FcμR Interacts and Cooperates with the B Cell Receptor To Promote B Cell Survival

Abstract

The IgM FcR (FcμR) promotes B cell survival, but the molecular mechanism remains largely unknown. We show using FcμR−/− and wild-type mice that FcμR specifically enhanced B cell survival induced by BCR cross-linking with F(ab′)2-anti-IgM Abs while having no effect on survival when the B cells were activated by CD40 ligation or LPS stimulation. FcμR expression was markedly upregulated by anti-IgM stimulation, which may promote enhanced FcμR signaling in these cells. Immunofluorescence and confocal microscopy analyses demonstrated that FcμR colocalized with the BCR on the plasma membrane of primary B cells. Coimmunoprecipitation analysis further revealed that FcμR physically interacted with the BCR complex. Because NF-κB plays a prominent role in B cell survival, we analyzed whether FcμR was involved in BCR-triggered NF-κB activation. FcμR did not affect BCR-triggered IκBα phosphorylation characteristic of the canonical NF-κB activation pathway but promoted the production of the noncanonical NF-κB pathway component p52. Consistent with the elevated p52 levels, FcμR enhanced BCR-triggered expression of the antiapoptotic protein BCL-xL. Importantly, FcμR stimulation alone in the absence of BCR signaling had no effect on either IκBα phosphorylation or the expression of p52 and BCL-xL. Therefore, FcμR relied on the BCR signal to activate the noncanonical NF-κB pathway and enhance B cell survival. These results reveal a cross-talk downstream of FcμR and BCR signaling and provide mechanistic insight into FcμR-mediated enhancement of B cell survival after BCR stimulation.

Surface receptor Toso controls B cell–mediated regulation of T cell immunity

“…As Toso interacts with the membrane BCR complex (22) and given the effects of Toso deficiency on B2-effector cell survival/ proliferation, we examined the role of Toso in proximal BCRmediated signaling events and early markers of B cell activation. Upon stimulation with anti-IgM, Toso-deficient B2-effector cells exhibited slightly impaired and less sustained phosphorylation of the tyrosine kinase Btk, indicating attenuated BCR signaling (Figure 6J).…”

“…The exact molecular mechanism of how Toso affects BCR responsiveness is currently unknown. As an IgM-binding molecule, Toso may interact directly with membrane-bound IgM-containing BCR complexes (22) or, alternatively, may indirectly affect B cell signaling via recognition of soluble IgM immune complexes. Increased tonic signaling in Toso-deficient B cells (21) could not be confirmed in our study and may be related to the unusual occurrence of a lymphoproliferative disorder in this particular strain of mice, which has not been observed in any other strain of Toso-deficient mice.…”

“…Subsequently, additional studies have identified Toso as an Fc receptor for soluble IgM (Fcμ receptor) (19,20). More recently, it has been demonstrated that Toso physically interacts with membrane IgMcontaining B cell antigen receptor (BCR) complexes on the surface of mature B cells and/or within the trans-Golgi network of developing B cells (21,22). Functionally, increasing evidence suggests that Toso serves as a physiologically important immunoregulatory molecule for B and T cells.…”

“…Toso-deficient mice are also largely resistant to the development of EAE and exhibit reduced pathogenic T cell responses (29). The mechanism underlying the phenotypic defects of Toso-deficient mice remains a controversial issue, and models involving different effector mechanisms and different immune cell types have been proposed (21,22,27,29). Particularly, it is unclear whether the effects of Toso on tolerance in the B cell compartment are interrelated with impaired immune protection in Toso-deficient mice.…”

Site-SpecificN-Glycosylation of Recombinant Pentameric and Hexameric Human IgM

“…IgM is primarily involved in complement activation [4,5] and immune surveillance by acting as a quality control mechanism in the body [2,6,7]. Recent discovery of a polymeric IgM specific receptor, FcμR, on B-and T-cells provided evidence of IgM playing a role in B-cell survival and immune system development [8][9][10]. In circulation, IgM is commonly present as a pentameric form, held together by a J-chain (Figure 1), which is required for translocation from the blood to the mucus layer on exposed epithelial surfaces [11].…”