Abstract
B-cells integrate antigen-specific signals transduced via the B-cell receptor (BCR) and antigen non-specific co-stimulatory signals provided by cytokines and CD40 ligation in order to produce IgG antibodies. Toll-like receptors (TLRs) also provide co-stimulation, but the requirement for TLRs to generate T-cell independent and T-cell dependent antigen specific antibody responses is debated. Little is known about the role of B-cell expressed TLRs in inducing antigen-specific antibodies to antigens that also activate TLR signaling. We found that mice lacking functional TLR4 or its adaptor molecule MyD88 harbored significantly less IgG3 natural antibodies to LPS, and required higher amounts of LPS to induce anti-LPS IgG3. In vitro, BCR and TLR4 signaling synergized, lowering the threshold for production of T-cell independent IgG3 and IL-10. Moreover, BCR and TLR4 directly associate through the transmembrane domain of TLR4. Thus, in vivo, BCR/TLR synergism could facilitate the induction of IgG3 antibodies against microbial antigens that engage both innate and adaptive B-cell receptors. Vaccines might exploit BCR/TLR synergism to rapidly induce antigen-specific antibodies before significant T-cell responses arise.
Highlights
Antibodies perform a broad array of functions dictated by the constant region of their heavy chain
In this work we report that TLR4 synergizes with the B-cell antigen receptor (BCR) to control the induction of IgG3 antibodies to LPS
The control exerted by TLR4 in the induction of anti-LPS IgG is the result of synergism between TLR4 and BCR signaling pathways triggered with limiting amounts of LPS in the absence of T-cell help
Summary
Antibodies perform a broad array of functions dictated by the constant region of their heavy chain. IgG production usually results from the integration of two signals: An antigen specific signal provided via the B-cell antigen receptor (BCR), and co-stimulatory signals provided by T cells and dendritic cells in the form of cytokines and/or membrane-bound ligands [2]. This two signal requirement limits the risk of undesired immunopathology but imposes a 5–7 day delay in the induction of an effective antibody response, a delay that might be far too long to fight fast growing pathogens. In the more physiological set up of an infection, the collaboration between TLR and BCR signaling might be important for the early activation of pathogen-specific B cells that help contain the infection until the establishment of a mature T cell response
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