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.

Production of Ins(1,3,4,5)P4 mediated by the kinase Itpkb inhibits store-operated calcium channels and regulates B cell selection and activation

Nature Immunology volume 8, pages 514–521 (2007)Cite this article

A Corrigendum to this article was published on 01 July 2007

This article has been updated

Abstract

Antigen receptor–mediated production of inositol-1,4,5-trisphosphate (Ins(1,4,5)P3) in lymphocytes triggers the release of Ca2+ from intracellular stores; this release of Ca2+ results in the opening of store-operated Ca2+ channels in the plasma membrane. Here we report that mice lacking Ins(1,4,5)P3 3-kinase B (Itpkb), which converts Ins(1,4,5)P3 to inositol-1,3,4,5-tetrakisphosphate (Ins(1,3,4,5)P4), had impaired B lymphocyte development and defective immunoglobulin G3 antibody responses to a T lymphocyte–independent antigen. Itpkb-deficient B lymphocytes had the phenotypic and functional features of tolerant B lymphocytes and showed enhanced activity of store-operated Ca2+ channels after B lymphocyte receptor stimulation, which was reversed by the provision of exogenous Ins(1,3,4,5)P4. Our data identify Itpkb and its product Ins(1,3,4,5)P4 as inhibitors of store-operated Ca2+ channels and crucial regulators of B cell selection and activation.

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

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

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

Figure 1: Development of Itpkb−/− B lymphocytes.
Figure 2: B lymphocyte–autonomous defects in Itpkb−/− mice.
Figure 3: Itpkb−/− B lymphocytes show diminished BCR-mediated proliferation and activation.
Figure 4: Impaired T cell–independent antibody responses to TNP-Ficoll immunization in Itpkb−/− mice.
Figure 5: Normal activation of BCR signaling pathways but enhanced Ca2+ influx in Itpkb−/− B lymphocytes.
Figure 6: Ins(1,3,4,5)P4 inhibits the entry of SOC in B lymphocytes.

Change history

  • 24 May 2007

    In the version of this article initially published, two labels in the key to Figure 6c are reversed. The blue line is “Ins(1,3,4,5)P4 (300 μM)” and the green line is “Ins(1,4,5,6)P4 (300 μM).” The error has been corrected in the HTML and PDF versions of the article.

References

  1. Pillai, S., Cariappa, A. & Moran, S.T. Positive selection and lineage commitment during peripheral B-lymphocyte development. Immunol. Rev. 197, 206–218 (2004).

    Article  CAS  Google Scholar 

  2. Srivastava, B., Lindsley, R.C., Nikbakht, N. & Allman, D. Models for peripheral B lymphocyte development and homeostasis. Semin. Immunol. 17, 175–182 (2005).

    Article  CAS  Google Scholar 

  3. Rolink, A.G., Andersson, J. & Melchers, F. Molecular mechanisms guiding late stages of B-lymphocyte development. Immunol. Rev. 197, 41–50 (2004).

    Article  CAS  Google Scholar 

  4. Cariappa, A. & Pillai, S. Antigen-dependent B-lymphocyte development. Curr. Opin. Immunol. 14, 241–249 (2002).

    Article  CAS  Google Scholar 

  5. Miosge, L.A. & Goodnow, C.C. Genes, pathways and checkpoints in lymphocyte development and homeostasis. Immunol. Cell Biol. 83, 318–335 (2005).

    Article  CAS  Google Scholar 

  6. Harnett, M.M., Katz, E. & Ford, C.A. Differential signalling during B-lymphocyte maturation. Immunol. Lett. 98, 33–44 (2005).

    Article  CAS  Google Scholar 

  7. Cornall, R.J. et al. Polygenic autoimmune traits: Lyn, CD22, and SHP-1 are limiting elements of a biochemical pathway regulating BCR signaling and selection. Immunity 8, 497–508 (1998).

    Article  CAS  Google Scholar 

  8. Gallo, E.M., Cante-Barrett, K. & Crabtree, G.R. Lymphocyte calcium signaling from membrane to nucleus. Nat. Immunol. 7, 25–32 (2006).

    Article  CAS  Google Scholar 

  9. Parekh, A.B. & Putney, J.W., Jr . Store-operated calcium channels. Physiol. Rev. 85, 757–810 (2005).

    Article  CAS  Google Scholar 

  10. Irvine, R.F. & Schell, M.J. Back in the water: the return of the inositol phosphates. Nat. Rev. Mol. Lymphocyte Biol. 2, 327–338 (2001).

    Article  CAS  Google Scholar 

  11. Xia, H.J. & Yang, G. Inositol 1,4,5-trisphosphate 3-kinases: functions and regulations. Lymphocyte Res 15, 83–91 (2005).

