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.
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Pillai, S., Cariappa, A. & Moran, S.T. Positive selection and lineage commitment during peripheral B-lymphocyte development. Immunol. Rev. 197, 206–218 (2004).
Srivastava, B., Lindsley, R.C., Nikbakht, N. & Allman, D. Models for peripheral B lymphocyte development and homeostasis. Semin. Immunol. 17, 175–182 (2005).
Rolink, A.G., Andersson, J. & Melchers, F. Molecular mechanisms guiding late stages of B-lymphocyte development. Immunol. Rev. 197, 41–50 (2004).
Cariappa, A. & Pillai, S. Antigen-dependent B-lymphocyte development. Curr. Opin. Immunol. 14, 241–249 (2002).
Miosge, L.A. & Goodnow, C.C. Genes, pathways and checkpoints in lymphocyte development and homeostasis. Immunol. Cell Biol. 83, 318–335 (2005).
Harnett, M.M., Katz, E. & Ford, C.A. Differential signalling during B-lymphocyte maturation. Immunol. Lett. 98, 33–44 (2005).
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).
Gallo, E.M., Cante-Barrett, K. & Crabtree, G.R. Lymphocyte calcium signaling from membrane to nucleus. Nat. Immunol. 7, 25–32 (2006).
Parekh, A.B. & Putney, J.W., Jr . Store-operated calcium channels. Physiol. Rev. 85, 757–810 (2005).
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).
Xia, H.J. & Yang, G. Inositol 1,4,5-trisphosphate 3-kinases: functions and regulations. Lymphocyte Res 15, 83–91 (2005).
Hermosura, M.C. et al. InsP4 facilitates store-operated calcium influx by inhibition of InsP3 5-phosphatase. Nature 408, 735–740 (2000).
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).
Pouillon, V. et al. Inositol 1,3,4,5-tetrakisphosphate is essential for T lymphocyte development. Nat. Immunol. 4, 1136–1143 (2003).
Culton, D.A. et al. Early preplasma lymphocytes define a tolerance checkpoint for autoreactive B lymphocytes. J. Immunol. 176, 790–802 (2006).
Martin, F. & Kearney, J.F. B1 lymphocytes: similarities and differences with other B lymphocyte subsets. Curr. Opin. Immunol. 13, 195–201 (2001).
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).
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).
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).
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).
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).
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).
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).
Chamberlain, P.P. et al. Structural insights into enzyme regulation for inositol 1,4,5-trisphosphate 3-kinase B. Biochemistry 44, 14486–14493 (2005).
Chen, J. et al. CD22 attenuates calcium signaling by potentiating plasma membrane calcium-ATPase activity. Nat. Immunol. 5, 651–657 (2004).
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).
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).
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).
Hardy, R.R. B-1 B lymphocytes: development, selection, natural autoantibody and leukemia. Curr. Opin. Immunol. 18, 547–555 (2006).
Hayakawa, K. et al. Positive selection of natural autoreactive B lymphocytes. Science 285, 113–116 (1999).
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).
Goodnow, C.C. et al. Self-tolerance checkpoints in B lymphocyte development. Adv. Immunol. 59, 279–368 (1995).
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).
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).
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).
Kurosaki, T. et al. Regulation of the phospholipase C-γ2 pathway in B lymphocytes. Immunol. Rev. 176, 19–29 (2000).
Prakriya, M. et al. Orai1 is an essential pore subunit of the CRAC channel. Nature 443, 230–233 (2006).
Vig, M. et al. CRACM1 is a plasma membrane protein essential for store-operated Ca2+ entry. Science 312, 1220–1223 (2006).
Soboloff, J. et al. Orai1 and STIM reconstitute store-operated calcium channel function. J. Biol. Chem. 281, 20661–20665 (2006).
Hardy, R.R. et al. B-lymphocyte commitment, development and selection. Immunol. Rev. 175, 23–32 (2000).
We thank C. Trussell, D. Li and S. Zaharevitz for technical assistance, and R. Glynne, B. Wen and C. Schemdt for discussions.
The authors declare no competing financial interests.
Itpkb protein expression. (PDF 562 kb)
Impaired BCR-induced cell cycle progression in Itpkb−/− B lymphocytes. (PDF 577 kb)
Serum Ig quantities. (PDF 1590 kb)
Reduced BCR-stimulated PLC-γ2 activation in Itpkb−/− B lymphocytes. (PDF 560 kb)
Elevated Ca2+ entry in immature and mature in Itpkb−/− B lymphocytes. (PDF 2157 kb)
IP4 inhibits SOC channel activity but does not alter membrane potential. (PDF 557 kb)
Itpkb regulates calcium homeostasis and B lymphocyte fate selection. (PDF 1538 kb)
Total number of splenic B cell subsets. (PDF 1392 kb)
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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
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