scholarly journals BCL6 is critical for the development of a diverse primary B cell repertoire

2010 ◽  
Vol 207 (6) ◽  
pp. 1209-1221 ◽  
Author(s):  
Cihangir Duy ◽  
J. Jessica Yu ◽  
Rahul Nahar ◽  
Srividya Swaminathan ◽  
Soo-Mi Kweon ◽  
...  
Keyword(s):  
Dna Damage ◽  
B Cells ◽  
B Cell ◽  
Light Chain ◽  
Gene Rearrangement ◽  
Chain Gene ◽  
Cell Repertoire ◽  
Light Chain Gene ◽  
B Cell Repertoire ◽  
Induced Apoptosis

BCL6 protects germinal center (GC) B cells against DNA damage–induced apoptosis during somatic hypermutation and class-switch recombination. Although expression of BCL6 was not found in early IL-7–dependent B cell precursors, we report that IL-7Rα–Stat5 signaling negatively regulates BCL6. Upon productive VH-DJH gene rearrangement and expression of a μ heavy chain, however, activation of pre–B cell receptor signaling strongly induces BCL6 expression, whereas IL-7Rα–Stat5 signaling is attenuated. At the transition from IL-7–dependent to –independent stages of B cell development, BCL6 is activated, reaches expression levels resembling those in GC B cells, and protects pre–B cells from DNA damage–induced apoptosis during immunoglobulin (Ig) light chain gene recombination. In the absence of BCL6, DNA breaks during Ig light chain gene rearrangement lead to excessive up-regulation of Arf and p53. As a consequence, the pool of new bone marrow immature B cells is markedly reduced in size and clonal diversity. We conclude that negative regulation of Arf by BCL6 is required for pre–B cell self-renewal and the formation of a diverse polyclonal B cell repertoire.

scholarly journals Phospholipase Cγ2 Contributes to Light-Chain Gene Activation and Receptor Editing

2007 ◽  
Vol 27 (17) ◽  
pp. 5957-5967 ◽  
Author(s):  
Li Bai ◽  
Yuhong Chen ◽  
Yinghong He ◽  
Xuezhi Dai ◽  
Xueyan Lin ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Light Chain ◽  
Gene Activation ◽  
Chain Gene ◽  
Receptor Editing ◽  
Light Chain Gene ◽  
Transitional Type

ABSTRACT Phospholipase Cγ2 (PLCγ2) is critical for pre-B-cell receptor (pre-BCR) and BCR signaling. Current studies discovered that PLCγ2-deficient mice had reduced immunoglobulin λ (Igλ) light-chain usage throughout B-cell maturation stages, including transitional type 1 (T1), transitional type 2 (T2), and mature follicular B cells. The reduction of Igλ rearrangement by PLCγ2 deficiency was not due to specifically increased apoptosis or decreased proliferation of mutant Igλ+ B cells, as lack of PLCγ2 exerted a similar effect on apoptosis and proliferation of both Igλ+ and Igκ+ B cells. Moreover, PLCγ2-deficient IgHEL transgenic B cells exhibited an impairment of antigen-induced receptor editing among both the endogenous λ and κ loci in vitro and in vivo. Importantly, PLCγ2 deficiency impaired BCR-induced expression of IRF-4 and IRF-8, the two transcription factors critical for λ and κ light-chain rearrangements. Taken together, these data demonstrate that the PLCγ2 signaling pathway plays a role in activation of light-chain loci and contributes to receptor editing.

scholarly journals Molecular requirements for the mu-induced light chain gene rearrangement in pre-B cells.

