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.

  • Article
  • Published:

Inositol 1,3,4,5-tetrakisphosphate is essential for T lymphocyte development

Nature Immunology volume 4, pages 1136–1143 (2003)Cite this article

Abstract

Inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) is phosphorylated by Ins(1,4,5)P3 3-kinase, generating inositol 1,3,4,5-tetrakisphosphate (Ins(1,3,4,5)P4). The physiological function of Ins(1,3,4,5)P4 is still unclear, but it has been reported to be a potential modulator of calcium mobilization. Disruption of the gene encoding the ubiquitously expressed Ins(1,4,5)P3 3-kinase isoform B (Itpkb) in mice caused a severe T cell deficiency due to major alterations in thymocyte responsiveness and selection. However, we were unable to detect substantial defects in Ins(1,4,5)P3 amounts or calcium mobilization in Itpkb−/− thymocytes. These data indicate that Itpkb and Ins(1,3,4,5)P4 define an essential signaling pathway for T cell precursor responsiveness and development.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Targeted disruption of mouse Itpkb.
Figure 2: Characterization of Itpkb-deficient mice.
Figure 3: Impaired T cell development in Itpkb mutant mice.
Figure 4: Production of inositol phosphates in thymocytes.
Figure 5: Reconstitution of SCID mice.
Figure 6: Impaired positive and negative selection in Itpkb−/− thymocytes.
Figure 7: Calcium mobilization in thymocytes.
Figure 8: Targeted disruption of Itpkc.

Similar content being viewed by others

References

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

    Article  CAS  Google Scholar 

  2. Shears, S.B. The versatility of inositol phosphates as cellular signals. Biochim. Biophys. Acta 1436, 49–67 (1998).

    Article  CAS  Google Scholar 

  3. Zilberman, Y., Howe, L.R., Moore, J.P., Hesketh, T.R. & Metcalfe, J.C. Calcium regulates inositol 1,3,4,5-tetrakisphosphate production in lysed thymocytes and in intact cells stimulated with concanavalin A. EMBO J. 6, 957–962 (1987).

    Article  CAS  Google Scholar 

  4. Guse, A.H., Greiner, E., Emmrich, F. & Brand, K. Mass changes of inositol 1,3,4,5,6-pentakisphosphate and inositol hexakisphosphate during cell cycle progression in rat thymocytes. J. Biol. Chem. 268, 7129–7133 (1993).

    CAS  PubMed  Google Scholar 

  5. Communi, D., Vanweyenberg, V. & Erneux, C. Molecular study and regulation of D-myo-inositol 1,4,5-trisphosphate 3-kinase. Cell Signal. 7, 643–650 (1995).

    Article  CAS  Google Scholar 

  6. Dewaste, V. et al. Cloning and expression of a cDNA encoding human inositol 1,4,5-trisphosphate 3-kinase C. Biochem. J. 352, 343–351 (2000).

    Article  CAS  Google Scholar 

  7. Dewaste, V., Roymans, D., Moreau, C. & Erneux, C. Cloning and expression of a full-length cDNA encoding human inositol 1,4,5-trisphosphate 3-kinase B. Biochem. Biophys. Res. Commun. 291, 400–405 (2002).

    Article  CAS  Google Scholar 

  8. Takazawa, K., Perret, J., Dumont, J.E. & Erneux, C. Molecular cloning and expression of a human brain inositol 1,4,5-trisphosphate 3-kinase. Biochem. Biophys. Res. Commun. 174, 529–535 (1991).

    Article  CAS  Google Scholar 

  9. Vanweyenberg, V., Communi, D., D'Santos, C.S. & Erneux, C. Tissue- and cell-specific expression of Ins(1,4,5)P3 3-kinase isoenzymes. Biochem. J. 306, 429–435 (1995).

    Article  CAS  Google Scholar 

  10. Dewaste, V. et al. The three isoenzymes of human inositol 1,4,5-trisphosphate 3-kinase show specific intracellular localization but comparable Ca2+ responses upon transfection in COS-7 cells. Biochem. J. 374, 41–49 (2003).

    Article  CAS  Google Scholar 

  11. Mailleux, P., Takazawa, K., Erneux, C. & Vanderhaeghen, J.J. Inositol 1,4,5-trisphosphate 3-kinase distribution in the rat brain. High levels in the hippocampal CA1 pyramidal and cerebellar Purkinje cells suggest its involvement in some memory processes. Brain Res. 539, 203–210 (1991).

