A self-reinforcing regulatory network triggered by limiting IL-7 activates pre-BCR signaling and differentiation

Ochiai, Kyoko; Maienschein‐Cline, Mark; Mandal, Malay; Triggs, Joseph; Bertolino, Eric; Sciammas, Roger; Dinner, Aaron R.; Clark, Marcus R.; Singh, Harinder

doi:10.1038/ni.2210

Cited by 149 publications

(262 citation statements)

References 38 publications

(96 reference statements)

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“…This is reminiscent of the synergism between pre-BCR and IL-7 signals that was revealed in previous studies. 16,33 Although signal transduction downstream of pre-BCR remains to be fully characterized, similar signaling complexes are formed following the engagement of BCR and pre-BCR. [34][35][36] Because TLR4 signaling is shown to synergize with BCR-delivered signals during the activation of mature B cells, 37,38 it would not be surprising if the TLR4 signaling pathway also interacts with pre-BCR signaling during pre-B-cell development.…”

Section: Synergism Of Lps and Il-7 Signals In The Promotion Of Pre-bcmentioning

confidence: 99%

“…A similar inhibitory effect was also observed in the cultures of large pre-B cells (Figure 2b), which was another IL-7-responsive population of B-cell precursors. 16 The reduced proliferative response prompted us to examine the expression of IL-7 receptors in LPS-treated cells. Indeed, culture with LPS alone caused a substantial reduction in the cell surface expression of IL-7Ra in pro-B cells ( Figure 2c) and large pre-B cells (data not shown).…”

Section: Increased Pro-b and Pre-b Cells In C3h/hej Micementioning

confidence: 99%

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Toll-like receptor 4-mediated signaling regulates IL-7-driven proliferation and differentiation of B-cell precursors

Han

Wang

et al. 2013

Cell Mol Immunol

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Lipopolysaccharide (LPS) is known to be a potent activator of mature B cells by signaling through Toll-like receptor 4 (TLR4). Its impact on early B-cell development, however, is not well defined. When comparing to C3H/HeN mice, TLR4-mutant C3H/HeJ mice showed an increase in the number of pro-B and pre-B cells in the bone marrow. When cultured in the presence of IL-7, the proliferation of pro-B and large pre-B cells was significantly inhibited by LPS, possibly due to reduced IL-7 receptor-a (IL-7Ra) expression. Meanwhile, the generation of IgM 1 /IgD 1 B cells was greatly enhanced in IL-7 cultures of pro-B and pre-B cells. Consistent with these results, treatment with LPS facilitated the progression of adoptively transferred B220 1 IgM 2 IgD 2 precursors into IgD 1 cells. Overall, these data suggest that LPS has a profound influence on early B-cell development, which may contribute to the deregulated B-cell development under physiological and pathological conditions such as bacterial infections.

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Section: Synergism Of Lps and Il-7 Signals In The Promotion Of Pre-bcmentioning

confidence: 99%

Section: Increased Pro-b and Pre-b Cells In C3h/hej Micementioning

confidence: 99%

Toll-like receptor 4-mediated signaling regulates IL-7-driven proliferation and differentiation of B-cell precursors

Han

Wang

et al. 2013

Cell Mol Immunol

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“…We used this cell system as a model because Irf4 Ϫ/Ϫ Irf8 Ϫ/Ϫ pre-B cells are dependent on IL-7 for proliferation in vitro, which stimulates the PI3K pathway (30) and inhibits the nuclear accumulation of endogenous Bach2. 3 By staining the cells with anti-FLAG antibodies, we found that FLAG-Bach2 was present mainly in the cytoplasmic region with an exclusion from the nuclear region in ϳ75% of the cells (Fig.…”

Section: Mutations Of Bach2 Ser-509 or Ser-535 Reduce The Mobilitymentioning

confidence: 99%

“…Ϫ/Ϫ pre-B cells were cultured as reported previously (30). In the SILAC experiment, Iscove's modified Dulbecco's medium for SILAC (Thermo Fisher Scientific) containing 10% dialyzed FBS (Thermo Fisher Scientific) and 2-mercaptoethanol was used by adding either 0.4 mM L-lysine-HCl with 0.2 mM L-arginine-HCl (Sigma) as the "light" medium or 0.4 mM L-lysine-HCl-13 C 6 with 0.2 mM L-arginineHCl-13 C 6 (Wako) as the "heavy" medium.…”

Section: Irf8mentioning

confidence: 99%

The Transcription Factor Bach2 Is Phosphorylated at Multiple Sites in Murine B Cells but a Single Site Prevents Its Nuclear Localization

