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Regulation of B-cell survival by BAFF-dependent PKCδ-mediated nuclear signalling

Abstract

Approximately 65% of B cells generated in human bone marrow are potentially harmful autoreactive B cells1. Most of these cells are clonally deleted in the bone marrow, while those autoreactive B cells that escape to the periphery are anergized or perish before becoming mature B cells2,3,4,5. Escape of self-reactive B cells from tolerance permits production of pathogenic auto-antibodies6; recent studies suggest that extended B lymphocyte survival is a cause of autoimmune disease in mice and humans7. Here we report a mechanism for the regulation of peripheral B-cell survival by serine/threonine protein kinase Cδ (PKCδ): spontaneous death of resting B cells is regulated by nuclear localization of PKCδ that contributes to phosphorylation of histone H2B at serine 14 (S14-H2B). We show that treatment of B cells with the potent B-cell survival factor BAFF (‘B-cell-activating factor belonging to the TNF family’) prevents nuclear accumulation of PKCδ. Our data suggest the existence of a previously unknown BAFF-induced and PKCδ-mediated nuclear signalling pathway which regulates B-cell survival.

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Figure 1: PKCδ-deficient B cells are independent of BAFF.
Figure 2: PKCδ promotes B-cell survival.
Figure 3: Nuclear expression of PKCδ in ex vivo isolated B cells is negatively regulated by BAFF.
Figure 4: PKCδ contributes to cell-death-related phosphorylation of S14-H2B.

References

  1. Wardemann, H. et al. Predominant autoantibody production by early human B cell precursors. Science 301, 1374–1377 (2003)

    ADS  CAS  Article  Google Scholar 

  2. Goodnow, C. C. et al. Altered immunoglobulin expression and functional silencing of self-reactive B lymphocytes in transgenic mice. Nature 334, 676–682 (1988)

    ADS  CAS  Article  Google Scholar 

  3. Nemazee, D. A. & Burki, K. Clonal deletion of B lymphocytes in a transgenic mouse bearing anti-MHC class I antibody genes. Nature 337, 562–566 (1989)

    ADS  CAS  Article  Google Scholar 

  4. Erikson, J. et al. Expression of anti-DNA immunoglobulin transgenes in non-autoimmune mice. Nature 349, 331–334 (1991)

    ADS  CAS  Article  Google Scholar 

  5. Hartley, S. B. et al. Elimination from peripheral lymphoid tissues of self-reactive B lymphocytes recognizing membrane-bound antigens. Nature 353, 765–769 (1991)

    ADS  CAS  Article  Google Scholar 

  6. Goodnow, C. C. Balancing immunity and tolerance: deleting and tuning lymphocyte repertoires. Proc. Natl Acad. Sci. USA 93, 2264–2271 (1996)

    ADS  CAS  Article  Google Scholar 

  7. Mackay, F. & Kalled, S. L. TNF ligands and receptors in autoimmunity: an update. Curr. Opin. Immunol. 14, 783–790 (2002)

    CAS  Article  Google Scholar 

  8. Mackay, F. et al. Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations. J. Exp. Med. 190, 1697–1710 (1999)

    CAS  Article  Google Scholar 

  9. Gross, J. A. et al. TACI and BCMA are receptors for a TNF homologue implicated in B-cell autoimmune disease. Nature 404, 995–999 (2000)

    ADS  CAS  Article  Google Scholar 

  10. Khare, S. D. et al. Severe B cell hyperplasia and autoimmune disease in TALL-1 transgenic mice. Proc. Natl Acad. Sci. USA 97, 3370–3375 (2000)

    ADS  CAS  Article  Google Scholar 

  11. Mecklenbräuker, I., Saijo, K., Zheng, N. Y., Leitges, M. & Tarakhovsky, A. Protein kinase Cδ controls self-antigen-induced B-cell tolerance. Nature 416, 860–865 (2002)

    ADS  Article  Google Scholar 

  12. Pelletier, M. et al. Comparison of soluble decoy IgG fusion proteins of BAFF-R and BCMA as antagonists for BAFF. J. Biol. Chem. 278, 33127–33133 (2003)

    CAS  Article  Google Scholar 

  13. Thompson, J. S. et al. BAFF-R, a newly identified TNF receptor that specifically interacts with BAFF. Science 293, 2108–2111 (2001)

    ADS  CAS  Article  Google Scholar 

  14. Yan, M. et al. Identification of a novel receptor for B lymphocyte stimulator that is mutated in a mouse strain with severe B cell deficiency. Curr. Biol. 11, 1547–1552 (2001)

    CAS  Article  Google Scholar 

  15. Khan, W. N. et al. Defective B cell development and function in Btk-deficient mice. Immunity 3, 283–299 (1995)

    CAS  Article  Google Scholar 

  16. Woodland, R. T., Schmidt, M. R., Korsmeyer, S. J. & Gravel, K. A. Regulation of B cell survival in xid mice by the proto-oncogene bcl-2. J. Immunol. 156, 2143–2154 (1996)