    CAS  Google Scholar 

  12. Hermosura, M.C. et al. InsP4 facilitates store-operated calcium influx by inhibition of InsP3 5-phosphatase. Nature 408, 735–740 (2000).

    Article  CAS  Google Scholar 

  13. Wen, B.G. et al. Inositol (1,4,5) trisphosphate 3 kinase B controls positive selection of T lymphocytes and modulates Erk activity. Proc. Natl. Acad. Sci. USA 101, 5604–5609 (2004).

    Article  CAS  Google Scholar 

  14. Pouillon, V. et al. Inositol 1,3,4,5-tetrakisphosphate is essential for T lymphocyte development. Nat. Immunol. 4, 1136–1143 (2003).

    Article  CAS  Google Scholar 

  15. Culton, D.A. et al. Early preplasma lymphocytes define a tolerance checkpoint for autoreactive B lymphocytes. J. Immunol. 176, 790–802 (2006).

    Article  CAS  Google Scholar 

  16. Martin, F. & Kearney, J.F. B1 lymphocytes: similarities and differences with other B lymphocyte subsets. Curr. Opin. Immunol. 13, 195–201 (2001).

    Article  CAS  Google Scholar 

  17. Thurnheer, M.C., Zuercher, A.W., Cebra, J.J. & Bos, N.A. B1 lymphocytes contribute to serum IgM, but not to intestinal IgA, production in gnotobiotic Ig allotype chimeric mice. J. Immunol. 170, 4564–4571 (2003).

    Article  CAS  Google Scholar 

  18. Mongini, P.K., Stein, K.E. & Paul, W.E. T lymphocyte regulation of IgG subclass antibody production in response to T-independent antigens. J. Exp. Med. 153, 1–12 (1981).

    Article  CAS  Google Scholar 

  19. Guinamard, R., Okigaki, M., Schlessinger, J. & Ravetch, J.V. Absence of marginal zone B lymphocytes in Pyk-2-deficient mice defines their role in the humoral response. Nat. Immunol. 1, 31–36 (2000).

    Article  CAS  Google Scholar 

  20. Lane, P.J., Gray, D., Oldfield, S. & MacLennan, I.C. Differences in the recruitment of virgin B lymphocytes into antibody responses to thymus-dependent and thymus-independent type-2 antigens. Eur. J. Immunol. 16, 1569–1575 (1986).

    Article  CAS  Google Scholar 

  21. Martin, F., Oliver, A.M. & Kearney, J.F. Marginal zone and B1 B lymphocytes unite in the early response against T-independent blood-borne particulate antigens. Immunity 14, 617–629 (2001).

    Article  CAS  Google Scholar 

  22. Wilcox, R.A., Challiss, R.A., Liu, C., Potter, B.V. & Nahorski, S.R. Inositol-1,3,4,5-tetrakisphosphate induces calcium mobilization via the inositol-1,4,5-trisphosphate receptor in SH-SY5Y neuroblastoma lymphocytes. Mol. Pharmacol. 44, 810–817 (1993).

    CAS  PubMed  Google Scholar 

  23. Bird, G.S. & Putney, J.W., Jr . Effect of inositol 1,3,4,5-tetrakisphosphate on inositol trisphosphate-activated Ca2+ signaling in mouse lacrimal acinar lymphocytes. J. Biol. Chem. 271, 6766–6770 (1996).

    Article  CAS  Google Scholar 

  24. Chamberlain, P.P. et al. Structural insights into enzyme regulation for inositol 1,4,5-trisphosphate 3-kinase B. Biochemistry 44, 14486–14493 (2005).

    Article  CAS  Google Scholar 

  25. Chen, J. et al. CD22 attenuates calcium signaling by potentiating plasma membrane calcium-ATPase activity. Nat. Immunol. 5, 651–657 (2004).

    Article  CAS  Google Scholar 

  26. Su, T.T., Guo, B., Wei, B., Braun, J. & Rawlings, D.J. Signaling in transitional type 2 B lymphocytes is critical for peripheral B-lymphocyte development. Immunol. Rev. 197, 161–178 (2004).

    Article  CAS  Google Scholar 

  27. Benschop, R.J., Brandl, E., Chan, A.C. & Cambier, J.C. Unique signaling properties of B lymphocyte antigen receptor in mature and immature B lymphocytes: implications for tolerance and activation. J. Immunol. 167, 4172–4179 (2001).

    Article  CAS  Google Scholar 

  28. King, L.B., Norvell, A. & Monroe, J.G. Antigen receptor-induced signal transduction imbalances associated with the negative selection of immature B lymphocytes. J. Immunol. 162, 2655–2662 (1999).

