Toll-like receptor 9 antagonizes antibody affinity maturation

Abstract

Key events in T cell-dependent antibody responses, including affinity maturation, are dependent on the B cell’s presentation of antigen to helper T cells at critical check points in germinal center formation in secondary lymphoid organs. Here we show that Toll-like receptor 9 (TLR9) signaling blocked the ability of antigen-specific B cells to capture, process and present antigen and to activate antigen-specific helper T cells in vitro. In a mouse model in vivo and in a human clinical trial the TLR9 agonist, CpG, enhanced the magnitude of the antibody response to a protein vaccine but failed to promote affinity maturation. Thus, TLR9 signaling may enhance antibody titers at the expense of the ability of B cells to engage in germinal center events that are highly dependent on B cells’ antigen capture and presentation.

Toll-like receptors in immunity and inflammatory diseases: Past, present, and future

“…TLR7 and TLR9 are both expressed by murine and human B cells [346]. The CpG ODN mediated activation of TLR9 on B cells increased the magnitude of the antibody response to the protein antigen but inhibited process of antibody affinity maturation both in mice and in human clinical trials [347]. Thus, the activation of TLR9 on B cells has a potential to affect antibody response during various vaccination strategies where various TLR9-agonists are used as adjuvants.…”

Exhaustion may not be in the human B cell vocabulary, at least not in malaria

“…However, if naive B cells capture antigen from the FDC in the presence of TLR agonists, as would occur in malaria, the B cells would be unable to process and present the antigen to T H cells. 49 We demonstrated that signaling through TLR9 in response to its ligand CpG induced rapid naive B cell proliferation but blocked BCR-dependent antigen processing and presentation resulting in a failure of B cells to interact with and activate CD4 + T cells in vitro. Considering the first checkpoint in antigen-driven B cell activation in which naive B cells engage antigen and signal in response to it, it has been suggested that chronic exposure to parasite-derived low affinity "decoy" antigens might function to divert B cells to ineffective low affinity non-GC responses.…”

“…46 Recent studies also suggest that parasite PAMPs, in particular ligands for TLR9, including hemozoin, 48 may dramatically alter the naive B cell's ability to pass through this first checkpoint. 49 We demonstrated that signaling through TLR9 in response to its ligand CpG induced rapid naive B cell proliferation but blocked BCR-dependent antigen processing and presentation resulting in a failure of B cells to interact with and activate CD4 + T cells in vitro. 49 BCR-dependent processing was blocked after antigen internalization during the transport of antigen to acidic intracellular antigen-processing compartments.…”

“…Considering the first checkpoint in antigen-driven B cell activation in which naive B cells engage antigen and signal in response to it, it has been suggested that chronic exposure to parasite-derived low affinity "decoy" antigens might function to divert B cells to ineffective low affinity non-GC responses. 49 These findings suggest that in chronic malaria infections in which parasite-derived TLR ligands are present, B cells would fail to present antigen to primed T FH and enter into GC responses, but rather would proliferate and differentiate into short-lived PCs (Figure 3). 46 Recent studies also suggest that parasite PAMPs, in particular ligands for TLR9, including hemozoin, 48 may dramatically alter the naive B cell's ability to pass through this first checkpoint.…”

“…We speculate that in the presence of TLR agonists but in the absence of T cell help, some B cells will proliferate and differentiate into short-lived PCs and in the additional presence of γIFN produced by T FH-1 cells that are preferentially activated in malaria, some B cells will differentiate into atypical MBCs and excluded from differentiation into the classical MBCs pool in GCs? 49 BCR-dependent processing was blocked after antigen internalization during the transport of antigen to acidic intracellular antigen-processing compartments. 30 However, our recent results indicate that low affinity B cells may not be excluded at this checkpoint as they have relatively low affinity thresholds for signaling and antigen-gathering and internalization.…”