Abstract
C3dg is a cleavage product of the C3 component of complement that can facilitate the coligation of the complement receptor 2 (CR2/CD21) with the BCR via C3dg/Ag complexes. This interaction can greatly amplify BCR-mediated signaling events and acts to lower the threshold for B cell activation. Although previous studies have used anti-CR2 Abs or used chimeric Ags in the context of BCR transgenic mice as surrogate C3d-containing ligands, we have used a physiological form of C3d to study signaling in B cells from wild-type C57BL/6 mice. We find that while CR2-enhanced BCR signaling causes intracellular Ca2+ mobilization and total pTyr phosphorylation of an intensity comparable to optimal BCR ligation using anti-IgM Abs, it does so with limited activation of inhibitory effectors (such as CD22, Src homology region 2 domain containing phosphatase 1, and SHIP-1) and without substantial receptor cross-linking. In summary, we demonstrate that CR2-enhanced BCR signaling may proceed not only through the previously described amplification of positive signaling pathways, but is potentially augmented by a lack of normal inhibitory/feedback signaling.
Highlights
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We demonstrate that physical association between antiIgM and C3dg with sa is essential for induction of signaling (Fig. 1C) and that this effect is receptor (CR2) specific as B cells from Cr2Ϫ/Ϫ mice were unresponsive to anti-IgM/C3dg/sa stimulation (Fig. 1B)
That anti-IgM/C3dg/sa conjugates did not stimulate B cells from CR2-deficient or CD19-deficient mice (Figs. 1B and 2B) demonstrates the receptor-specificity of the C3dg conjugates and the importance of CD19 in CR2-enhanced BCR signaling, respectively. This latter fact was independently confirmed by the ability of anti-CD19 Ab to functionally substitute for C3dg to stimulate B cells (Fig. 2C)
Summary
CR2, complement receptor type 2; CRAC, Ca2ϩ release-activated channel; pTyr, tyrosine phosphorylation; sa, streptavidin; SHP, Src homology region 2 domain containing phosphatase; SMAC, supramolecular activation complexes; SOC, store-operated channel; BLNK, B cell linker protein. To the maintenance of self-tolerance [10]. In addition to these activities, CR2 regulates B cell Ag presentation [11, 12], signaling events, and transcriptional activation of target genes [3, 13]. While induced coligation of CD19 alone with the BCR can recapitulate much of the initial signal amplification, several downstream events and outcomes appear unique to the CR2/ CD19/CD81 complex. CR2-mediated BCR signal amplification as well as extend our understanding of the molecular details by identifying further targets of CR2-BCR coligation as well as intrinsic differences in complement-dependent and -independent B cell signaling pathways
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