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Compensation between Vav-1 and Vav-2 in B cell development and antigen receptor signaling

Nature Immunology volume 2, pages 548–555 (2001)Cite this article

Abstract

Vav-1 and Vav-2 are closely related Dbl-homology GTP exchange factors (GEFs) for Rho GTPases. Mutation of Vav-1 disrupts T cell development and T cell antigen receptor–induced activation, but has comparatively little effect on B cells. We found that combined deletion of both Vav-1 and Vav-2 in mice resulted in a marked reduction in mature B lymphocyte numbers. Vav-1−/−Vav-2−/− B cells were unresponsive to B cell antigen receptor (BCR)-driven proliferation in vitro and to thymus-indepen-dent antigen in vivo. BCR-stimulated intracellular calcium mobilization was greatly impaired in Vav-1−/−Vav-2−/− B cells. These findings establish a role for Vav-2 in BCR calcium signaling and reveal that the Vav family of GEFs is critical to B cell development and function.

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Figure 1: Generation of Vav-2−/− mutant mice.
Figure 2: T lymphocyte differentiation in Vav-mutant mice.
Figure 3: B lymphocyte differentiation in Vav-mutant mice.
Figure 4: Impaired antigen receptor–activated B cell proliferation and humoral responses in Vav-deficient mice.
Figure 5: Vav-2 in BCR signaling and tyrosine phosphorylation in Vav-1−/−Vav-2−/− B cells.
Figure 6: Vav-1−/−Vav-2−/− B cells do not mobilize calcium activated by BCR.

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Acknowledgements

We thank J. Penninger and T. Wirth for critical reading of the manuscript, U. R. Rapp for support and A. Heiter and S. Rotzoll for technical help. We also thank J. Wienands and M. Reth for reagents used in initial studies and W.-D. Jin for help in the early stages of this work, which was initiated when A. C. and M. B. were at the Bristol-Myers Squibb Pharmaceutical Research Institute. Supported by grants from DFG (Fi2-1) and Thyssen Stiftung (to K.-D. F) and SFB465 (to L. N. and K.-D. F.).

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Authors and Affiliations

  1. Abteilung Physiologische Chemie, Universität Ulm, Albert-Einstein-Allee 11, Ulm, D-89069, Germany

    Kerry Tedford, Irute Girkontaite, Gordon Chan, Vadim Sakk & Klaus-Dieter Fischer

  2. Institut für Medizinische Strahlenkunde und Zellforschung (MSZ), Universität Würzburg, Versbacher Strasse 5, Würzburg, D-97078, Germany

    Kerry Tedford & Gordon Chan

  3. Institut für Virologie und Immunobiologie, Universität Würzburg, Versbacher Strasse 7, Würzburg, D-97078, Germany

    Lars Nitschke

  4. Department of Medicine, University of Chicago, Chicago, 60637, IL, USA

    Amanda Charlesworth

  5. M. Barbacid Centro Nacional de Investigaciones Oncologicas Carlos III, Majadahonda, 28220, Madrid, Spain

    Mariano Barbacid

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Correspondence to Klaus-Dieter Fischer.

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Tedford, K., Nitschke, L., Girkontaite, I. et al. Compensation between Vav-1 and Vav-2 in B cell development and antigen receptor signaling. Nat Immunol 2, 548–555 (2001). https://doi.org/10.1038/88756

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