Receptor editing in CD45-deficient immature B cells

In the mouse, Bruton’s tyrosine kinase (Btk) is essential for efficient developmental progression of CD43+CD2− large cycling into CD43−CD2+ small resting pre-B cells in the bone marrow and of IgMhigh transitional type 2 B cells into IgMlow mature B cells in the spleen. In this study, we show that the impaired induction of cell surface changes in Btk-deficient pre-B cells was still noticeable in κ+ immature B cells, but was largely corrected in λ+ immature B cells. As λ gene rearrangements are programmed to follow κ rearrangements and λ expression is associated with receptor editing, we hypothesized that the transit time through the pre-B cell compartment or receptor editing may affect the extent of the cellular maturation defects in Btk-deficient B cells. To address this issue, we used 3-83μδ transgenic mice, which prematurely express a complete B cell receptor and therefore manifest accelerated B cell development. In Btk-deficient 3-83μδ mice, the IgM+ B cells in the bone marrow exhibited a very immature phenotype (pre-BCR+CD43+CD2−) and were arrested at the transitional type 1 B cell stage upon arrival in the spleen. However, these cellular maturation defects were largely restored when Btk-deficient 3-83μδ B cells were on a centrally deleting background and therefore targeted for receptor editing. Providing an extended time window for developing B cells by enforced expression of the antiapoptotic gene Bcl-2 did not alter the Btk dependence of their cellular maturation. We conclude that premature B cell receptor expression amplifies the cellular maturation defects in Btk-deficient B cells, while extensive receptor editing reduces these defects.

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“…Ϫ/Ϫ and CD19 Ϫ/Ϫ mice showed relatively mild defects in the transitional B cell compartment in the spleen (39,42,43).…”

Section: Discussionmentioning

confidence: 99%

Cellular Maturation Defects in Bruton’s Tyrosine Kinase-Deficient Immature B Cells Are Amplified by Premature B Cell Receptor Expression and Reduced by Receptor Editing

Middendorp

Hendriks

2004

The Journal of Immunology

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“…In these studies, however, tonic signals have not been measured directly. In contrast, lack of CD45 has no effect on B cell development and positive selection (45).…”

Section: Establishment Of Appropriate Tonic Tyrosine Phosphorylation mentioning

confidence: 94%

Modification of Ligand-independent B Cell Receptor Tonic Signals Activates Receptor Editing in Immature B Lymphocytes

Zohar

Diamant

Ostrovsky

et al. 2004

Journal of Biological Chemistry

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Maturation of B lymphocytes strictly depends on the signaling competence of the B cell antigen receptor (BCR). Autoreactive receptors undergo negative selection and can be replaced by receptor editing. In addition, the process of maturation of non-self B cells and migration to the spleen, referred to as positive selection, is limited by the signaling competence of the BCR. Using 3-83Tg mice deficient of CD19 we have shown that signaling incompetence not only blocks positive selection but also activates receptor editing. Here we study the role of ligand-independent BCR tonic tyrosine phosphorylation signals in activation of receptor editing. We find that editing, immature 3-83Tg B cells deficient of CD19 have elevated BCR tonic signals and that lowering these tonic signals effectively suppresses receptor editing. Furthermore, we show that elevation of BCR tonic signals in non-editing, immature 3-83Tg B cells stimulates significant receptor editing. We also show that positive selection and developmental progression from the bone marrow to the spleen are limited to cells capable of establishing appropriate tonic signals, as in contrast to immature cells, splenic 3-83Tg B cells deficient of CD19 have BCR tonic signals similar to those of the control 3-83Tg cells. This developmental progression is accompanied by activation of molecules signaling for growth and survival. Hence, we suggest that ligand-independent BCR tonic signals are required for promoting positive selection and suppressing the receptor-editing mechanism in immature B cells.Formation and expression of the antigen receptor are hallmarks of T and B lymphocyte development. During early stages of development the expressed receptor signals for both positive and negative selection, whereas in mature cells it signals for activation (1-3). Continuous receptor expression and signaling are also critical for cell survival, as ablation of the antigen receptor results in death of the lymphocytes, which occurs more rapidly in B cells (4, 5). Hence, life and death of lymphocytes depend not only on the specificity of the antigen receptor but also on its signaling capacity.The B cell antigen receptor (BCR) 1 specificity is important for negative selection, aiming to extinguish self-reactivity (1, 3, 6). The encountering of self-antigen in the bone marrow (BM) stimulates secondary immunoglobulin gene rearrangements to express a new receptor, a mechanism called receptor editing (7,8). This salvage mechanism allows extended survival and multiple V(D)J recombination attempts for self-reactive B cells and was found to contribute in generating the B cell repertoire (9, 10). In contrast to negative selection, it is unclear what signals for developmental progression and maturation of non-self B cells, a process also referred to as positive selection (2,3,11,12). Several studies have utilized signaling mutated mice to show that expression of a non-self receptor is not sufficient for B cell maturation. In these mice, B cell development and/or maturation is severely impaired, su...

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“…3) (42). Modification of these signals by lack of CD19 or CD45 coreceptors or Btk have no effect on receptor editing stimulated by multivalent membrane-bound Ag (45,70,71). Analysis of affinity threshold revealed that receptor editing was efficiently stimulated by MHC Ags with affinities of Ͼ5 ϫ 10 4 M Ϫ1 (72).…”

Section: Receptor Editing In Negative Selectionmentioning

confidence: 99%

Receptor Editing in Positive and Negative Selection of B Lymphopoiesis

Edry

Melamed

2004

The Journal of Immunology

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lymphopoiesis is guided by Ig gene rearrangement and construction of the Ag receptor. Several selection checkpoints have been described along the developmental pathway aiming to test the competence of the new receptor and to ensure the generation of mature B cells expressing nonself receptors that are functionally responsive. Early immunological models predicted that a B cell that fails to fulfill both requirements aborts developmental progression and undergoes apoptosis in the bone marrow (BM).3 Studies showing an alternative salvage pathway for these cells have been published at the late 1980s and early 1990s. These studies suggested that B cells expressing a defective and/or self-reactive receptor undergo secondary Ig gene rearrangement to replace this receptor, rather then undergoing a default apoptosis. This salvage mechanism was first characterized in central tolerance of immature B cells undergoing negative selection and was termed receptor editing (1). Secondary V(D)J recombination has been demonstrated both at the H chain (HC) and the L chain (LC) loci, though through different mechanisms. At the locus, secondary recombination replaces the entire pre-existing V J by recombination of an upstream V to a downstream J . Such mechanism of secondary recombination is not applicable at the HC locus, as no more D regions are left available after primary VDJ formation. Instead, receptor editing at the HC locus uses cryptic recombination signal sequences (RSS), embedded in many V H genes, to allow upstream V H genes to recombine with the existing VDJ and to produce hybrid V H genes ( Fig. 1) (1). It was later shown that B cell development also depends on BCR expression and appropriate signaling, a process referred as positive selection (2-6). Developing B cells expressing defective and/or inefficient receptors are developmentally arrested, but can be rescued by secondary recombination that replaces the HC or the LC. Thus, receptor editing, mediated by secondary V(D)J recombination, is an important mechanism contributing to both positive and negative selection in B lymphopoiesis. HC receptor editing in selection of early B cell precursorsB lymphocytes rearrange HC V, D, and J gene segments at the pro-B stage. A productive VDJ encodes H chain that pairs with the surrogate L (SL) chain components, VpreB and 5, and is expressed as pre-BCR (reviewed in Refs. 3 and 5). Signaling from the pre-BCR is required to suppress V(D)J recombination and to establish allelic exclusion at the HC locus (7,8). Appropriate pre-BCR also signals for positive selection and proliferative expansion (5, 7). It is not clear whether these signals are generated from pre-BCR aggregation (3), or mediated by an interaction with putative ligand expressed on stromal cells (9). Failure to express the pre-BCR abrogate allelic exclusion and allows ongoing V(D)J recombination (3, 5). Also, lack or insufficient pre-BCR signaling imposes developmental arrest in several signaling mutated mice (reviewed in Refs. 10 -12). Hence, expression and signaling of t...

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Receptor editing in CD45-deficient immature B cells

Cited by 9 publications

References 69 publications

Cellular Maturation Defects in Bruton’s Tyrosine Kinase-Deficient Immature B Cells Are Amplified by Premature B Cell Receptor Expression and Reduced by Receptor Editing

Cellular Maturation Defects in Bruton’s Tyrosine Kinase-Deficient Immature B Cells Are Amplified by Premature B Cell Receptor Expression and Reduced by Receptor Editing

Modification of Ligand-independent B Cell Receptor Tonic Signals Activates Receptor Editing in Immature B Lymphocytes

Receptor Editing in Positive and Negative Selection of B Lymphopoiesis

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