1991 ◽  
Vol 10 (8) ◽  
pp. 2147-2155 ◽  
Author(s):  
A. Iglesias ◽  
M. Kopf ◽  
G.S. Williams ◽  
B. Bühler ◽  
G. Köhler
Keyword(s):  
B Cells ◽  
Light Chain ◽  
Gene Rearrangement ◽  
Chain Gene ◽  
Light Chain Gene ◽  
Chain Gene Rearrangement

scholarly journals ImmunoglobulinλGene Rearrangement Can PrecedeκGene Rearrangement

1990 ◽  
Vol 1 (1) ◽  
pp. 53-57 ◽  
Author(s):  
Jörg Berg ◽  
Mindy Mcdowell ◽  
Hans-Martin Jäck ◽  
Matthias Wabl
Keyword(s):  
B Cell ◽  
Heavy Chain ◽  
Light Chain ◽  
Gene Rearrangement ◽  
Germ Line ◽  
Stochastic Theory ◽  
Chain Gene ◽  
Light Chain Gene ◽  
Line Configuration ◽  
Chain Gene Rearrangement

Immunoglobulin genes are generated during differentiation of B lymphocytes by joining gene segments. A mouse pre-B cell contains a functional immunoglobulin heavy-chain gene, but no light-chain gene. Although there is only one heavy-chain locus, there are two lightchain loci:κandλ.It has been reported thatκloci in the germ-line configuration are never (in man) or very rarely (in the mouse) present in cells with functionally rearrangedλ-chain genes. Two explanations have been proposed to explain this: (a) the ordered rearrangement theory, which postulates that light-chain gene rearrangement in the pre-B cell is first attempted at theκlocus, and that only upon failure to produce a functionalκchain is there an attempt to rearrange theλlocus; and (b) the stochastic theory, which postulates that rearrangement at theλlocus proceeds at a rate that is intrinsically much slower than that at theκlocus. We show here thatλ-chain genes are generated whether or not theκlocus has lost its germ-line arrangement, a result that is compatible only with the stochastic theory.

scholarly journals Immunoglobulin x light chain gene promoter and enhancer are not responsible for B-cell restricted gene rearrangement

1989 ◽  
Vol 17 (18) ◽  
pp. 7403-7415 ◽  
Author(s):  
Michele Goodhardt ◽  
Charles Babinet ◽  
Georges Lutfalla ◽  
Sacha Kallenbach ◽  
Patricia Caveher ◽  
...  
Keyword(s):  
B Cell ◽  
Light Chain ◽  
Gene Rearrangement ◽  
Gene Promoter ◽  
Chain Gene ◽  
Light Chain Gene

scholarly journals Bruton’s Tyrosine Kinase and SLP-65 Regulate Pre-B Cell Differentiation and the Induction of Ig Light Chain Gene Rearrangement

2006 ◽  
Vol 176 (8) ◽  
pp. 4543-4552 ◽  
Author(s):  
Rogier Kersseboom ◽  
Van B. T. Ta ◽  
A. J. Esther Zijlstra ◽  
Sabine Middendorp ◽  
Hassan Jumaa ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Light Chain ◽  
Gene Rearrangement ◽  
Chain Gene ◽  
B Cell Differentiation ◽  
Bruton's Tyrosine Kinase ◽  
Light Chain Gene ◽  
Chain Gene Rearrangement

scholarly journals Expression of a Targeted λ1 Light Chain Gene Is Developmentally Regulated and Independent of Igκ Rearrangements

2003 ◽  
Vol 197 (9) ◽  
pp. 1165-1172 ◽  
Author(s):  
Philipp Oberdoerffer ◽  
Tatiana I. Novobrantseva ◽  
Klaus Rajewsky
Keyword(s):  
B Cell ◽  
Light Chain ◽  
Gene Rearrangement ◽  
Gene Segment ◽  
Chain Gene ◽  
Wild Type ◽  
Immunoglobulin Light Chain ◽  
Developmentally Regulated ◽  
Light Chain Gene

Immunoglobulin light chain (IgL) rearrangements occur more frequently at Igκ than at Igλ. Previous results suggested that the unrearranged Igκ locus negatively regulates Igλ transcription and/or rearrangement. Here, we demonstrate that expression of a VJλ1-joint inserted into its physiological position in the Igλ locus is independent of Igκ rearrangements. Expression of the inserted VJλ1 gene segment is developmentally controlled like that of a VJκ-joint inserted into the Igκ locus and furthermore coincides developmentally with the occurrence of Igκ rearrangements in wild-type mice. We conclude that developmentally controlled transcription of a gene rearrangement in the Igλ locus occurs in the presence of an unrearranged Igκ locus and is therefore not negatively regulated by the latter. Our data also indicate light chain editing in ∼30% of λ1 expressing B cell progenitors.