    CAS  PubMed  Google Scholar 

  17. Claudio, E., Brown, K., Park, S., Wang, H. & Siebenlist, U. BAFF-induced NEMO-independent processing of NF-κB2 in maturing B cells. Nature Immunol. 3, 958–965 (2002)

    CAS  Article  Google Scholar 

  18. Kayagaki, N. et al. BAFF/BLyS receptor 3 binds the B cell survival factor BAFF ligand through a discrete surface loop and promotes processing of NF-κB2. Immunity 17, 515–524 (2002)

    CAS  Article  Google Scholar 

  19. Mischak, H. et al. Overexpression of protein kinase C-δ and -ɛ in NIH3T3 cells induces opposite effects on growth, morphology, anchorage dependence, and tumorigenicity. J. Biol. Chem. 268, 6090–6096 (1993)

    CAS  PubMed  Google Scholar 

  20. Emoto, Y. et al. Proteolytic activation of protein kinase C δ by an ICE-like protease in apoptotic cells. EMBO J. 14, 6148–6156 (1995)

    CAS  Article  Google Scholar 

  21. Ghayur, T. et al. Proteolytic activation of protein kinase C δ by an ICE/CED 3-like protease induces characteristics of apoptosis. J. Exp. Med. 184, 2399–2404 (1996)

    CAS  Article  Google Scholar 

  22. DeVries, T. A., Neville, M. C. & Reyland, M. E. Nuclear import of PKCδ is required for apoptosis: identification of a novel nuclear import sequence. EMBO J. 21, 6050–6060 (2002)

    CAS  Article  Google Scholar 

  23. Reyland, M. E., Anderson, S. M., Matassa, A. A., Barzen, K. A. & Quissell, D. O. Protein kinase C δ is essential for etoposide-induced apoptosis in salivary gland acinar cells. J. Biol. Chem. 274, 19115–19123 (1999)

    CAS  Article  Google Scholar 

  24. Ajiro, K. Histone H2B phosphorylation in mammalian apoptotic cells. An association with DNA fragmentation. J. Biol. Chem. 275, 439–443 (2000)

    CAS  Article  Google Scholar 

  25. Cheung, W. L. et al. Apoptotic phosphorylation of histone H2B is mediated by mammalian sterile twenty kinase. Cell 113, 507–517 (2003)

    CAS  Article  Google Scholar 

  26. Fernandez-Capetillo, O., Allis, C. D. & Nussenzweig, A. Phosphorylation of histone H2B at DNA double-strand breaks. J. Exp. Med. 199, 1671–1677 (2004)

    CAS  Article  Google Scholar 

  27. Su, I. H. et al. Ezh2 controls B cell development through histone H3 methylation and Igh rearrangement. Nature Immunol. 4, 124–131 (2003)

    CAS  Article  Google Scholar 

  28. Van Parijs, L. et al. Uncoupling IL-2 signals that regulate T cell proliferation, survival, and Fas-mediated activation-induced cell death. Immunity 11, 281–288 (1999)

    CAS  Article  Google Scholar 

  29. Karpusas, M. et al. Crystal structure of extracellular human BAFF, a TNF family member that stimulates B lymphocytes. J. Mol. Biol. 315, 1145–1154 (2002)

    CAS  Article  Google Scholar 

  30. Saijo, K. et al. Protein kinase Cβ controls nuclear factor κB activation in B cells through selective regulation of the IκB kinase α. J. Exp. Med. 195, 1647–1652 (2002)

    CAS  Article  Google Scholar 

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Acknowledgements

We thank S. H. Ahn, D. Allis, M. Reyland, U. Siebenlist, the Rockefeller University Genotyping Resource Center and the MSKCC Genomics Core Laboratory for providing cells, vectors, reagents and technical assistance. We also thank E. Besmer for help with manuscript preparation, and A. Patke and members of the Tarakhovsky laboratory for discussions. This work was supported by The Irene Diamond Fund/Professorship Program (A.T.), the NIH (A.T.) and The S.L.E. Foundation (I.M.).

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Correspondence to Alexander Tarakhovsky.

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Supplementary information

Supplementary Methods (DOC 37 kb)

Supplementary Figure legends (DOC 28 kb)

Supplementary Figure 1

PKCδ does not control the expression of BAFF and its receptor. (PDF 18 kb)

Supplementary Figure 2

PKCδ does neither control the expression of IL-6 mRNA, secretion of IL-6 nor IL-6-dependent survival of peripheral B cells. (PDF 23 kb)

Supplementary Figure 3

3PKCδ does not control the expression of mRNAs encoding anti- or pro-apoptotic proteins in peripheral B cells and PKCd-deficient cells remain sensitive to BAFF. (PDF 112 kb)

Supplementary Table 1

Mouse microsatellite polymorphic sites used for genotyping of PKCδ-/- mice on C57BL/6 genetic background. (DOC 108 kb)

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Mecklenbräuker, I., Kalled, S., Leitges, M. et al. Regulation of B-cell survival by BAFF-dependent PKCδ-mediated nuclear signalling. Nature 431, 456–461 (2004). https://doi.org/10.1038/nature02955

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