Dynamics and magnitude of virus‐induced polyclonal B cell activation mediated by BCR‐independent presentation of viral antigen

Abstract

Hypergammaglobulinemia and production of autoantibodies occur during many viral infections, and studies have suggested that viral antigen-presenting B cells may become polyclonally activated by CD4 T cells in vivo in the absence of viral engagement of the BCR. However, we have reported that CD4 cells in lymphocytic choriomengitis virus (LCMV)-infected mice kill adoptively transferred B cells coated with LCMV class II peptides. We report here that most of the surviving naïve B cells presenting class II MHC peptides undergo an extensive differentiation process involving both proliferation and secretion of antibodies. Both events require CD4 cells and CD40/CD40L interactions but not MyD88-dependent signaling within the B cells. B cells taken from immunologically tolerant donor LCMV-carrier mice with high LCMV antigen load became activated following adoptive transfer into LCMV-infected hosts, suggesting that B cells present sufficient antigen for this process during a viral infection. No division or activation of B cells was detected at all in virus-infected hosts in the absence of cognate CD4 T cells and class II antigen. This approach, therefore, formally demonstrates and quantifies a virus-induced polyclonal proliferation and differentiation of B cells, which, due to their high proportion, would mostly have BCR not specific for the virus.

IL-4Rα-Associated Antigen Processing by B Cells Promotes Immunity in Nippostrongylus brasiliensis Infection

“…Initial analysis does not support these transferred B cells conferring protection via an early production of IL-13 ( Figure S5 ). However, rapid antigen processing and presentation may be mediated by B cells directly loading soluble peptide onto MHCII [29], [30] or via antigen internalisation and processing by Toll like receptors (TLR) [31], [32], [33].…”

IL-4–producing B cells regulate T helper cell dichotomy in type 1- and type 2-controlled diseases

“…Besides BCR signaling, recent reports indicate that B cells can respond to antigen and become "innately" activated via alternative mechanisms such as activation of endosomal Toll-like receptors or direct peptide loading, which has been shown to lead to early B cell cytokine production, again mimicking an autocrine loop (37)(38)(39)(40). Furthermore, B cells are competent APCs (4), which would allow the B cells to present the acquired antigen and, together with the cytokine it secretes, facilitate the aforementioned paracrine activation of neighboring immune cells, as previously demonstrated during the early stages of bacterial and viral infection (41).…”

High Efficiency of Antiviral CD4+ Killer T Cells

“…It is therefore of interest that GP 92 -sensitized B cells were previously reported to evade destruction by GP 92 -specific CD8 + effector T cells [39]. In our hands, a significant fraction of B cells coated with the GP 92 peptide was readily killed in an in vivo CTL assay conducted on day 8 after LCMV challenge (not shown), and the fact that the GP 92 -specific CD8 + T cell population substantially contracts on subsequent days [16] may contribute to the divergent results obtained by Jellison et al who performed their in vivo assays on day 10 after LCMV infection [39].…”

“…It is therefore of interest that GP 92 -sensitized B cells were previously reported to evade destruction by GP 92 -specific CD8 + effector T cells [39]. In our hands, a significant fraction of B cells coated with the GP 92 peptide was readily killed in an in vivo CTL assay conducted on day 8 after LCMV challenge (not shown), and the fact that the GP 92 -specific CD8 + T cell population substantially contracts on subsequent days [16] may contribute to the divergent results obtained by Jellison et al who performed their in vivo assays on day 10 after LCMV infection [39]. In addition, and despite the intermediate to high affinity with which GP 92 binds to H2-D b [30], [31], the peptide exhibits a reduced capacity to form stable complexes with H2-D b which may contribute to the induction of smaller (“subdominant”) CD8 + T cell populations in the context of an acute LCMV challenge [32], and possibly could affect the experimental readout in an in vivo CTL assay [39].…”

“…To circumvent the issues of peptide binding affinity and complex stability, it will be informative to utilize targets engineered to prevent peptide dissociation from MHC-II and MHC-I molecules. We predict that such target cells will be destroyed in their entirety by antiviral CD4 + and CD8 + CTL and should provide a useful tool to analyze in vivo killing kinetics with more accuracy; such targets would also be helpful to further investigate the phenomenon of polyclonal B cell activation/proliferation observed for B cell subsets that survived, presumably due to timely target cell desensitization, an in vivo encounter with CD4 + but not CD8 + CTL ([39] and data not shown).…”