Phospholipase Cγ2 Is Essential in the Functions of B Cell and Several Fc Receptors

Wang, Demin; Feng, Jian; Wen, Renren; Marine, Jean–Christophe; Sangster, Mark Y.; Parganas, Evan; Hoffmeyer, Angelika; Jackson, Carl W.; Cleveland, John L.; Murray, Peter J.; Ihle, James N.

doi:10.1016/s1074-7613(00)00005-4

Cited by 440 publications

(463 citation statements)

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“…We found that DC obtained from mice lacking PLCg2 [24] exhibited impaired capacity of antigen presentation and induction of T H 1 and T H 17 cells in response to b-glucan. Mechanistically, PLCg2-deficient DC failed to secrete cytokines, such as IL-12, IL-6 and IL-23, which are important for the generation of T H 1 and T H 17 cells.…”

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confidence: 86%

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Requirement of phospholipase C‐γ2 (PLCγ2) for Dectin‐1‐induced antigen presentation and induction of T_H1/T_H17 polarization

et al. 2009

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DC recognize microbial components through an array of receptors known as PRR. PRR initiate intracellular signals, which engender DC with the capacity to stimulate T-cell responses. Dectin-1 is a PRR that recognizes b-glucan, a major constituent of many fungi's outer cell wall. Here we show that Dectin-1 activates DC through phospholipase (PLC)c2 signaling. PLCc2-deficient DC were unable to expand antigen-specific T cells and induce T H 1 and T H 17 differentiation in response to b-glucan. Mechanistically, PLCc2-deficiency impaired the capacity of DC to secrete polarizing cytokines following exposure to b-glucan. Dectin-1 required PLCc2 to activate MAPK, AP-1 and NF-jB, which induce cytokine gene expression. Moreover, PLCc2 controlled Dectin-1-mediated NFAT activation and induction of NFAT-dependent genes such as IL-2, cyclooxigenase-2 and Egr transcription factors. We conclude that PLCc2 is a crucial signaling mediator that modifies DC gene expression program to activate DC responses to b-glucan-containing pathogens.Key words: DC . Dectin-1 . PLCg . Signaling Supporting Information available online Introduction DC play a key role in gathering information from the surrounding environment and initiating appropriate immune responses when needed [1,2]. Because they bridge innate and adaptive immunity, DC are equipped with a multitude of intracellular and cell surface receptors that sense microbial components and trigger host responses to invading pathogens. These receptors, collectively known as PRR, include TLR [3], C-type lectins such as Dectin-1 [4], scavenger receptors [5], the nucleotide-binding oligomerization domain (NOD) proteins NOD1 and NOD2, the NOD-like receptors and the RIG-like receptors [6].Dectin-1 recognizes b-glucan, a major constituent of many fungi's outer cell wall [4,7] and triggers intracellular signals through a cytoplasmic tyrosine motif resembling the ITAM. Upon ligand binding, this motif is phosphorylated by src family kinases [8] and recruits the tyrosine kinase Syk [9], which initiates a signaling cascade leading to NF-kB [10], NFAT [11] and MAPK [12] activation. Along with Bcl-10 and MALT1, CARD9 is a crucial mediator in the ITAM-signaling pathway that links recognition of b-glucan by Dectin-1 to NF-kB and MAPK activation [13,14]. Overall, the Syk-CARD9 pathway is essential for [20,21]. Syk, together with the tyrosine kinases BTK and Src, activate PLCg through tyrosine phosphorylation [22]. Another downstream ITAM mediator, PI-3K, activates PLCg by generating phosphatidylinositol 3,4,5 trisphosphate, which binds the pleckstrin homology domain of PLCg, promoting PLCg recruitment to the cell membrane. Thus, the ability of Dectin-1 to initiate an ITAM-Syk-signaling pathway [9] provides a rationale for studying the role of PLCg in Dectin-1-mediated antimicrobial responses in DC.PLCg includes two isoforms, PLCg1 and PLCg2, which hydrolyze membrane phosphatidylinositol 4,5-biphosphate into inositol 1,4,5-trisphosphate and diacylglicerol (DAG) [20]. Inositol 1,4,5-trisphosphate triggers the ...

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“…PLCg2 À/À and BTK À/À -deficient mice have been previously described [24,43]. All animal studies were approved by the Washington University animal studies committee.…”

Section: Micementioning

confidence: 99%

Requirement of phospholipase C‐γ2 (PLCγ2) for Dectin‐1‐induced antigen presentation and induction of T_H1/T_H17 polarization

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“…However, PLCc2 contributes to the health and survival of both wild-type [2/20 PLCc2 -/-mice died within the 16-wk study period (Fig. 4A)] [17] and BLNK -/-mice via other undefined mechanisms.…”

Section: Differential Roles For Btk and Plcc2 In Pre-b Cell Tumor Supmentioning

confidence: 99%

“…A similar disease results from mutation of the human BLNK gene [9]. Mice lacking Btk [10][11][12], BLNK [13][14][15][16], or PLCc2 [17,18] have a milder phenotype with the predominant defect at the T2 to mature transition in the periphery. Btk -/-mice have a reduced frequency of Igk-expressing cells due to a role for Btk in Igk rearrangement in pre-B cells [19].…”

