Basal Immunoglobulin Signaling Actively Maintains Developmental Stage in Immature B Cells

Tze, Lina E.; Schram, Brian R.; Lam, Kong-Peng; Hogquist, Kristin A.; Hippen, Keli L.; Liu, Jiabin; Shinton, Susan A.; Otipoby, Kevin L.; Rodine, Peter R.; Vegoe, Amanda L.; Kraus, Manfred; Hardy, Richard R.; Schlissel, Mark S.; Rajewsky, Klaus; Behrens, Timothy W.

doi:10.1371/journal.pbio.0030082

Cited by 119 publications

(145 citation statements)

References 51 publications

Supporting

Mentioning

136

Contrasting

Order By: Relevance

“…Several studies have now indicated that it is the strength of the BCR signal that determines whether the BCR-triggered cells are allowed to progress in development (positive selection) or will have to undergo receptor editing in order to be rescued [48][49][50][51][52][53][54][55][56][57]. Thus immature B cells that express a non-auto-reactive receptor consisting of an efficiently interacting combination of IgH and IgL chains seem to receive the right amount of BCR signaling (also called tonic or basal BCR signaling), which allows them to progress in development and are thus positively selected [48][49][50][51][52][53][54][55][56][57]. These cells then switch off RAG expression and are allowed to migrate to the spleen.…”

Section: Immature Bone Marrow B Cellsmentioning

confidence: 99%

Tolerance checkpoints in B‐cell development: Johnny B good

et al. 2009

View full text Add to dashboard Cite

B-cell development up to the immature B-cell stage takes place in the bone marrow, while final maturation into mature B cells occurs in the spleen. During differentiation, the precursor and immature B cells have to pass several checkpoints, including those in which they are censored for being auto-reactive, and therefore being potentially dangerous. Numerous studies have shown that the immature B-cell stage in the bone marrow and the transitional B-cell stages in the spleen comprise distinct checkpoints at which autoreactivity is censored. Recently, evidence has been provided that the large pre-BII stage in the bone marrow, at which the pre-BCR is expressed, is yet another B-cell tolerance checkpoint. Here, we review these findings and speculate on directions for possible further experimentation.Key words: B cells . Negative selection . Positive selection . Receptor editing . Tolerance Introduction B-cell development, as it takes place in the bone marrow and spleen, can be subdivided into various stages based on the expression of different cell-surface and intra-cellular markers, the cell cycle profile and the rearrangement status of the cell's Ig-heavy (IgH) and Ig-light (IgL) chains [1][2][3][4]. In Fig. 1, the different stages of B-cell development in the bone marrow and spleen and the most important cell-surface markers by which different subpopulations can be distinguished are depicted. Moreover, the stages in which censoring for auto-reactivity takes place are shown in gray.The earliest B-lineage cell type found in the bone marrow is the pro/pre-BI cell. This cell type is characterized by the expression of CD19 and CD117 (c-kit) and the IgH chain loci are in a rearranged D-J configuration [4][5][6]. Under physiological conditions, these cells are already committed to the B-cell lineage. However, their commitment can be reversed by the ablation of the B-cell identity gene Pax5 [7][8][9]. Pro/pre-BI cells are the direct precursors of large pre-BII cells, which have lost CD117 expression and gained the expression of CD25 [3]. At this stage of differentiation, the IgH chain loci are V to D-J rearranged and those that have done this successfully (synthesized a m-heavy (mH) chain) are positively selected within this compartment. This positive selection is mediated by the pre-BCR, which is composed of the mH chain and the surrogate light chain proteins . Moreover, the pre-BCR induces a strong proliferation of these positively selected pre-B cells [12,13]. A very recent report indicates that the pre-BCR might also be involved in the censoring of B-cell auto-reactivity [16]. These findings will be discussed in the section Large pre-BII cells.Pre-BCR signaling down-modulates transcription of the surrogate light chain genes , and thereby extinguishes its own expression. Upon down-modulation of surface pre-BCR expression, cells stop proliferating and enter the small pre-BII compartment [3]. At this developmental stage, [18][19][20]. It is at this stage of development that, for the first time, cells are censored for t...

show abstract

Section: Immature Bone Marrow B Cellsmentioning

confidence: 99%

Tolerance checkpoints in B‐cell development: Johnny B good

et al. 2009

View full text Add to dashboard Cite

show abstract

“…We recently reported that deletion of the BCR from immature B cells generated in IL-7 BM cultures following Cre-mediated excision of a floxed H chain led to the induction of Rag expression and a new L chain rearrangements (29). Incubation of immature B cells with a tyrosine kinase inhibitor or a PI3K inhibitor led to a similar phenotype.…”

mentioning

confidence: 95%

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

Schram

Tze

Ramsey

et al. 2008

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…Even low surface expression of a non-selfreactive BCR has been reported to result in secondary L chain rearrangement (15). In a more recent study, Tze et al (16) reported that interruption of basal signaling through the BCR results in apparent reversion of affected B cells to an earlier developmental stage and secondary L chain rearrangement. Reversion of immature B cells to an earlier stage during the course of normal B cell differentiation was actually suggested earlier by Mehr et al (17) based on mathematical modeling of the kinetics of developing B cell subsets in BM.…”

mentioning

confidence: 99%

“…The above findings have led to the suggestion that down-regulation of sIgM on immature B cells may directly trigger secondary L chain rearrangement (15,16). Accordingly, one would predict that dsDNA breaks indicative of ongoing secondary L chain gene rearrangement would be present in sIgM Ϫ/low autoreactive B cells.…”

mentioning

confidence: 99%

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

Kiefer

Nakajima

Oshinsky

et al. 2008

The Journal of Immunology

View full text Add to dashboard Cite

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.

show abstract

Basal Immunoglobulin Signaling Actively Maintains Developmental Stage in Immature B Cells

Cited by 119 publications

References 51 publications

Tolerance checkpoints in B‐cell development: Johnny B good

Tolerance checkpoints in B‐cell development: Johnny B good

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

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

Contact Info

Product

Resources

About