V(D)J Recombinase Activity in a Subset of Germinal Center B Lymphocytes

Han, Shuhua; Dillon, Stacey R.; Zheng, Biao; Shimoda, Michiko; Schlissel, Mark S.; Kelsoe, Garnett

doi:10.1126/science.278.5336.301

Cited by 264 publications

(213 citation statements)

References 29 publications

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“…RAG expression and L chain editing in the SPL have been reported earlier in immunized mice (67)(68)(69)(70)(71) and in LPS/IL-4-stimulated splenic B cells (72). However, such RAG expression and L chain editing may not occur, as initially thought, in mature splenic (germinal center) B cells.…”

Section: Rag Expression and L Chain Editing In B Cells Deficient For mentioning

confidence: 88%

Antigen Receptor Editing in Anti-DNA Transitional B Cells Deficient for Surface IgM

Kiefer

Nakajima

Oshinsky

et al. 2008

The Journal of Immunology

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In response to encounter with self-Ag, autoreactive B cells may undergo secondary L chain gene rearrangement (receptor editing) and change the specificity of their Ag receptor. Knowing at what differentiative stage(s) developing B cells undergo receptor editing is important for understanding how self-reactive B cells are regulated. In this study, in mice with Ig transgenes coding for anti-self (DNA) Ab, we report dsDNA breaks indicative of ongoing secondary L chain rearrangement not only in bone marrow cells with a pre-B/B cell phenotype but also in immature/transitional splenic B cells with little or no surface IgM (sIgM−/low). L chain-edited transgenic B cells were detectable in spleen but not bone marrow and were still found to produce Ab specific for DNA (and apoptotic cells), albeit with lower affinity for DNA than the unedited transgenic Ab. We conclude that L chain editing in anti-DNA-transgenic B cells is not only ongoing in bone marrow but also in spleen. Indeed, transfer of sIgM−/low anti-DNA splenic B cells into SCID mice resulted in the appearance of a L chain editor (Vλx) in the serum of engrafted recipients. Finally, we also report evidence for ongoing L chain editing in sIgMlow transitional splenic B cells of wild-type mice.

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Section: Rag Expression and L Chain Editing In B Cells Deficient For mentioning

confidence: 88%

Antigen Receptor Editing in Anti-DNA Transitional B Cells Deficient for Surface IgM

Kiefer

Nakajima

Oshinsky

et al. 2008

The Journal of Immunology

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“…the bone marrow and in germinal centers (10,15,17,18). However, these two cell populations differ in that, unlike the bone marrow cells, BCR cross-linking in the germinal center cells leads to down-regulation of RAG expression (18,20).…”

Section: Bcr Cross-linking Decreases Rag2 Expression In 38c-13 Cellsmentioning

confidence: 99%

Secondary V(D)J Rearrangements and B Cell Receptor-Mediated Down-Regulation of Recombination Activating Gene-2 Expression in a Murine B Cell Line

Maës

Caspi

Rougeon

et al. 2000

The Journal of Immunology

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It has recently become clear that recombination of Ig genes is not restricted to B cell precursors but that secondary rearrangements can also occur under certain conditions in phenotypically immature bone marrow and peripheral B cells. However, the nature of these cells and the regulation of secondary V(D)J recombination in response to B cell receptor (BCR) stimulation remain controversial. In the present study, we have analyzed secondary light chain gene rearrangements and recombination activating gene (RAG) expression in the surface IgM+, IgD− murine B cell line, 38C-13, which has previously been found to undergo κ light chain replacement. We find that 38C-13 cells undergo spontaneous secondary Vκ-Jκ and RS rearrangements in culture, with recombination occurring on both productive and nonproductive alleles. Both 38C-13 cells and the Id-negative variants express the RAG genes, indicating that the presence of RAG does not depend on activation via the 38C-13 BCR. Moreover, BCR cross-linking in 38C-13 cells leads to a rapid and reversible down-regulation of RAG2 mRNA. Therefore, 38C-13 cells resemble peripheral IgM+, IgD− B cells undergoing light chain gene rearrangement and provide a possible in vitro model for studying peripheral V(D)J recombination.