    Article  CAS  Google Scholar 

  12. Jun, K. et al. Enhanced hippocampal CA1 LTP but normal spatial learning in inositol 1,4,5-trisphosphate 3-kinase(A)-deficient mice. Learn. Mem. 5, 317–330 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Singer, S.M. & Nash, T.E. T-cell-dependent control of acute Giardia lamblia infections in mice. Infect. Immun. 68, 170–175 (2000).

    Article  CAS  Google Scholar 

  14. Farr, A.G. & Anderson, S.K. Epithelial heterogeneity in the murine thymus: fucose-specific lectins bind medullary epithelial cells. J. Immunol. 134, 2971–2977 (1985).

    CAS  PubMed  Google Scholar 

  15. Starr, T.K., Jameson, S.C. & Hogquist, K.A. Positive and negative selection of T cells. Annu. Rev. Immunol. 21, 139–176 (2003).

    Article  CAS  Google Scholar 

  16. Kisielow, P., Bluthmann, H., Staerz, U.D., Steinmetz, M. & von Boehmer, H. Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4+8+ thymocytes. Nature 333, 742–746 (1988).

    Article  CAS  Google Scholar 

  17. Hogquist, K.A. et al. T cell receptor antagonist peptides induce positive selection. Cell 76, 17–27 (1994).

    Article  CAS  Google Scholar 

  18. Swat, W., Dessing, M., von Boehmer, H. & Kisielow, P. CD69 expression during selection and maturation of CD4+8+ thymocytes. Eur. J. Immunol. 23, 739–746 (1993).

    Article  CAS  Google Scholar 

  19. Sentman, C.L., Shutter, J.R., Hockenbery, D., Kanagawa, O. & Korsmeyer, S.J. bcl-2 inhibits multiple forms of apoptosis but not negative selection in thymocytes. Cell 67, 879–888 (1991).

    Article  CAS  Google Scholar 

  20. Zhu, D.M., Tekle, E., Chock, P.B. & Huang, C.Y. Reversible phosphorylation as a controlling factor for sustaining calcium oscillations in HeLa cells: Involvement of calmodulin-dependent kinase II and a calyculin A-inhibitable phosphatase. Biochemistry 35, 7214–7223 (1996).

    Article  CAS  Google Scholar 

  21. 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 

  22. Loomis-Husselbee, J.W. et al. Modulation of Ins(2,4,5)P3-stimulated Ca2+ mobilization by ins(1,3,4,5)P4: enhancement by activated G-proteins, and evidence for the involvement of a GAP1 protein, a putative Ins(1,3,4,5)P4 receptor. Biochem. J. 331, 947–952 (1998).

    Article  CAS  Google Scholar 

  23. Coulie, P.G. et al. Identification of a murine monoclonal antibody specific for an allotypic determinant on mouse CD3. Eur. J. Immunol. 21, 1703–1709 (1991).

    Article  CAS  Google Scholar 

  24. Serfling, E. et al. The role of NF-AT transcription factors in T cell activation and differentiation. Biochim. Biophys. Acta 1498, 1–18 (2000).

    Article  CAS  Google Scholar 

  25. Oukka, M. et al. The transcription factor NFAT4 is involved in the generation and survival of T cells. Immunity. 9, 295–304 (1998).

    Article  CAS  Google Scholar 

  26. van Ewijk, W., Shores, E.W. & Singer, A. Crosstalk in the mouse thymus. Immunol. Today 15, 214–217 (1994).

    Article  CAS  Google Scholar 

  27. El Daher, S.S. et al. Distinct localization and function of (1,4,5)IP3 receptor subtypes and the (1,3,4,5)IP4 receptor GAP1(IP4BP) in highly purified human platelet membranes. Blood 95, 3412–3422 (2000).

    CAS  PubMed  Google Scholar 

  28. Dolmetsch, R.E., Xu, K. & Lewis, R.S. Calcium oscillations increase the efficiency and specificity of gene expression. Nature 392, 933–936 (1998).

    Article  CAS  Google Scholar 

  29. da Silva, C.P., Emmrich, F. & Guse, A.H. Adriamycin inhibits inositol 1,4,5-trisphosphate 3-kinase activity in vitro and blocks formation of inositol 1,3,4,5-tetrakisphosphate in stimulated Jurkat T-lymphocytes. Does inositol 1,3,4,5-tetrakisphosphate play a role in Ca2+-entry? J. Biol. Chem. 269, 12521–12526 (1994).

    CAS  PubMed  Google Scholar 

  30. Cullen, P.J. et al. Identification of a specific Ins(1,3,4,5)P4-binding protein as a member of the GAP1 family. Nature 376, 527–530 (1995).

    Article  CAS  Google Scholar 

  31. Cullen, P.J. Bridging the GAP in inositol 1,3,4,5-tetrakisphosphate signalling. Biochim. Biophys. Acta 1436, 35–47 (1998).

