Bruton's Tyrosine Kinase Regulates the Activation of Gene Rearrangements at the λ Light Chain Locus in Precursor B Cells in the Mouse

Dingjan, Gemma M.; Middendorp, Sabine; Dahlenborg, Katarina; Maas, Alex; Grosveld, Frank; Hendriks, Rudolf W.

doi:10.1084/jem.193.10.1169

Cited by 51 publications

(84 citation statements)

References 49 publications

(86 reference statements)

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“…We previously showed that B cells from Btk-deficient mice have a ϳ50% reduction in the frequency of Ig L chain expression, already at the immature B cell stage in the bone marrow (16). This finding implicated Btk in the regulation of the activation of the locus for V(D)J recombination in pre-B cells (16).…”

Section: Ig L Chain Usage In Btk Mutant Micementioning

confidence: 99%

“…IL-7-driven BM cultures and determination of IL-7-dependent proliferative responses of total BM cells have been described previously (14,16). Mature B cell fractions were purified from spleen, using standard NH 4 Cl lysis to deplete erythrocytes, followed by complement-mediated T cell lysis, as described previously (25).…”

Section: In Vitro (Pre-)b Cell Culturesmentioning

confidence: 99%

“…Mature B cell fractions were purified from spleen, using standard NH 4 Cl lysis to deplete erythrocytes, followed by complement-mediated T cell lysis, as described previously (25). The enriched B cell fractions were cultured in vitro in the presence or absence of LPS, 5 g/ml anti-CD40, or polyclonal goat anti-mouse IgM (Southern Biotechnology Associates, Birmingham, AL), as described previously (16). To measure DNA synthesis, cells were pulsed with [ 3 H]thymidine for 16 -20 h, harvested, and counted using standard methods.…”

Section: In Vitro (Pre-)b Cell Culturesmentioning

confidence: 99%

“…Btk-deficient cells manifest a specific developmental delay within the small pre-B cell compartment of ϳ3 h in vivo. The finding of reduced L chain usage in Btk-deficient mice implicates Btk in the regulation of the activation of the locus for V(D)J recombination in pre-B cells (16).…”

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confidence: 99%

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Function of Bruton’s Tyrosine Kinase during B Cell Development Is Partially Independent of Its Catalytic Activity

Middendorp¹,

Dingjan²,

Maas

et al. 2003

The Journal of Immunology

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The Tec family member Bruton’s tyrosine kinase (Btk) is a cytoplasmic protein tyrosine kinase that transduces signals from the pre-B and B cell receptor (BCR). Btk is involved in pre-B cell maturation by regulating IL-7 responsiveness, cell surface phenotype changes, and the activation of λ L chain gene rearrangements. In mature B cells, Btk is essential for BCR-mediated proliferation and survival. Upon BCR stimulation, Btk is transphosphorylated at position Y551, which promotes its catalytic activity and subsequently results in autophosphorylation at position Y223 in the Src homology 3 domain. To address the significance of Y223 autophosphorylation and the requirement of enzymatic activity for Btk function in vivo, we generated transgenic mice that express the autophosphorylation site mutant Y223F and the kinase-inactive mutant K430R, respectively. We found that Y223 autophosphorylation was not required for the regulation of IL-7 responsiveness and cell surface phenotype changes in differentiating pre-B cells, or for peripheral B cell differentiation. However, expression of the Y223F-Btk transgene could not fully rescue the reduction of λ L chain usage in Btk-deficient mice. In contrast, transgenic expression of kinase-inactive K430R-Btk completely reconstituted λ usage in Btk-deficient mice, but the defective modulation of pre-B cell surface markers, peripheral B cell survival, and BCR-mediated NF-κB induction were partially corrected. From these findings, we conclude that: 1) autophosphorylation at position Y223 is not essential for Btk function in vivo, except for regulation of λ L chain usage, and 2) during B cell development, Btk partially acts as an adapter molecule, independent of its catalytic activity.

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Section: Ig L Chain Usage In Btk Mutant Micementioning

confidence: 99%

Section: In Vitro (Pre-)b Cell Culturesmentioning

confidence: 99%

Section: In Vitro (Pre-)b Cell Culturesmentioning

confidence: 99%

mentioning

confidence: 99%

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Function of Bruton’s Tyrosine Kinase during B Cell Development Is Partially Independent of Its Catalytic Activity

Middendorp¹,

Dingjan²,

Maas

et al. 2003

The Journal of Immunology

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“…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]. Several other early events in B cell development are partially impaired in mice lacking individual signalosome components.…”

Section: Introductionmentioning

confidence: 99%

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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Receptor editing in CD45-deficient immature B cells

Leider

Melamed

2002

Eur. J. Immunol.

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B cell receptor signaling threshold regulates negative selection of autoreactive B cells and determines the mechanism of B cell tolerance. Using mice carrying immunoglobulin transgene specificfor MHC class I antigen Kk (3–83Tg mice), and IL‐7‐driven bone marrow (BM) culture system, we have previously shown that receptor editing is a major mechanism in B cell tolerance. To test the role of BCR signaling competence on the induction of tolerance‐mediated receptor editing, we crossed the 3–83Tg mice with mice deficient in CD45, a protein tyrosine phosphatase that functions asa positive regulator of the BCR signaling. We found that in the absence of self‐antigen allelic exclusion is efficiently imposed in 3–83Tg CD45–/– mice, although numbers of peripheral B cells are reduced. Using our BM culture system, we show here that immature 3–83Tg CD45–/– B cells encountering self‐antigen are developmentally arrested and undergo secondary light chain recombination and receptor editing, not different than CD45‐sufficient cells. Thus, lack of CD45 does not abolish the receptor editing competence in immature B cells encountering high avidity membrane‐bound antigen.

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Bruton's Tyrosine Kinase Regulates the Activation of Gene Rearrangements at the λ Light Chain Locus in Precursor B Cells in the Mouse

Cited by 51 publications

References 49 publications

Function of Bruton’s Tyrosine Kinase during B Cell Development Is Partially Independent of Its Catalytic Activity

Function of Bruton’s Tyrosine Kinase during B Cell Development Is Partially Independent of Its Catalytic Activity

Btk and phospholipase Cγ2 can function independently during B cell development

Receptor editing in CD45-deficient immature B cells

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