Calcium signalling and cell-fate choice in B cells

Abstract

Alterations in the cytosolic concentration of calcium ions (Ca 2+ ) transmit information that is crucial to the development and function of B cells. Cytosolic Ca 2+ concentration is determined by a balance of active transport and gradient driven Ca 2+ fluxes, both of which are subject to the influence of multiple receptors and environmental sensing pathways. Recent advances in genomics have allowed for the compilation of an increasingly comprehensive list of Ca 2+ transporters and channels expressed by B cells. The accumulating understanding of the function and regulation of these proteins has begun to shift the frontier of Ca 2+ physiology in B cells from molecular analysis to determining how diverse inputs to cytosolic Ca 2+ concentration are integrated in specific immunological contexts.

Switch-like activation of Bruton’s tyrosine kinase by membrane-mediated dimerization

“…Btk is then activated, allowing it to activate phospholipase C-γ2 (PLC-γ2). PLC-γ2 hydrolyzes PIP 2 into inositol (1,4,5)-trisphosphate (IP 3 ) and diacylglycerol (DAG), leading to calcium flux and cellular activation (Hendriks et al, 2014;Scharenberg et al, 2007). Mutations in Btk have been shown to result in X-linked agammaglobulinemia, an autoimmune disease (Tsukada et al, 1993).…”

Rac-mediated Stimulation of Phospholipase Cγ2 Amplifies B Cell Receptor-induced Calcium Signaling

“…In mouse B cells, the costimulatory effect of CD19 on BCR-mediated increases in [Ca 2ϩ ] i was clearly reduced in B cells from rac2 Ϫ/Ϫ mice (19). Previously, these effects were mainly ascribed to the known interactions of CD19 with the RhoGEF Vav and to the positive interaction of Vav, presumably via activated Rac, with phosphatidylinositol 4-phosphate 5-kinase and/or PI3K, followed by indirect activation of PLC␥ 2 (6,42). Our current results strongly suggest that Rac enhances BCR-mediated Ca 2ϩ signaling in B cells by direct interaction with and activation of PLC␥ 2 .…”

“…Several lines of evidence have already suggested that PLC␥ 2 and Rac are both activated by BCR ligation, although a direct interaction of the two signaling molecules has received relatively little attention (6,26,42,43). Thus, several elements of the canonical B cell receptor signaling cascade, e.g.…”

“…Interaction-Within minutes after BCR-mediated B cell activation, several transcription factors, including the Ca 2ϩ -dependent transcription factor NFAT1c, are translocated into the nucleus to induce transcription of regulatory genes involved in B cell-fate decisions (6). To determine the role of a functional Rac-PLC␥ 2 interaction in this response, a C-terminally truncated NFAT1c construct consisting of the N-terminal transactivation and the calcineurin-binding domain (amino acids 1-400) fused to the red fluorescent protein td-RFP611 was introduced into PLC␥ 2 Ϫ/Ϫ DT40 B cells and PLC␥ 2 Ϫ/Ϫ DT40 B cells stably expressing either WT or F897Q mutant PLC␥ 2 , and its nuclear translocation following BCR ligation was analyzed by spinning disk fluorescence microscopy (Fig.…”

“…In B lymphocytes, receptors for cell surface immunoglobulins such as the B cell receptors (BCR), cleavage fragments of the third complement component (CD19/CD21) (3), bacterial, viral, or autoimmunity host DNA (toll-like receptors) (4), and even certain G-protein-coupled chemokine receptors (5) mediate activation of PLC␥ 2 , one of the two human PLC␥ isoforms. The activity of PLC␥ 2 controls many B cell functions, such as protein kinase signaling, nucleocytoplasmic trafficking of transcription factors, proliferation, differentiation, cytoskeletal reorganization, cell adhesion and migration, immunological synapse formation, affinity maturation, autoimmunity, homing to and retention in tissue microenvironments, survival, and susceptibility to transformation (6,7).…”