Toll-Like Receptors and B-Cell Receptors Synergize to Induce Immunoglobulin Class-Switch DNA Recombination: Relevance to Microbial Antibody Responses

Abstract

Differentiation of naïve B cells, including immunoglobulin (Ig) class switch DNA recombination (CSR), is critical for the immune response and depends on the extensive integration of signals from the B cell receptor (BCR), tumor necrosis factor (TNF) receptor family members, Toll-like receptors (TLRs) and cytokine receptors. TLRs and BCR synergize to induce CSR in T cell-dependent and T cell-independent antibody responses to microbial pathogens. BCR triggering together with simultaneous endosomal TLR engagement leads to enhanced B cell differentiation and antibody responses. The requirement of both BCR and TLR engagement would ensure appropriate antigen-specific activation in an infection. Co-stimulation of TLRs and BCR likely plays a significant role in anti-microbial antibody responses to contain pathogen loads until the T cell-dependent antibody responses peak. Furthermore, the temporal sequence of different signals is also critical for optimal B cell responses, as exemplified by the activation of B cells by initial TLR engagement, leading to the upregulation of co-stimulatory CD80 and MHC-II receptors, which, in turn, result in more efficient interactions with T cells, thereby enhancing the germinal center (GC) reaction and antibody affinity maturation. Overall, BCR and TLR stimulation and the integration with signals from the pathogen or immune cells and their products, determine the ensuing B cell antibody response.

Toll-like receptor signaling pathway in chronic lymphocytic leukemia: distinct gene expression profiles of potential pathogenic significance in specific subsets of patients

“…[11][12][13][14] The stimulation of surface or endosomal TLR leads to the activation of NF-kB and the induction of activationinduced cytidine deaminase, which, in combination with cytokines, induces class switch recombination to specific isotypes. [15][16][17] This depends on correct intracellular trafficking and localization of the engaged TLR and on the presence of other signals, such as those emanating from the BcR. 10,[18][19][20] The activation of B cells by TLR engagement may lead to a more efficient interaction with T cells and dendritic cells due to up-regulation of the co-stimulatory CD80 and MHCII molecules.…”

Coinfection with Streptococcus pneumoniae Modulates the B Cell Response to Influenza Virus

“…Because B cells integrate signals through the BCR and T helper cell-derived costimulation that synergize with signals from TLRs and cytokine receptors (38), we hypothesized that an altered milieu in the context of a bacterial coinfection with S. pneumoniae would affect the B cell response to IAV infection. Here, we established two models of RT coinfection to investigate how the presence of S. pneumoniae either prior to or following IAV infection impacts the generation and maintenance of antiviral Ab responses.…”

TLR4- and TRIF-dependent stimulation of B lymphocytes by peptide liposomes enables T cell–independent isotype switch in mice

“…25 Whether the stimulation of antibody responses requires the involvement of TLRs in general is currently a matter of debate, [26][27][28] but it has become clear that TLR signaling can influence B-cell responses directly. 29 In vitro, the direct stimulation of TLR4 25 or TLR9 29 on B cells has been shown to strengthen B-cell receptor signaling and immunoglobulin class switch. The requirement for direct triggering of TLR on B lymphocytes was recently demonstrated for TD antigens displayed on synthetic nanoparticles, where TLR4 and TLR7 ligands synergistically increased antigen-specific antibody responses.…”