The Igκ 3′ Enhancer Influences the Ratio of Igκ versus Igλ B Lymphocytes

Gorman, James R.; Stoep, Nienke van der; Monroe, R. J.; Cogné, Michel; Davidson, Laurie A.; Alt, Frederick W.

doi:10.1016/s1074-7613(00)80319-2

Cited by 156 publications

(143 citation statements)

References 61 publications

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“…Two basic models have been proposed to account for allelic exclusion: the regulated model and the stochastic model. In the regulated model, a functional rearrangement on one allele provides a signal that prevents, through feedback inhibition, further rearrangements on the other allele (74,75). In the stochastic model, the probability and efficiency of V(D)J rearrangement is sufficiently low that allelic exclusion is obtained by "default.…”

Section: Discussionmentioning

confidence: 99%

B Cell Receptor Basal Signaling Regulates Antigen-Induced Ig Light Chain Rearrangements

Schram

Tze

Ramsey

et al. 2008

The Journal of Immunology

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BCR editing in the bone marrow contributes to B cell tolerance by orchestrating secondary Ig rearrangements in self-reactive B cells. We have recently shown that loss of the BCR or a pharmacologic blockade of BCR proximal signaling pathways results in a global “back-differentiation” response in which immature B cells down-regulate genes important for the mature B cell program and up-regulate genes characteristic of earlier stages of B cell development. These observations led us to test the hypothesis that self-Ag-induced down-regulation of the BCR, and not self-Ag-induced positive signals, lead to Rag induction and hence receptor editing. Supporting this hypothesis, we found that immature B cells from xid (x-linked immunodeficiency) mice induce re-expression of a Rag2-GFP bacterial artificial chromosome reporter as well as wild-type immature B cells following Ag incubation. Incubation of immature B cells with self-Ag leads to a striking reversal in differentiation to the pro-/pre-B stage of development, consistent with the idea that back-differentiation results in the reinduction of genes required for L chain rearrangement and receptor editing. Importantly, Rag induction, the back-differentiation response to Ag, and editing in immature and pre-B cells are inhibited by a combination of phorbol ester and calcium ionophore, agents that bypass proximal signaling pathways and mimic BCR signaling. Thus, mimicking positive BCR signals actually inhibits receptor editing. These findings support a model whereby Ag-induced receptor editing is inhibited by BCR basal signaling on developing B cells; BCR down-regulation removes this basal signal, thereby initiating receptor editing.

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Section: Discussionmentioning

confidence: 99%

B Cell Receptor Basal Signaling Regulates Antigen-Induced Ig Light Chain Rearrangements

Schram

Tze

Ramsey

et al. 2008

The Journal of Immunology

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“…Ig light-chain gene transcription and recombination are dependent on the activity of several enhancer elements (Hagman et al 1990;Gorman et al 1996;Xu et al 1996;Inlay et al 2002). The locus has two distinct enhancers (Ei and E3Ј ), whereas the locus has two duplicated enhancers (E 2-4, E 3-1).…”

Section: Irf-48 −/− Pre-b Cells Are Impaired For Light-chain Gene Trmentioning

confidence: 99%

IRF-4,8 orchestrate the pre-B-to-B transition in lymphocyte development

Lu¹,

Medina²,

Lancki³

et al. 2003

Genes Dev.

240

229

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IRF-4,8 are two specialized members of the interferon regulatory factor (IRF) family that have been implicated in regulating immunoglobulin (Ig) light-chain gene transcription during B-lymphocyte development (Pongubala et al. 1992;Eisenbeis et al. 1995;Shaffer et al. 1997;Brass et al. 1999; Muljo and Schlissel 2002). They are more highly related to one another than to other IRFs and are selectively expressed in the lymphoid and myeloid lineages of the immune system (for review, see Taniguchi et al. 2001). IRF-4,8 bind very weakly to DNA-containing IRF sites, but are recruited to their binding sites via interactions with other transcription factors. In particular, the related Ets family transcription factors PU.1 and Spi-B have been shown to recruit IRF-4 or IRF-8 to Ets-IRF composite elements (EICE) in Ig 3Ј and enhancers (Pongubala et al. 1992;Eisenbeis et al. 1995;Brass et al. 1999;Escalante et al. 2002). These heterodimeric protein complexes have been implicated in the control of Ig light-chain gene transcription. PU.1 is required for early B-cell development and Spi-B is important for B-cell activation (Scott et al. 1994;Su et al. 1997). It remains to be determined whether PU.1/Spi-B regulate Ig light-chain gene expression during the pre-B-to-B transition. IRF-4 −/− mutant mice exhibit profound defects in B-and T-cell activation that are manifested in the failure to mount antibody, cytotoxic, or antitumor responses (Mittrucker et al. 1997;Rengarajan et al. 2002). IRF-8 −/− mutant mice are impaired in macrophage development, highly susceptible to viral infections, and manifest a chronic myelogenous leukemia-like syndrome (Holtschke et al. 1996). Loss of either IRF-4 or IRF-8 does not block the generation of B lymphocytes. Given their structural relatedness and similar molecular properties, we sought to examine whether they function redundantly to regulate Ig lightchain gene expression and the pre-B-to-B transition. (Fig. 1A). Strikingly, the double mutant mice lacked sIgM + peripheral B lymphocytes (Fig. 1B). In contrast, splenic T lymphocytes, (CD4 + or CD8 + ) were present in the double mutant mice, albeit with reduced numbers (Fig. 1C). We note that loss of IRF-4 and IRF-8 does not impair T-cell development in the thymus (data not shown). We next examined B-cell generation in the bone marrow. Immature IgM + B cells were absent in the IRF-4,8 −/− bone marrow (Fig. 1D). These results establish that the combined loss of IRF-4,8 causes a lineage-specific block to B-cell development. It should be noted that as is the case for IRF-8 −/− mice, there was an increase in the numbers of myeloid cells Fig. 2A). The levels of HSA expression on the mutant B220 + , CD43 + , BP-1 + , B-lineage cells were particularly high, suggesting that they represent transitional pre-B cells, which are a subset of fraction C cells in the nomenclature of Hardy et al. (1991). The disproportionate increase in the percentage fraction C cells in the IRF-4,8 −/− bone marrow ( Fig. 2A) was also reflected in a substantial increase in their a...