Section: Introductionmentioning

confidence: 99%

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Btk and phospholipase Cγ2 can function independently during B cell development

et al. 2007

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The pre-BCR and the BCR regulate B cell development via a signalosome nucleated by the adaptor protein B cell linker protein (BLNK). Formation of this complex facilitates activation of phospholipase C (PLC) c2 by Bruton's tyrosine kinase (Btk). To determine whether Btk and PLCc2 also have separate functions, we generated Btk -/-PLCc2 -/-mice. They demonstrated a block in development at the pre-B stage and increased pre-BCR surface expression. This phenotype was more severe than that of Btk -/-or PLCc2 -/-mice. Although both Btk and PLCc2 were required for proliferation of splenic B cells in response to BCR cross-linking, they contributed differently to anti-IgM-induced phosphorylation of ERK. Btk -/-and PLCc2 -/-mice each had a reduced frequency of Igk-expressing B cells and impaired migration of pre-B cells towards stromal cellderived factor 1. However, the increase in pre-B cell malignancy that occurs in BLNK -/-mice in the absence of Btk was not observed in the absence of PLCc2. Thus, Btk and PLCc2 act both in concert and independently throughout B cell development. IntroductionSignals from the B cell antigen receptor (BCR) regulate multiple stages of B lymphopoiesis [1]. In pre-B cells, the pre-BCR signals for proliferation, allelic exclusion of the IgH locus, down-regulation of VpreB and k5 expression, and light chain rearrangement. The pre-BCR is predominantly intracellular and is believed to signal in a ligand-independent manner. The BCR is first expressed on the surface of immature B cells. Antigen encounter at this stage results in negative selection via deletion, anergy, or receptor editing. A tonic BCR signal is required for differentiation beyond the T2 stage in the periphery and survival of mature B cells. Mature B cells proliferate and differentiate upon stimulation with foreign antigen in the appropriate context. BCR and pre-BCR signaling is mediated by a signalosome composed of Syk, Bruton's tyrosine kinase (Btk), B cell linker protein (BLNK; also known as SLP65 and BASH), and phospholipase C (PLC) c2 [2-4]. Receptor cross-linking activates Syk, which phosphorylates the adaptor protein BLNK. Btk and PLCc2 bind to phosphorylated BLNK via their SH2 domains. Btk then phosphorylates and activates PLCc2, resulting in changes in intracellular Ca 2+ and the activation of protein kinase Cb. Btk can also mediate BCR-stimulated Ca 2+ flux [5] and B cell development [6] independently of its catalytic activity. Btk acts as an adaptor to recruit and activate phosphatidylinositol 4-phosphate 5-kinase (PIP5K) [5], which produces the substrate for PLCc2. Thus, Btk signals through PLCc2 directly, by phosphorylation, and indirectly, by increasing substrate availability.Loss of Btk function causes the human immunodeficiency X-linked agammaglobulinemia (XLA) [7,8], which is characterized by a block in B cell development at the pre-B stage. A similar disease results from

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Early Events in B Lymphocyte Activation

2003

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B cell activation can be quantitated indirectly by assaying antibody production or directly by measuring cellular changes that occur immediately after exposure to an activation signal. This unit provides methods for the latter (direct) approach--namely, methods for quantifying early parameters of B cell activation such as increases in intracellular ionized calcium concentration [Ca2+]I, cell size, and MHC class II-antigen expression. These assays are not so much B cell specific as activation specific; as such they are a useful means of providing information about cellular events that are independent of antibody secretion. While the protocols included in this unit have been specifically designed for use with murine B cells, they can also be used with B cells obtained from other species. In addition, the method described here also applies to T cells.

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Phospholipase Cγ2 Is Essential in the Functions of B Cell and Several Fc Receptors

Cited by 440 publications

References 52 publications

Requirement of phospholipase C‐γ2 (PLCγ2) for Dectin‐1‐induced antigen presentation and induction of T_H1/T_H17 polarization

Requirement of phospholipase C‐γ2 (PLCγ2) for Dectin‐1‐induced antigen presentation and induction of T_H1/T_H17 polarization

Btk and phospholipase Cγ2 can function independently during B cell development

Early Events in B Lymphocyte Activation

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Phospholipase Cγ2 Is Essential in the Functions of B Cell and Several Fc Receptors

Cited by 440 publications

References 52 publications

Requirement of phospholipase C‐γ2 (PLCγ2) for Dectin‐1‐induced antigen presentation and induction of TH1/TH17 polarization

Requirement of phospholipase C‐γ2 (PLCγ2) for Dectin‐1‐induced antigen presentation and induction of TH1/TH17 polarization

Btk and phospholipase Cγ2 can function independently during B cell development

Early Events in B Lymphocyte Activation

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Requirement of phospholipase C‐γ2 (PLCγ2) for Dectin‐1‐induced antigen presentation and induction of T_H1/T_H17 polarization

Requirement of phospholipase C‐γ2 (PLCγ2) for Dectin‐1‐induced antigen presentation and induction of T_H1/T_H17 polarization