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

Abstract

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.

IFN Regulatory Factor 8 Restricts the Size of the Marginal Zone and Follicular B Cell Pools

“…In the absence of ligand stimulation, BCR basal signaling is essential for survival (33) and differentiation (34). Monroe and colleagues showed that the cytoplasmic tails of Iga and Igβ in the absence of Ag binding are sufficient to drive FO B2 but not MZ and B1 cell differentiation (34, 35). Consistent with this finding, Hayakawa et al (36) showed that immature B cells expressing a transgenic BCR specific for the self Thy-1 glycoprotein develop into FO B2 cells in the absence of Thy-1 expression.…”

Differential regulation of TLR4 expression in human B cells and monocytes

“…However, published work has shown that peripheral B cell survival is absolutely dependent on low-level “tonic” signaling through the B cell receptor (Bannish et al, 2001; Lam et al, 1997) and that even naïve B cells have low-level activation of the Igμ signaling pathway (Fuentes-Panana et al, 2006). It is possible that Igμ-mediated tonic signaling, along with the elevated levels of soluble and/or cell-associated CD40, TLR ligands and cytokines present in inflammatory disease patients (Al-Attas et al, 2009; Cani et al, 2007; Creely et al, 2007; Jinchuan et al, 2004; Liu et al, 1999; Varo et al, 2003), are sufficient to induce B cell TLR4 activation in vivo, even in the absence of the activation history that characterizes the memory compartment.…”

B Cell Depletion with Anti-CD79 mAbs Ameliorates Autoimmune Disease in MRL/lpr Mice

“…Unlike CD20, CD79α and CD79β have important signaling functions for B cells as they couple to MHC II and BCR (19) and initiate downstream tyrosine phosphorylation and intracellular release of Ca 2+ . It is appreciated that CD79α (Igα) and CD79β (Igβ) participate in both Ag-dependent and Ag-independent signaling (20). Thus, unlike anti-CD20, anti-CD79 Abs might have dual functions in vivo.…”