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“…Interestingly, targeted deletions of either the kappa intron or 3Ј enhancer results in a decreased efficiency of recombination at kappa (18,59). These results suggest that while both enhancers contribute to activation of kappa recombination, neither enhancer is strictly required.…”

Section: Discussionmentioning

confidence: 92%

“…In addition, it has been demonstrated previously that induction of germ line transcription of the unrearranged kappa Ig lightchain and heavy-chain loci is accompanied by an increased frequency of gene rearrangement (44, 45). More direct evidence that cis-acting transcriptional regulatory elements are involved in recombination has been demonstrated by integration of recombination substrates by using transfection approaches (5, 6, 11, 24, 35), transgenic approaches (15-17, 20, 21), and targeted knockouts of endogenous sequences (18,48,54,59). …”

mentioning

confidence: 99%

“…Two tissue-specific transcriptional enhancers contribute to the developmental regulation of expression: one between the joining (J)-and constant (C)-region exons referred to as the intron enhancer (40), and another located 9 kb downstream of the C-region exon (3ЈKE) (27). Each of these elements plays a role in the developmental regulation of kappa transcription, and many have been implicated in a potential role in regulation of V -to-J recombination (13,18,22,59).Induction of kappa transcription by cytokines and mitogens, including lipopolysaccharide (LPS), in Abelson virus-transformed pre-B-cell lines has provided an important model sys- …”

mentioning

confidence: 99%

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Coordinate Transcription and V(D)J Recombination of the Kappa Immunoglobulin Light-Chain Locus: NF-κB-Dependent and -Independent Pathways of Activation

O'Brien

Oltz

Ness

1997

Molecular and Cellular Biology

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To further elucidate the potential role of mitogens and cytokines in regulation of the kappa immunoglobulin light-chain locus, we have characterized the activation of transcription factor binding, kappa germ line transcription, DNase I hypersensitivity, and V -to-J recombination upon induction of model pre-B-cell lines. We find that both lipopolysaccharide (LPS) and gamma interferon (IFN-␥) are capable of activating germ line transcription, DNase I hypersensitivity, and recombination of the kappa locus. We also find that transforming growth factor ␤ is capable of completely inhibiting LPS activation of transcription and recombination but has no apparent effect on activation of transcription factor binding, It is becoming increasingly clear that the tissue-specific and developmentally regulated transcription and recombination of immunoglobulin (Ig) gene segments represent overlapping points of control during B-cell development. The concomitant activation of transcription and recombination of all Ig loci has led to the suggestion that transcription of unrearranged Ig genes plays a key role in regulating recombination (23, 31, 37, 44-46, 55, 60, 61). A number of observations have provided strong support for this hypothesis. First, while a common V(D)J recombinase is expressed in both B cells and T cells, functional recombination of Ig genes is restricted to B cells, where they are also transcriptionally active (62). While ectopic expression of the recombinase activating genes RAG-1 and RAG-2 has been shown to confer V(D)J recombinase activity to integrated and extrachromosomal substrates in nonlymphoid cells, the endogenous Ig loci, which are transcriptionally silent in these cells, do not undergo recombination (19,25,33). In addition, it has been demonstrated previously that induction of germ line transcription of the unrearranged kappa Ig lightchain and heavy-chain loci is accompanied by an increased frequency of gene rearrangement (44, 45). More direct evidence that cis-acting transcriptional regulatory elements are involved in recombination has been demonstrated by integration of recombination substrates by using transfection approaches (5, 6, 11, 24, 35), transgenic approaches (15-17, 20, 21), and targeted knockouts of endogenous sequences (18,48,54,59).While there is strong evidence that cis-acting transcriptional regulatory regions within the kappa Ig light-chain locus play a role in recombination, the mechanism by which they regulate recombination and the trans-acting factors involved have yet to be elucidated. The observation that cells are able to regulate the ability of the endogenous kappa locus to serve as a substrate for the V(D)J recombinase has led to the suggestion that transcription may target the locus by providing accessibility of the locus to the recombinase (see reviews in references 32, 39, and 47). The mechanism by which transcription may mediate accessibility is not clear; however, changes in local chromatin structure within the kappa locus have been shown to occur upon transcriptional ac...

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The Igκ 3′ Enhancer Influences the Ratio of Igκ versus Igλ B Lymphocytes

Cited by 156 publications

References 61 publications

B Cell Receptor Basal Signaling Regulates Antigen-Induced Ig Light Chain Rearrangements

B Cell Receptor Basal Signaling Regulates Antigen-Induced Ig Light Chain Rearrangements

IRF-4,8 orchestrate the pre-B-to-B transition in lymphocyte development

Coordinate Transcription and V(D)J Recombination of the Kappa Immunoglobulin Light-Chain Locus: NF-κB-Dependent and -Independent Pathways of Activation

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