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

Abstract

Inositol 1,4,5-trisphosphate (Ins(1,4,5)P(3)) is phosphorylated by Ins(1,4,5)P(3) 3-kinase, generating inositol 1,3,4,5-tetrakisphosphate (Ins(1,3,4,5)P(4)). The physiological function of Ins(1,3,4,5)P(4) 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)P(3) 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)P(3) amounts or calcium mobilization in Itpkb(-/-) thymocytes. These data indicate that Itpkb and Ins(1,3,4,5)P(4) define an essential signaling pathway for T cell precursor responsiveness and development.

Regulation of innate immunity by inositol 1,3,4,5-tetrakisphosphate

“…Surprisingly, in InsP3KB null T cells, no substantial defects in Ins(1,4,5)P3 amounts or calcium mobilization was detected. 9,10 In neutrophils, disruption of InsP3KB does not affect the overall calcium signaling in the presence of extracellular calcium. 16 However, more detailed investigation revealed a much decreased calcium release from intracellular store and an enhanced calcium influx through store-operated calcium channels in InsP3KB null neutrophils stimulated with chemokines.…”

“…The absolute number of lymphocytes in peripheral blood was reduced significantly in the InsP3KB knockout mice. [9][10][11][12] However, intriguingly, disruption of InsP3KB resulted in elevated peripheral blood neutrophil count, indicating an augmentation of neutrophil production from bone marrow. Fluorescence-Activated Cell-sorting (FACS) analysis of bone marrow cells revealed an elevation of granulocyte monocytes progenitors (GMP) population in the knockout mice.…”

“…In addition, the amounts of mature B-and T-cells are dramatically decreased in the InsP3KB knockout mice, resulting in reduction of the serum level of IgG which is essential for opsinization and phagocytosis. [9][10][11][12] We conducted an in vitro bacteria killing assay using purified neutrophils and serum from wild-type and InsP3KB knockout mice (Fig. 2B).…”

“…Two independent studies showed that disruption of InsP3KB led to dramatic decrease of cellular Ins(1,3,4,5)P4 level, impaired T cell development, and defective thymocyte selection. 9,10 Disruption of InsP3KB also induces B cell death and impaired B cell development. 11,12 In addition, we recently showed that InsP3KB is the major InsP3K isoform in neutrophils.…”

Specific expression and function of inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) in wild type and knock-out mice

“…Production and analysis of mice genetically-deficient for Itpka and Itpkb have strongly helped to characterize the in vivo functions of these enzymes and the corresponding mechanisms of Ins(1,3,4,5)P4 action (Pouillon et al, 2013;Schurmans et al, 2011Schurmans et al, , 2015. By contrast, the physiological function of ITPKC is poorly characterized in vivo: Itpkc-deficient mice have been generated in our laboratory, but these mice appear healthy with a normal lifespan and growth (Pouillon et al, 2003). No gross morphological alterations have been detected in organs isolated from these mice.…”