Lymphopenia in interleukin (IL)-7 gene-deleted mice identifies IL-7 as a nonredundant cytokine.

Freeden-Jeffry, Ursula von; Vieira, Paulo; Lucian, Linda; McNeil, Tom; Burdach, Stefan; Murray, Richard M.

doi:10.1084/jem.181.4.1519

Cited by 1,315 publications

(1,040 citation statements)

References 27 publications

(26 reference statements)

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“…In addition to signals from the pre-BCR, early B cell development depends on other stimuli such as IL-7 [32] and SDF-1 [33]. Neither Btk nor PLCc2 are required for pre-B cell responses to IL-7 [17,20] (Fig.…”

Section: Both Btk and Plcc2 Contribute To Migration Of Pre-b Cells Tomentioning

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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Section: Both Btk and Plcc2 Contribute To Migration Of Pre-b Cells Tomentioning

confidence: 99%

Btk and phospholipase Cγ2 can function independently during B cell development

et al. 2007

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“…Interestingly, the phenotype of the above-mentioned pre-B cell line at non-permissive temperatures resembles that of the pre-B cells in interleukin 7 (IL-7) or interleukin 7 receptor (IL-7R) de®cient mice (Corcoran et al, 1998;Peschon et al, 1994;von Freeden-Je ry et al, 1995). Targeted disruption of IL-7 or IL-7R genes in mice results in a severe defect in the B cell compartment, especially the subset undergoing IgH rearrangement (Corcoran et al, 1998).…”

Section: Abl Proteins and B Cell Developmentmentioning

confidence: 99%

JAK-STAT signaling activated by Abl oncogenes

2000

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“…Similarly, transgenic overexpression of IL-7 (Tg IL-7) caused mixed T-and B-cell lymphomas that arose by oligoclonal expansion of variable subsets, which could form masses upon transfer to either immunocompetent or nude mice (Rich et al, 1993). As IL-7 is essential for both T-and B-cell development in mice and T cells in humans (Peschon et al, 1994;von Freeden-Jeffry et al, 1995;Kovanen and Leonard, 2004), we aimed to determine whether the signals necessary for lymphocyte homeostasis and development could be separated from those required for transformation.…”

Section: Introductionmentioning

confidence: 99%

Selective ablation of the YxxM motif of IL-7Rα suppresses lymphomagenesis but maintains lymphocyte development

et al. 2010

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Tumor progression is a multiple step process in which, in addition to oncogenic mutation, other supporting factors can contribute to transformation. The role these factors have in cancer is an open question. Using the El-myc model of B-cell transformation, we evaluated the contribution of the cytokine interleukin-7 (IL-7) in supporting lymphomagenesis. We have previously shown that disruption of the Y449xxM motif of the IL-7 receptor alpha (IL-7Ra) in a knock-in mouse model (IL-7Ra 449F ) has minor effects on lymphocyte production, but interferes with the activation of survival effectors. To address the hypothesis that targeted signal ablation would selectively affect lymphocyte transformation, IL-7Ra 449F mice were crossed with two lymphomagenesis models, transgenic (Tg) IL-7 and El-myc mice. We found that the loss of IL-7Ra Y449 signaling prevented Tg IL-7-mediated T-and B-lymphocyte transformation and decreased the development of El-myc-induced B-cell tumors. We showed that the IL-7Ra 449F mutation prevented increased survival of Tg IL-7 CD8 T cells, and decreased viability of bone marrow progenitor B cells, as well as Elmyc-induced proliferation. This study shows that IL-7Ra Y449 is important for lymphocyte transformation, and that unlike deficiencies in pre-B cell receptor signaling, Myc overexpression cannot compensate for the loss of IL-7Ra signals in early B-cell development.

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Lymphopenia in interleukin (IL)-7 gene-deleted mice identifies IL-7 as a nonredundant cytokine.

Cited by 1,315 publications

References 27 publications

Btk and phospholipase Cγ2 can function independently during B cell development

Btk and phospholipase Cγ2 can function independently during B cell development

JAK-STAT signaling activated by Abl oncogenes

Selective ablation of the YxxM motif of IL-7Rα suppresses lymphomagenesis but maintains lymphocyte development

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