Toll-like receptors--sentries in the B-cell response

Abstract

Toll-like receptors (TLR) play a central role in the initiation of the innate immune response to pathogens. Upon recognition of molecular motifs specific for microbial molecules TLR mediate pro-inflammatory cytokine secretion and enhance antigen presentation; in B cells they further promote expansion, class switch recombination and immunoglobulin secretion. As a result of their adjuvant properties, TLR ligands have become an integral component of antimicrobial vaccines. In spite of this, little is known of the direct effects of TLR engagement on B-lymphocyte function. The scope of this review is to outline the differences in TLR expression and reactivity in murine and human B-cell subsets and to provide an overview of the currently available literature. We will further discuss the possible roles of TLR in regulating B-cell effector functions and shaping antibody-mediated defence against microbial pathogens in vivo.

Figure 1

Role of Toll-like receptor (TLR) in B-cell functions. The graph depicts the main functions exerted by the B cell. The TLR that have been proven to impact these functions are indicated above the arrows. mTLR = murine TLR; hTLR = human TLR; TLR = murine and human TLR. Question marks (?) indicate that a function has not been addressed in B cells but may be postulated based on data obtained in other cellular systems or from clinical case studies.

Figure 2

Models for Toll-like receptor (TLR) -mediated B-cell activation. The graphs summarize different models for the role of TLR in B-cell activation in different B-cell subsets or environments that have been presented in this review. Because cytokines can modulate all types of B-cell responses they are depicted in all graphs as Signal 4. (a) This graph depicts the classical T-cell-dependent response where sole B-cell receptor (BCR) ligation (Signal 1) induces apoptosis and sets the requirement for T-cell co-stimulation via CD40–CD40 ligand interaction (Signal 2) which then allows B-cell expansion. (b) Based on the concept proposed by Lanzavecchia and colleagues naïve B cells require three signals for potent activation: (i) BCR (Signal 1), (ii) CD40 ligation (Signal 2) and (iii) TLR (Signal 3). (c) The model suggested by Marshak-Rothstein and colleagues implies that a TLR ligand (nucleic acid) -bearing BCR stimulus promotes the internalization of BCR antigen (Signal 1) together with the TLR-activating nucleic acid (Signal 3), which thereby gains access to endosomally localized TLR. Additional co-stimulation via CD40–CD40 ligand (Signal 2) interaction is, of course, possible. (d) T-cell-independent type I (TI-1) antigens such as lipopolysaccharide (LPS) or flagellin concomitantly activate specific BCRs as BCR antigens (Signal 1) and the respective surface TLR on accessory cells, e.g. antigen-presenting cells (APC). The APC will either directly interact with B cells or indirectly modulate B-cell function via cytokine secretion (Signal 4). (e) T-cell-independent type II (TI-2) antigens are carbohydrate polymers that are recognized by specific BCRs in B-cell subsets such as marginal zone B cells where BCR bind capsular polysaccharides (Signal 1). As a result of the nature of the antigen surface, TLR ligands are co-expressed and provide B-cell co-stimulation via TLR Signal 3.