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“…[15][16][17][18][19][20] Recent studies proposed an interesting model in which mature B cells also undergo a similar process, termed receptor editing, in GCs of secondary lymphoid follicles after stimulation by Tdependent (TD) Ags. [21][22][23][24][25] This notion has been supported by the detection of rag1/rag2 transcripts and by the evidence of immunoglobulin gene rearrangements in situ, suggesting that receptor editing occurs in the GC light zone. 21 In addition, stimulation with anti-CD40 monoclonal antibody (mAb) plus interleukin-4 (IL-4), or lipopolysaccharide (LPS) plus IL-4, induced the up-regulation of rag1/rag2 transcripts and immunoglobulin gene rearrangements in mature surface immunoglobulin M (sIgM) ϩ B cells in vitro.…”

Section: Introductionmentioning

confidence: 49%

“…The observation of no RAG1/GFP signal in the centrocyte region of the GCs was surprising because others had reported RAG re-expression after immunization. [21][22][23][24][25] Loss of GFP expression in GCs could be due to differences of Ags or the immunization protocol. Therefore, we immunized mice with the same batch of NP-CGG and by the same immunization protocol described previously.…”

Section: Localization Of Rag1/gfp ؉ Cells In Peripheral Lymphoid Orgamentioning

confidence: 99%

Localization of recombination activating gene 1/green fluorescent protein (RAG1/GFP) expression in secondary lymphoid organs after immunization with T-dependent antigens in rag1/gfpknockin mice

Igarashi

Kuwata

Kiyota

et al. 2001

Blood

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IntroductionB cells are generated in the fetal liver or the adult bone marrow (BM) after immunoglobulin gene rearrangements that create a primary repertoire of random antibody (Ab) specificity. 1-3 B cells that react to various self-antigens (Ags) at immature stages are thought to experience anergy after encountering Ags or to be eliminated by apoptotic mechanisms in the BM microenvironment. [4][5][6] It has been suggested that a substantial proportion of B cells reactive to self-Ags undergoes a process known as receptor editing in which secondary immunoglobulin gene rearrangements replace variable (V) gene segments, generating a new Ab specificity as a part of the primary Ab repertoire. 7-11 B cells recruited to the circulation are stimulated by Ags and helper-T (Th) cells in the T cell area of secondary lymphoid organs. 12-14 Such Ag-driven B cells subsequently undergo rapid proliferation to become centroblasts located in the dark zone of germinal centers (GCs) and then arrest cell cycling and become small centrocytes in the light zone. [15][16][17][18][19][20] Recent studies proposed an interesting model in which mature B cells also undergo a similar process, termed receptor editing, in GCs of secondary lymphoid follicles after stimulation by Tdependent (TD) Ags. [21][22][23][24][25] This notion has been supported by the detection of rag1/rag2 transcripts and by the evidence of immunoglobulin gene rearrangements in situ, suggesting that receptor editing occurs in the GC light zone. 21 In addition, stimulation with anti-CD40 monoclonal antibody (mAb) plus interleukin-4 (IL-4), or lipopolysaccharide (LPS) plus IL-4, induced the up-regulation of rag1/rag2 transcripts and immunoglobulin gene rearrangements in mature surface immunoglobulin M (sIgM) ϩ B cells in vitro. 22,[24][25][26] These results suggested that mature B cells frequently undergo receptor editing in GCs after stimulation with Ags. The receptor editing mechanism might provide a more flexible and diverse Ab specificity response than the one produced solely by the somatic mutation mechanism. The receptor editing in GCs could be a requisite molecular event for an immediate and effective response producing high-affinity Abs against various antigenic stimuli. Alternatively, receptor editing could salvage B cells carrying anti-self specificities.The reactivation of rag gene expression has been suggested as one mechanism for the immunoglobulin gene rearrangements that occur in receptor revision. 27,28 To demonstrate direct in vivo evidence of the induction of RAG molecules in GCs and to measure the frequency of cells undergoing receptor editing (or receptor revision), we examined lymphoid organs for RAG1/green fluorescent protein (GFP) signal using immunized or unimmunized rag1/gfp knockin mice. Unimmunized heterozygous rag1/gfp knockin mice express GFP that can be detected at high sensitivity by microscopic observation of splenic sections. Surprisingly, when we examined GCs of immunized mice, we observed that the RAG1/GFP signal was not significantly indu...

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V(D)J Recombinase Activity in a Subset of Germinal Center B Lymphocytes

Cited by 264 publications

References 29 publications

Antigen Receptor Editing in Anti-DNA Transitional B Cells Deficient for Surface IgM

Antigen Receptor Editing in Anti-DNA Transitional B Cells Deficient for Surface IgM

Secondary V(D)J Rearrangements and B Cell Receptor-Mediated Down-Regulation of Recombination Activating Gene-2 Expression in a Murine B Cell Line

Localization of recombination activating gene 1/green fluorescent protein (RAG1/GFP) expression in secondary lymphoid organs after immunization with T-dependent antigens in rag1/gfpknockin mice

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