Ando¹,

Shima

Tamahara

et al. 2016

Journal of Biological Chemistry

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2), and Irf (3) families have been well studied in the context of the immune system in part due to their clear and established association with the upstream signaling cascades. In contrast, although the phosphatidylinositol 3-kinase (PI3K) pathway is critically important for the regulation of immune cells, its downstream transcription factors are still unclear except for the Foxo family (4). In this study, we investigated the possibility that the transcription factor Bach2 might be regulated in B cells by the PI3K pathway. Salient features of Bach2 relevant to this study are as follows.Bach2 regulates the immune cells at multiple points. During the development of B cells from the progenitor cells, Bach2, together with its related factor Bach1, represses the expression of myeloid genes. The repression of the myeloid program is critical for the progenitor cells to be committed to the B cell fate (5). At the stage of pre-B cells, the successful completion of antibody heavy chain gene rearrangement is monitored by the lack or presence of pre-B cell receptor (pre-BCR 2 checkpoint). Bach2 plays a critical role in negative selection (i.e. elimination of cells unsuccessful in the rearrangement) at the pre-BCR checkpoint (6). In mature B cells, Bach2 is required for the class switch recombination (CSR) and somatic hypermutation that diversify the effector function and antigen affinity, respectively, of antibody molecules in response to antigen and other stimulation (7). Bach2 promotes CSR by delaying the expression of Blimp-1, the master regulator of plasma cell differentiation, and thereby securing a time window for CSR before the terminal differentiation to plasma cells (8 -10). A reduction in the Bach2 expression in memory B cells is involved in their rapid plasma cell differentiation upon antigen re-exposure (11). An integral view of the Bach2 functions in B cells has been proposed as a gene regulatory network (GRN) consisting of Bach2 and other * This work was supported by Grants-in-aid 15H02506, 25670156, 24390066, 23116003, 21249014, 17054028, and 25291042

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“…Autocrine IL-7 production would result in increased pro-B cell proliferation and may thereby hamper V(D)J recombination, because the Rag2 protein is unstable in cycling cells (44,45). Moreover, IL-7R signaling is also coupled to phosphatidylinositol-3-OH kinase and Akt activation, which suppresses the expression of Rag proteins as well as FoxO1, Pax5, and Ikaros (46,47). To directly examine whether enhanced IL-7R signaling in pro-B cells is associated with limited IgH locus accessibility, we analyzed V H gene usage in Tg mice in which overexpression of IL-7 is driven by the mouse MHC class II Ea promoter (48).…”

Section: Slp65mentioning

confidence: 99%

Highly Restricted Usage of Ig H Chain VH14 Family Gene Segments in Slp65-Deficient Pre-B Cell Leukemia in Mice

Bruijn

Matheson

et al. 2012

The Journal of Immunology

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Mice deficient for the adapter protein Slp65 (also known as Blnk), a key component in precursor-BCR (pre-BCR) signaling, spontaneously develop pre-B cell leukemia. In these leukemias, proliferation is thought to be driven by constitutive Jak3/Stat5 signaling, mostly due to autocrine production of IL-7, together with high surface expression of the pre-BCR. In this study, we investigated whether particular IgH specificities would predispose Slp65-deficient pre-B cells to malignant transformation. Whereas VH-D-JH junctions were diverse, we found highly restricted Ig VH gene usage: 55 out of 60 (∼92%) leukemias used a VH14/SM7-family gene, mainly VH14-1 and VH14-2. When combined with surrogate or conventional L chains, these VH14 IgH chains did not provide increased proliferative signals or exhibit enhanced poly- or autoreactivity. We therefore conclude that pre-BCR specificity per se did not contribute to oncogenic transformation. Remarkably, in a high proportion of Slp65-deficient leukemias, the nonexpressed IgH allele also harbored a VH14-family rearrangement (10 out of 50) or was in the germline configuration (10 out of 50). VH14-1 and VH14-2 gene regions differed from their neighboring VH genes in that they showed active H3K4me3 histone modification marks and germline transcription at the pro-B cell stage in Rag1-deficient mice. Taken together, these findings demonstrate that in Slp65-deficient mice, malignant transformation is largely limited to particular pre-B cells that originate from pro-B cells that had restricted IgH VH region accessibility at the time of VH-to D-JH recombination.

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A self-reinforcing regulatory network triggered by limiting IL-7 activates pre-BCR signaling and differentiation

Cited by 149 publications

References 38 publications

Toll-like receptor 4-mediated signaling regulates IL-7-driven proliferation and differentiation of B-cell precursors

Toll-like receptor 4-mediated signaling regulates IL-7-driven proliferation and differentiation of B-cell precursors

The Transcription Factor Bach2 Is Phosphorylated at Multiple Sites in Murine B Cells but a Single Site Prevents Its Nuclear Localization

Highly Restricted Usage of Ig H Chain VH14 Family Gene Segments in Slp65-Deficient Pre-B Cell Leukemia in Mice

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