Evidence for a Ligand-Mediated Positive Selection Signal in Differentiation to a Mature B Cell

Wang, Hongsheng; Clarke, Stephen H.

doi:10.4049/jimmunol.171.12.6381

Cited by 36 publications

(41 citation statements)

References 46 publications

(70 reference statements)

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“…This is consistent with the notion that the requirement for ligand in the generation of signals promoting B cell positive selection only applies to the maintenance of the mature B cell pool and not to newly formed B cells (35,36). There is persuasive evidence that ligand-independent BCR signaling is sufficient to drive B cell development through to the mature B cell pool (6).…”

Section: Discussionsupporting

confidence: 70%

Secreted IgM Enhances B Cell Receptor Signaling and Promotes Splenic but Impairs Peritoneal B Cell Survival

Notley

Baker

Ehrenstein

2010

The Journal of Immunology

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B cell survival has a central role in maintaining immune responses to foreign organisms while curbing autoimmunity. In this study, we show that mature B cell survival is impaired and B cell turnover is accelerated in the spleen of mice lacking secreted IgM. Although in vitro responses to BCR cross-linking were normal, there was a marked reduction in basal ERK and global tyrosine phosphorylation in splenic B cells from serum IgM-deficient mice, suggesting diminished interaction with cognate Ag in vivo. The provision of BAFF either in vitro or in vivo reversed the increase in B cell apoptosis, demonstrating that other survival signals can compensate for the loss of secreted IgM in the spleen. In striking contrast to the splenic compartment, peritoneal B cell survival was enhanced in secreted IgM-deficient mice, despite a similar reduction in basal BCR signaling compared with wild type mice. These results suggest that secreted IgM acts as an adjuvant, boosting BCR signals to maintain survival and maintenance of mature splenic B cells while increasing B cell apoptosis in the peritoneum. BAFF administration mitigated the consequences of secreted IgM deficiency on B cell survival in the spleen but not in the peritoneum. This work provides new insight into the regulation of B cell signaling and homeostasis in different peripheral compartments by secreted IgM.

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Section: Discussionsupporting

confidence: 70%

Secreted IgM Enhances B Cell Receptor Signaling and Promotes Splenic but Impairs Peritoneal B Cell Survival

Notley

Baker

Ehrenstein

2010

The Journal of Immunology

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“…In agreement with them, B cells expressing transgenic receptors lacking the H chain V region can successfully reconstitute a mature B cell population but failed to do so when mixed with B cells carrying ligand-binding competent receptors (76). This model will also reconcile the observation that transitional cells can be forced to differentiate into FO B cells in vitro by addition of low doses of anti-Ig␤ Ab, which might mimic a low-affinity ligand-receptor interaction (77). In this scenario, tonic signaling can be originated through aggregation-dependent as well as -independent mechanisms, and thus pre-BCR/BCR interactions with itself and with nonpolymorphic ligands or self-Ag might also be needed at different stages of development.…”

Section: Ligand-independent Bcr Signals Are Sufficient To Overcome Thsupporting

confidence: 48%

“…It is well-documented that self-reactive BCRs with affinities for cellular molecules such as phosphocholine and phosphatidyl choline preferentially differentiate into mature MZ and B1 B cells, and transgenic expression of these self-reactive BCRs mainly supports generation of these populations. These data strongly argue that generation of MZ and B1 cells requires positive selection mediated by BCR-Ag interactions (62,65,77,90). Accordingly, MZ and B1 cells are present in a semiactivated state in which they are constitutively secreting Ab.…”

Section: Only Fo B Cells Are Found In the Pool Of Mature B Cells Exprmentioning

confidence: 86%

Analysis of the Individual Contributions of Igα (CD79a)- and Igβ (CD79b)-Mediated Tonic Signaling for Bone Marrow B Cell Development and Peripheral B Cell Maturation

Fuentes‐Pananá

Bannish

Karnell

et al. 2006

The Journal of Immunology

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The individual contribution of Igα and Igβ for BCR-triggered fates is unclear. Prior evidence supports conflicting ideas concerning unique as well as redundant functions for these proteins in the context of BCR/pre-BCR signaling. Part of this ambiguity may reflect the recent appreciation that Igα and Igβ participate in both Ag-independent (tonic) and Ag-dependent signaling. The present study undertook defining the individual requirement for Igα and Igβ under conditions where only ligand-independent tonic signaling was operative. In this regard, we have constructed chimeric proteins containing one or two copies of the cytoplasmic domains of either Igα or Igβ and Igα/Igβ heterodimers with targeted Tyr→Phe modifications. The ability of these proteins to act as surrogate receptors and trigger early bone marrow and peripheral B cell maturation was tested in RAG2−/− primary pro-B cell lines and in gene transfer experiments in the μMT mouse model. We considered that the threshold for a functional activity mediated by the pre-BCR/BCR might only be reached when two functional copies of the Igα/Igβ ITAM domain are expressed together, and therefore the specificity conferred by these proteins can only be observed in these conditions. We found that the ligand-independent tonic signal is sufficient to drive development into mature follicular B cells and both Igα and Igβ chains supported formation of this population. In contrast, neither marginal zone nor B1 mature B cell subsets develop from bone marrow precursors under conditions where only tonic signals are generated.

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“…Together, these findings implied that BCR signal strength could specify any of three alternative fates at the TR stage: differentiative failure, continued survival or tolerogenic elimination. This tripartite distribution of BCR-mediated effects was directly demonstrated by Wang and Clarke, using a transgenic BCR model coupled with differing doses of anticlonotypic antibody [11]. Finally, subthreshold BCR signals are not only essential for continued differentiation at the TR stage, but are also required for survival in the mature peripheral pools.…”

Section: B Cells Undergo Both Negative and Positive Selection As Theymentioning

confidence: 72%

BAFF and the plasticity of peripheral B cell tolerance

Stadanlick

Cancro

2008

Current Opinion in Immunology

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BAFF and its receptors play a crucial role in peripheral B cell selection and survival, by dictating the set point for mature primary B cell numbers and adjusting thresholds for specificity-based selection during transitional differentiation. The notion that selective stringency can be varied on the basis of homeostatic demands reveals a previously unappreciated degree of plasticity in B cell tolerance, and suggests a paradigm that unites peripheral negative and positive selection with the maintenance of mature B cell numbers. Moreover, it implies a developmentally regulated coupling of BCR and BAFF receptors at the transitional stages and beyond.

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Evidence for a Ligand-Mediated Positive Selection Signal in Differentiation to a Mature B Cell

Cited by 36 publications

References 46 publications

Secreted IgM Enhances B Cell Receptor Signaling and Promotes Splenic but Impairs Peritoneal B Cell Survival

Secreted IgM Enhances B Cell Receptor Signaling and Promotes Splenic but Impairs Peritoneal B Cell Survival

Analysis of the Individual Contributions of Igα (CD79a)- and Igβ (CD79b)-Mediated Tonic Signaling for Bone Marrow B Cell Development and Peripheral B Cell Maturation

BAFF and the plasticity of peripheral B cell tolerance

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