The role of the B cell receptor V region in peripheral B cell survival

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.

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

confidence: 66%

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

“…It has also been determined that ⌬V B cells have a short half-life (17). These features are similar to those observed in B cell tolerance models involving transgenic mice (15,16), and therefore we investigated the possibility that the truncated BCR induces tolerance on B cells.…”

mentioning

confidence: 60%

“…It is also of interest to note that ⌬V mature B cells are eliminated by competition with normal B cells (17), as are autoreactive B cells (47), raising the possibility that, in the latter case, competition occurs for T cell-derived factors.…”

Section: Discussionmentioning

confidence: 99%

Expression of a V Region-Less B Cell Receptor Confers a Tolerance-Like Phenotype on Transgenic B Cells

Corcos

Grandien

Vázquez

et al. 2001

Neoplastic B cells from H chain disease patients express a truncated B cell receptor (BCR), comprising a membrane Ig that lacks part of its extracellular domain. It has been speculated that deletion of the Ag binding domain would confer a constitutive activity on the BCR, as it has been shown for oncogenic growth factor receptors. A V region-less BCR has constitutive activity, because in transgenic mice it causes inhibition of endogenous H chain gene rearrangements and relieves the requirement for surrogate L chain in pre-B cell development. However, it has been speculated that normal Ag receptors also display constitutive activity. Here we show that transgenic B cells expressing a membrane H chain disease protein on their surface are phenotypically and functionally similar to B cells developing in the presence of their cognate Ag and that cells with normal levels of mutant BCR are eliminated in spleen via a bcl-2 sensitive pathway while progressing toward the mature stage. In contrast, cells with lower levels of mutant receptors develop as mature B cells. These findings support the view that the truncated BCR has a constitutive activity that mimics ligand binding, in analogy to what has been shown for oncogenic growth factor receptors.

“…Furthermore, peripheral mature B cells that express BCR complexes that are incapable of binding conventional Ag compete poorly with ligand-binding sufficient B cells (65,66). This distinction may reflect the ability of Ag "tickled" B cells to more effectively compete for B cell-activating factor of the TNF family (BAFF) or other survival factors, as has been suggested by others (28,29,67,68).…”

Section: Discussionmentioning

confidence: 89%

Basal Igα/Igβ Signals Trigger the Coordinated Initiation of Pre-B Cell Antigen Receptor-Dependent Processes

Fuentes‐Pananá

Bannish

Shah

et al. 2004

The pro-B to pre-B transition during B cell development is dependent upon surface expression of a signaling competent pre-B cell Ag receptor (pre-BCR). Although the mature form of the BCR requires ligand-induced aggregation to trigger responses, the requirement for ligand-induced pre-BCR aggregation in promoting B cell development remains a matter of significant debate. In this study, we used transmission electron microscopy on murine primary pro-B cells and pre-B cells to analyze the aggregation state of the pre-BCR. Although aggregation can be induced and visualized following cross-linking by Abs to the pre-BCR complex, our analyses indicate that the pre-BCR is expressed on the surface of resting cells primarily in a nonaggregated state. To evaluate the degree to which basal signals mediated through nonaggregated pre-BCR complexes can promote pre-BCR-dependent processes, we used a surrogate pre-BCR consisting of the cytoplasmic regions of Igα/Igβ that is targeted to the inner leaflet of the plasma membrane of primary pro-B cells. We observed enhanced proliferation in the presence of low IL-7, suppression of VH(D)JH recombination, and induced κ light (L) chain recombination and cytoplasmic κ L chain protein expression. Interestingly, Igα/Igβ-mediated allelic exclusion was restricted to the B cell lineage as we observed normal TCRαβ expression on CD8-expressing splenocytes. This study directly demonstrates that basal signaling initiated through Igα/Igβ-containing complexes facilitates the coordinated control of differentiation events that are associated with the pre-BCR-dependent transition through the pro-B to pre-B checkpoint. Furthermore, these results argue that pre-BCR aggregation is not a requirement for pre-BCR function.