TLR signaling in B-cell development and activation

Abstract

Expression of Toll-like receptors (TLRs) in B cells provides a cell-intrinsic mechanism for innate signals regulating adaptive immune responses. In combination with other signaling pathways in B cells, including through the B-cell receptor (BCR), TLR signaling plays multiple roles in B-cell differentiation and activation. The outcome of TLR signaling in B cells is largely context-dependent, which partly explains discrepancies among in vitro and in vivo studies, or studies using different immunogens. We focus on recent findings on how B-cell-intrinsic TLR signaling regulates antibody responses, including germinal center formation and autoantibody production in autoimmune disease models. In addition, TLR signaling also acts on the precursors of B cells, which could influence the immune response of animals by shaping the composition of the immune system. With TLR signaling modulating immune responses at these different levels, much more needs to be understood before we can depict the complete functions of innate signaling in host defense.

Figure 1

Functions of TLR signaling in B-cell development and differentiation. TLRs are expressed through most stages of B-cell development, including HSCs and CLPs. Activation of TLR signaling in HSCs shifts their developmental potential towards myeloid cells. TLR signaling in CLPs causes cell differentiation into DCs instead of B cells. Transitional B cells can differentiate into mature B cells, plasma cells and IgM memory B cells upon TLR activation. The roles of TLR signaling in mature B cells are simplified here and are described in more detail elsewhere. Arrows with solid or dashed lines indicate that the processes respectively promoted or inhibited by TLR signaling. Abbreviations: CLP, common lymphoid progenitor; DC, dendritic cell; HSC, hematopoietic stem cell; TLR, Toll-like receptor.

Figure 2

Working model of how VLPs induce B-cell TLR signaling. A VLP containing CpG-ODN binds to an antigen-specific B cell and elicits BCR signaling by crosslinking surface BCRs (indicated by yellow stars). TLR9 is localized to endosomes and is only activated following VLP internalization. Abbreviations: BCR, B-cell receptor; ODN, oligodeoxynucleotide; TLR, Toll-like receptor; VLP, virus-like particle.