y. & Lanzavecchia, A. T lymphocyte costimulation mediated by reorganization of membrane microdomains. Science 283, 680–682 (1999).

    Article  ADS  CAS  Google Scholar 

  16. Cantrell, D. Lymphocyte signaling: a coordinating role for Vav. Curr. Biol. 8, R535–R538 (1998).

    Article  CAS  Google Scholar 

  17. Zamvil, S. S. & Steinman, L. The T lymphocyte in experimental allergic encephalomyelitis. Annu. Rev. Immunol. 8, 579–621 (1990).

    Article  CAS  Google Scholar 

  18. Bachmaier, K. et al. Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b. Nature 403, 211–216 (2000).

    Article  ADS  CAS  Google Scholar 

  19. Fischer K-D. et al. Vav is a regulator of cytoskeletal reorganization mediated by the T-cell receptor. Curr. Biol. 8, 554–562 (1998).

    Article  Google Scholar 

  20. Holsinger, L. J. et al. Defects in actin-cap formation in Vav-deficient mice implicate an actin requirement for lymphocyte signal transduction. Curr. Biol. 8, 563–572 (1998).

    Article  CAS  Google Scholar 

  21. Zhang, A., Alt, F. W., Davidson, L., Orkin, S. H. & Swat, W. Defective signaling through T- and B-cell antigen receptors in lymphoid cells lacking the vav proto-oncogene. Nature 374, 470–473 (1995).

    Article  ADS  CAS  Google Scholar 

  22. Tarakhovsky, A. et al. Defective antigen receptor-mediated proliferation of B and T cells in the absence of Vav. Nature 374, 467–470 (1995).

    Article  ADS  CAS  Google Scholar 

  23. Fischer, K. D. et al. Defective T-cell receptor signalling and positive selection of vav-deficient CD4+CD8+ thymocytes. Nature 374, 474–477 (1995).

    Article  ADS  CAS  Google Scholar 

  24. Wu, J., Motto, D. G., Koretzky, G. A. & Weiss, A. Vav and SLP-76 interact and functionally cooperate in IL-2 gene activation. Immunity 4, 593–602 (1996).

    Article  CAS  Google Scholar 

  25. Segal, B. M., Dwyer, B. K. & Shevach, E. M. An interleukin (IL)-10/IL-12 immunoregulatory circuit controls susceptibility to autoimmune disease. J. Exp. Med. 187, 537–546 (1998).

    Article  CAS  Google Scholar 

  26. Hardt, W. -D., Chen, L. M., Schuebel, K. E., Bustelo, X. R. & Galan, J. E. S. typhimurium encodes an activator of Rho GTPase that induces membrane ruffling and nuclear responses in host cells. Cell 93, 815–826 (1998).

    Article  CAS  Google Scholar 

Download references

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.

Author information

Author notes

  1. Yungping J. Chiang, Hemanta K. Kole, Shigetomo Fukuhara and J. Silvio Gutkind: These authors contributed equally to this work

Authors and Affiliations

  1. Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 12441 Parklawn Drive, Rockville, 20852, Maryland, USA

    Yungping J. Chiang, Hemanta K. Kole, Mayumi Naramura, Ren-Ju Hu, Ihn Kyung Jang & Hua Gu

  2. National Institutes of Health, 9,000 Rockville Pike, Bethesda, 20892, Maryland, USA

    Karen Brown & Ethan Shevach

  3. Oral and Pharyngeal Cancer Branch, NIDCR, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Shigetomo Fukuhara & J. Silvio Gutkind

Authors
  1. Yungping J. Chiang
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Hemanta K. Kole
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Karen Brown
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Mayumi Naramura
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Shigetomo Fukuhara
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Ren-Ju Hu
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Ihn Kyung Jang
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. J. Silvio Gutkind
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Ethan Shevach
    View author publications

    You can also search for this author inPubMed Google Scholar

  10. Hua Gu
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Hua Gu.

Supplementary Information

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/35003235

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing