Impaired Light Chain Allelic Exclusion and Lack of Positive Selection in Immature B Cells Expressing Incompetent Receptor Deficient of CD19

Leider, Nira; Sadeh, O.; Kraiem, Zaki; Melamed, Doron

doi:10.4049/jimmunol.168.11.5596

Cited by 55 publications

(87 citation statements)

References 71 publications

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“…Moreover, autoreactivity may not be the only way to promote receptor editing because some non-autoreactive knockin mice also showed extensive secondary rearrangements, likely due to a low expression of the knockin gene (27,28). It was also shown in CD19-deficient mice that a low BCR signaling could impair LC allelic exclusion (29). This finding is reminiscent of observations that HC and LC transgenes only induced allelic exclusion when expressed above a certain threshold (30).…”

supporting

confidence: 56%

Light chain inclusion permits terminal B cell differentiation and does not necessarily result in autoreactivity

Sirac

Carrion

Duchez

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Mice in which the J cluster was replaced with a V J rearranged gene were studied. More than 90% of B cells from homozygous mutant mice expressed the transgenic chain but showed a slightly reduced level of transcripts compared with WT B lymphocytes. Light chain inclusion was apparent in 10% of B cells from these mice and raised 25% in hemizygous mice with a still lower expression of the knockin chain. Beyond the rules of clonal selection, peripheral B cells developed in such animals, with included cells being activated and differentiating into class-switched or antibody-secreting cells. The high amount of included mature B cells was associated with an increase of hybrid ͞ immunoglobulins but not with the increased prevalence of autoantibodies. Altogether, these data suggest that light chain exclusion prevalent in normal B cells mostly results from ordered rearrangements and stochastic mechanisms but is neither tightly ensured by a stringent cell selection process nor absolutely required for normal B cell function.antibodies ͉ autoimmunity ͉ B lymphocytes ͉ gene regulation D uring B cell development, B cell receptor (BCR) assembly relies on an ordered process of rearrangements remodeling first the heavy chain (HC) locus and later on the and loci. Cells achieving expression of functional H and L chains and able to pair them can then express a unique form of functionally competent Ig at the cell surface and be selected according to the specificity of this receptor (1, 2). With very rare exceptions, B lymphocytes are thus monospecific and express a single H and L chain. This allelic and isotypic exclusion is fundamental to the establishment of the B cell repertoire and is in agreement with the clonal selection theory (3), first allowing during ontogeny the tolerization of clonal cells carrying a self-reactive BCR and later ensuring the specificity of antibody responses. Whereas this rule seems to be quite effective in the case of the HC (4, 5), it suffers remarkable exceptions at light chain (LC) loci. Indeed, several studies reported the presence of double-expressing ͞ B cells either at very low frequencies in normal mice or in human, and more abundantly in transgenic mice (6-9) and plasmocytomas (10). Little is known about the mechanisms involved in the allelic exclusion of LC even if recent studies highlighted the importance of asymmetric demethylation of the locus (11, 12) and feedback inhibition of the recombination machinery after the assembly and signaling by a non-self-reactive BCR (13-16). Beyond the initial rearrangements, exclusion also has to be maintained despite the accumulation of secondary rearrangements. The latter were first reported at high frequency in LC loci of mice transgenic for an autoreactive BCR, in which receptor editing restored self-tolerance (17-19). Receptor editing also occurs in normal mice during the selection of immature B cells and may be a major pathway of tolerance induction by rescuing cells with autoreactive BCR from deletion (or anergy) provided that they express a new recept...

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supporting

confidence: 56%

Light chain inclusion permits terminal B cell differentiation and does not necessarily result in autoreactivity

Sirac

Carrion

Duchez

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…This effect was negated in homozygous knock-in mice expressing higher levels of surface IgM. Additionally, incomplete isotype exclusion has been documented in mutant mice lacking the tyrosine kinase Lyn [26] or CD19 [27]. The finding that negative selection of immature B cells was intact in the absence of Syk was unexpected due to the loss of BCR-mediated signaling events in syk -/-transformed avian lymphocytes [11].…”

Section: Resultsmentioning

confidence: 99%

The tyrosine kinase Syk is required for light chain isotype exclusion but dispensable for the negative selection of B cells

2004

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In this study we set out to test whether Syk was required for negative selection of immature B cells. B cells expressing a B cell antigen receptor (BCR) transgene (3-83, anti-H-2K k ) underwent negative selection independently of Syk in both fetal liver organ culture and radiation chimera models. Furthermore, Syk-independent negative selection was not reversed by transgenic overexpression of Bcl-2. Receptor editing was not apparent in Syk-deficient B cells, presumably as a consequence of the failure of mature edited B cells to develop in the absence of Syk. Interestingly, light chain isotype exclusion by the BCR transgene failed in the absence of Syk. We observed a dramatic reduction in the overall BCR-mediated tyrosine phosphorylation of cellular proteins in Syk-deficient immature B cells. However, the tyrosine phosphorylation of a number of substrates including phospholipase C + 2, although reduced, was not completely abrogated. BCR ligation triggered an increase in calcium flux in the absence of Syk. Thus signaling events that mediate negative selection can still occur in the absence of Syk. This may be due to redundancy with zeta-associated protein 70 (ZAP-70), which we demonstrate to be expressed in immature B cells.

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“…RNA and cDNA Analysis-RNA preparation and RT-PCR amplification for RAG-2, B220, and actin were performed as we have described previously (23,26). PCR conditions and primer sequences were as described previously (23,26).…”

Section: Methodsmentioning

confidence: 99%

“…While most of the published data has probed the role of these co-receptors only upon BCR ligation, little is known about their function in regulating the ligand-independent BCR tonic signals in unstimulated cells. In an earlier study we showed that immature 3-83Tg CD19 Ϫ/Ϫ B cells fail positive selection and undergo intensive receptor editing in an attempt to express a new receptor (23). These studies raised the hypothesis that CD19 expression is important to set BCR tonic signaling for positive selection and provided a possible link between failure of positive selection and activation of receptor editing in immature B cells.…”

mentioning

confidence: 99%

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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Impaired Light Chain Allelic Exclusion and Lack of Positive Selection in Immature B Cells Expressing Incompetent Receptor Deficient of CD19

Cited by 55 publications

References 71 publications

Light chain inclusion permits terminal B cell differentiation and does not necessarily result in autoreactivity

Light chain inclusion permits terminal B cell differentiation and does not necessarily result in autoreactivity

The tyrosine kinase Syk is required for light chain isotype exclusion but dispensable for the negative selection of B cells

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

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