    CAS  PubMed  Google Scholar 

  29. Hardy, R.R. B-1 B lymphocytes: development, selection, natural autoantibody and leukemia. Curr. Opin. Immunol. 18, 547–555 (2006).

    Article  CAS  Google Scholar 

  30. Hayakawa, K. et al. Positive selection of natural autoreactive B lymphocytes. Science 285, 113–116 (1999).

    Article  CAS  Google Scholar 

  31. Goodnow, C.C., Crosbie, J., Jorgensen, H., Brink, R.A. & Basten, A. Induction of self-tolerance in mature peripheral B lymphocytes. Nature 342, 385–391 (1989).

    Article  CAS  Google Scholar 

  32. Goodnow, C.C. et al. Self-tolerance checkpoints in B lymphocyte development. Adv. Immunol. 59, 279–368 (1995).

    Article  CAS  Google Scholar 

  33. Cullen, P.J., Loomis-Husselbee, J., Dawson, A.P. & Irvine, R.F. Inositol 1,3,4,5-tetrakisphosphate and Ca2+ homoeostasis: the role of GAP1IP4BP. Biochem. Soc. Trans. 25, 991–996 (1997).

    Article  CAS  Google Scholar 

  34. Fukuda, M. & Mikoshiba, K. Structure-function relationships of the mouse Gap1m. Determination of the inositol 1,3,4,5-tetrakisphosphate-binding domain. J. Biol. Chem. 271, 18838–18842 (1996).

    Article  CAS  Google Scholar 

  35. Fukuda, M., Kojima, T., Kabayama, H. & Mikoshiba, K. Mutation of the pleckstrin homology domain of Bruton's tyrosine kinase in immunodeficiency impaired inositol 1,3,4,5-tetrakisphosphate binding capacity. J. Biol. Chem. 271, 30303–30306 (1996).

    Article  CAS  Google Scholar 

  36. Kurosaki, T. et al. Regulation of the phospholipase C-γ2 pathway in B lymphocytes. Immunol. Rev. 176, 19–29 (2000).

    Article  CAS  Google Scholar 

  37. Prakriya, M. et al. Orai1 is an essential pore subunit of the CRAC channel. Nature 443, 230–233 (2006).

    Article  CAS  Google Scholar 

  38. Vig, M. et al. CRACM1 is a plasma membrane protein essential for store-operated Ca2+ entry. Science 312, 1220–1223 (2006).

    Article  CAS  Google Scholar 

  39. Soboloff, J. et al. Orai1 and STIM reconstitute store-operated calcium channel function. J. Biol. Chem. 281, 20661–20665 (2006).

    Article  CAS  Google Scholar 

  40. Hardy, R.R. et al. B-lymphocyte commitment, development and selection. Immunol. Rev. 175, 23–32 (2000).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank C. Trussell, D. Li and S. Zaharevitz for technical assistance, and R. Glynne, B. Wen and C. Schemdt for discussions.

Author information

Authors and Affiliations

  1. The Genomics Institute of the Novartis Research Foundation, San Diego, California, 92121, USA

    Andrew T Miller, Mark Sandberg, Yina H Huang, Michael Young, Susan Sutton, Karsten Sauer & Michael P Cooke

Authors
  1. Andrew T Miller
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mark Sandberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yina H Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michael Young
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Susan Sutton
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Karsten Sauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Michael P Cooke
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael P Cooke.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Itpkb protein expression. (PDF 562 kb)

Supplementary Fig. 2

Impaired BCR-induced cell cycle progression in Itpkb−/− B lymphocytes. (PDF 577 kb)

Supplementary Fig. 3

Serum Ig quantities. (PDF 1590 kb)

Supplementary Fig. 4

Reduced BCR-stimulated PLC-γ2 activation in Itpkb−/− B lymphocytes. (PDF 560 kb)

Supplementary Fig. 5

Elevated Ca2+ entry in immature and mature in Itpkb−/− B lymphocytes. (PDF 2157 kb)

Supplementary Fig. 6

IP4 inhibits SOC channel activity but does not alter membrane potential. (PDF 557 kb)

Supplementary Fig. 7

Itpkb regulates calcium homeostasis and B lymphocyte fate selection. (PDF 1538 kb)

Supplementary Table 1

Total number of splenic B cell subsets. (PDF 1392 kb)

Supplementary Methods (PDF 72 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Miller, A., Sandberg, M., Huang, Y. et al. Production of Ins(1,3,4,5)P4 mediated by the kinase Itpkb inhibits store-operated calcium channels and regulates B cell selection and activation. Nat Immunol 8, 514–521 (2007). https://doi.org/10.1038/ni1458

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni1458

This article is cited by

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