    Article  CAS  Google Scholar 

  32. Amsen, D., Kruisbeek, A., Bos, J.L. & Reedquist, K. Activation of the Ras-related GTPase Rap1 by thymocyte TCR engagement and during selection. Eur. J. Immunol. 30, 2832–2841 (2000).

    Article  CAS  Google Scholar 

  33. Dong, C., Davis, R.J. & Flavell, R.A. MAP kinases in the immune response. Annu. Rev. Immunol. 20, 55–72 (2002).

    Article  CAS  Google Scholar 

  34. Werlen, G., Hausmann, B., Naeher, D. & Palmer, E. Signaling life and death in the thymus: timing is everything. Science 299, 1859–1863 (2003).

    Article  CAS  Google Scholar 

  35. Walker, S.A. et al. Analyzing the role of the putative inositol 1,3,4,5-tetrakisphosphate receptor GAP1IP4BP in intracellular Ca2+ homeostasis. J. Biol. Chem. 277, 48779–48785 (2002).

    Article  CAS  Google Scholar 

  36. Clement, S. et al. The lipid phosphatase SHIP2 controls insulin sensitivity. Nature 409, 92–97 (2001).

    Article  CAS  Google Scholar 

  37. Takazawa, K. et al. Rat brain inositol 1,4,5-trisphosphate 3-kinase. Ca2+-sensitivity, purification and antibody production. Biochem. J. 268, 213–217 (1990).

    Article  CAS  Google Scholar 

  38. Leo, O., Foo, M., Sachs, D.H., Samelson, L.E. & Bluestone, J.A. Identification of a monoclonal antibody specific for a murine T3 polypeptide. Proc. Natl. Acad. Sci. USA 84, 1374–1378 (1987).

    Article  CAS  Google Scholar 

  39. Pajak, B. et al. Immunohistowax processing, a new fixation and embedding method for light microscopy, which preserves antigen immunoreactivity and morphological structures: visualisation of dendritic cells in peripheral organs. J. Clin. Pathol. 53, 518–524 (2000).

    Article  CAS  Google Scholar 

  40. Baus, E., Urbain, J., Leo, O. & Andris, F. Flow cytometric measurement of calcium influx in murine T cell hybrids using Fluo-3 and an organic-anion transport inhibitor. J. Immunol. Methods 173, 41–47 (1994).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank E. Marion, O. Giot, C. Jacques and C. Moreau for technical assistance; the staff of the Laboratoire de Physiologie Animale for immunohistochemistry, technical discussions and help; A. Nagy for R1 embryonic stem cells; K. Rajewsky and R. Merino for anti–H-Y TCR and LckPr–Bcl2 transgenic mice, respectively; and J. Penninger for reviewing the manuscript. Supported by the Fondation David et Alice Van Buuren and the Fondation Hoguet (V.P.), and the Fonds de la Recherche Scientifique Médicale de Belgique, Interreg II (cofinanced by the Région Wallonne and the European Commission, FEDER), Action de Recherche Concertée of the Communauté Française de Belgique, and The Free University of Brussels.

Author information

Authors and Affiliations

  1. IRIBHM, IBMM, rue des Professeurs Jeener et Brachet 12, Gosselies, 6041, Belgium

    Valérie Pouillon & Stéphane Schurmans

  2. IRIBHM, Campus Erasme, route de Lennik 808, Brussels, 1070, Belgium

    Romana Hascakova-Bartova, Valérie Dewaste & Christophe Erneux

  3. Laboratoire de Physiologie Animale, IBMM, rue des Professeurs Jeener et Brachet 12, Gosselies, 6041, Belgium

    Bernard Pajak & Oberdan Leo

  4. Laboratoire de Chimie Biologique, IBMM, rue des Professeurs Jeener et Brachet 12, Gosselies, 6041, Belgium

    Emmanuelle Adam & Carine Van Lint

  5. Laboratoire de Microbiologie, CERIA, Avenue E. Gryson 1, Brussels, 1070, Belgium

    Françoise Bex

Authors
  1. Valérie Pouillon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Romana Hascakova-Bartova
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bernard Pajak
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Emmanuelle Adam
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Françoise Bex
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Valérie Dewaste
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Carine Van Lint
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Oberdan Leo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Christophe Erneux
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Stéphane Schurmans
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stéphane Schurmans.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pouillon, V., Hascakova-Bartova, R., Pajak, B. et al. Inositol 1,3,4,5-tetrakisphosphate is essential for T lymphocyte development. Nat Immunol 4, 1136–1143 (2003). https://doi.org/10.1038/ni980

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni980

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