scholarly journals Receptor Editing Occurs Frequently during Normal B Cell Development

1998 ◽  
Vol 188 (7) ◽  
pp. 1231-1238 ◽  
Author(s):  
Marc W. Retter ◽  
David Nemazee
Keyword(s):  
B Cells ◽  
B Cell ◽  
Light Chain ◽  
Cell Receptor ◽  
Feedback Mechanism ◽  
Chain Gene ◽  
Allelic Exclusion ◽  
Receptor Editing ◽  
Light Chain Gene ◽  
Immature B Cells

Allelic exclusion is established in development through a feedback mechanism in which the assembled immunoglobulin (Ig) suppresses further V(D)J rearrangement. But Ig expression sometimes fails to prevent further rearrangement. In autoantibody transgenic mice, reactivity of immature B cells with autoantigen can induce receptor editing, in which allelic exclusion is transiently prevented or reversed through nested light chain gene rearrangement, often resulting in altered B cell receptor specificity. To determine the extent of receptor editing in a normal, non-Ig transgenic immune system, we took advantage of the fact that λ light chain genes usually rearrange after κ genes. This allowed us to analyze κ loci in IgMλ+ cells to determine how frequently in-frame κ genes fail to suppress λ gene rearrangements. To do this, we analyzed recombined VκJκ genes inactivated by subsequent recombining sequence (RS) rearrangement. RS rearrangements delete portions of the κ locus by a V(D)J recombinase-dependent mechanism, suggesting that they play a role in receptor editing. We show that RS recombination is frequently induced by, and inactivates, functionally rearranged κ loci, as nearly half (47%) of the RS-inactivated VκJκ joins were in-frame. These findings suggest that receptor editing occurs at a surprisingly high frequency in normal B cells.

scholarly journals Dual Mechanism of Rag Gene Repression by c-Myb during Pre-B Cell Proliferation

2017 ◽  
Vol 37 (12) ◽  
Author(s):  
Greg A. Timblin ◽  
Liangqi Xie ◽  
Robert Tjian ◽  
Mark S. Schlissel
Keyword(s):  
B Cells ◽  
B Cell ◽  
Gene Rearrangement ◽  
Molecular Mechanisms ◽  
Regulatory Element ◽  
Clonal Expansion ◽  
Chain Gene ◽  
Transactivation Domain ◽  
Light Chain Gene ◽  
Chain Gene Rearrangement

ABSTRACT Developing B lymphocytes undergo clonal expansion following successful immunoglobulin heavy chain gene rearrangement. During this proliferative burst, expression of the Rag genes is transiently repressed to prevent the generation of double-stranded DNA (dsDNA) breaks in cycling large pre-B cells. The Rag genes are then reexpressed in small, resting pre-B cells for immunoglobulin light chain gene rearrangement. We previously identified c-Myb as a repressor of Rag transcription during clonal expansion using Abelson murine leukemia virus-transformed B cells. Nevertheless, the molecular mechanisms by which c-Myb achieved precise spatiotemporal repression of Rag expression remained obscure. Here, we identify two mechanisms by which c-Myb represses Rag transcription. First, c-Myb negatively regulates the expression of the Rag activator Foxo1, an activity dependent on M303 in c-Myb's transactivation domain, and likely the recruitment of corepressors to the Foxo1 locus by c-Myb. Second, c-Myb represses Rag transcription directly by occupying the Erag enhancer and antagonizing Foxo1 binding to a consensus forkhead site in this cis-regulatory element that we show is crucial for Rag expression in Abelson pre-B cell lines. This work provides important mechanistic insight into how spatiotemporal expression of the Rag genes is tightly controlled during B lymphocyte development to prevent mistimed dsDNA breaks and their deleterious consequences.

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