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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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.
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)
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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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