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Transcription factor Mef2c is required for B cell proliferation and survival after antigen receptor stimulation

Nature Immunology volume 9, pages 603–612 (2008)Cite this article

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Abstract

Calcineurin is required for B cell receptor (BCR)–induced proliferation of mature B cells. Paradoxically, loss of NFAT transcription factors, themselves calcineurin targets, induces hyperactivity, which suggests that calcineurin targets other than NFAT are required for BCR-induced proliferation. Here we demonstrate a function for the calcineurin-regulated transcription factor Mef2c in B cells. BCR-induced calcium mobilization was intact after Mef2c deletion, but loss of Mef2c caused defects in B cell proliferation and survival after BCR stimulation in vitro and lower T cell–dependent antibody responses and germinal center formation in vivo. Mef2c activity was specific to BCR stimulation, as Toll-like receptor and CD40 signaling induced normal responses in Mef2c-deficient B cells. Mef2c-dependent targets included the genes encoding cyclin D2 and the prosurvival factor Bcl-xL. Our results emphasize an unrecognized but critical function for Mef2c in BCR signaling.

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Figure 1: Mef2c has high expression in mature B cells and is efficiently deleted in splenic B cells of Mef2c-cKO mice.
Figure 2: B cell development in Mef2c-cKO mice.
Figure 3: Mef2c is required for B cell proliferation and survival in response to BCR stimulation.
Figure 4: Costimulation can restore the survival and proliferation of BCR-stimulated Mef2c-cKO B cells.
Figure 5: Mef2c-cKO mice have altered basal immunoglobulin titers and mount enhanced antibody responses to a T cell–independent antigen.
Figure 6: Mef2c-cKO mice have deficient responses to T cell–dependent antigens.
Figure 7: Early BCR-mediated signaling events in Mef2c-cKO B cells.
Figure 8: BCR-stimulated Mef2c-cKO B cells fail to induce Bcl-xL and cyclin D2.

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  • 08 May 2008

    In the version of this article initially published online, Figure 7c is incorrect. The error has been corrected for all versions of the article.

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Acknowledgements

Supported by the Howard Hughes Medical Institute (K.M.M.) and the National Institutes of Health (5P01AI031238 and 5T32HL007317).

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Authors and Affiliations

  1. Department of Pathology and Center for Immunology, Washington University School of Medicine, St. Louis, 63110, Missouri, USA

    Peter R Wilker, Masako Kohyama, Michelle M Sandau, Jörn C Albring & Kenneth M Murphy

  2. Department of Molecular Biology and Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, 75390, Texas, USA

    Osamu Nakagawa

  3. Center for Cardiovascular Sciences, Albany Medical Center, Albany, 12208, New York, USA

    John J Schwarz

  4. Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, 63110, Missouri, USA

    Kenneth M Murphy

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  1. Peter R Wilker
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Contributions

P.R.W. designed experiments, did research, analyzed and interpreted results, and wrote the manuscript; M.K. did immunohistochemistry; M.M.S. sorted B cell subsets and did Mef2c expression analysis; J.C.A. contributed gene expression microarray data for some mouse tissues; O.N. provided spleens from Srpk3-deficient mice; J.J.S. provided mice with a loxP-flanked Mef2c allele; and K.M.M. directed the study and wrote the manuscript.

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Correspondence to Kenneth M Murphy.

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Wilker, P., Kohyama, M., Sandau, M. et al. Transcription factor Mef2c is required for B cell proliferation and survival after antigen receptor stimulation. Nat Immunol 9, 603–612 (2008). https://doi.org/10.1038/ni.1609

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