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Review
. 2012 Aug;136(4):370-9.
doi: 10.1111/j.1365-2567.2012.03587.x.

Regulation of B-cell responses by Toll-like receptors

Edward P Browne  1
Affiliations
Review

Regulation of B-cell responses by Toll-like receptors

Edward P Browne. Immunology. 2012 Aug.

Abstract

The discovery of host-encoded gene products that sense molecular patterns in infectious microbes, and the demonstration of their role in triggering innate and adaptive immune responses, has been a key milestone in our understanding of immunology. Twenty-three years after Janeway first outlined the fundamental concepts of the 'pattern recognition' model, and 15 years since the identification of Toll-like receptors (TLRs) as pattern recognition receptors (PRRs), new insights continue to be revealed, and questions remain. For example, innate immune responses to microbes that are mediated by PRRs have historically been viewed as the domain of innate immune cell populations such as dendritic cells and macrophages. New evidence, however, has pointed to the role of B-cell-intrinsic TLR activation in shaping antibody responses. These studies have revealed that TLRs regulate a complex transcriptional network that controls multiple steps in the development of antigen-specific antibodies. This review covers these recent developments regarding the role of TLRs in B-cell gene expression and function in vitro and in vivo, and highlights the remaining challenges in the field, with particular emphasis on the role of TLRs in antibody responses to viral infection. A more complete understanding of how TLRs regulate antibody responses will lead to improved vaccine design.

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Figures

Figure 1
Figure 1
B-cell intrinsic regulation of antibody responses by Toll-like receptors (TLRs). TLR ligation by microbes contributes to the initial activation of antigen-specific follicular B cells, in combination with B-cell receptor (BCR) stimulation by antigen, and CD40 stimulation by follicular helper T cells (Tfh). Activated B cells then develop into germinal centre (GC) B cells and undergo multiple rounds of proliferation, somatic hypermutation and class switch recombination. TLR ligation enhances GC reactions. GC B cells can then undergo apoptosis or further develop into long-lived B-cell populations such as antibody-secreting plasma cells, or memory B cells. Plasma cells abundantly express TLRs, and TLR ligation enhances antibody secretion.
Figure 2
Figure 2
Potential routes of Toll-like receptor (TLR) stimulation in B cells by viruses. Viruses can bind to and enter B cells through several different pathways. B-cell receptors (BCRs) specific for viral antigens can bind and internalize virus, or viral particles can enter through binding either their natural entry receptor or a carbohydrate-binding lectin such as DC-SIGN. Antibody-coated viruses could also potentially enter B cells through Fc receptor-mediated internalization. Internalized virus is then degraded in endosomes to release viral genomic nucleic acid, which can stimulate the endosomal TLRs such as TLR7, TLR8, TLR9 or TLR3. Replicating virus in the B-cell cytoplasm could also potentially be delivered to endosomal TLRs by autophagy.
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