A recent report in Nature provides the latest instalment in the popular Toll-like receptor (TLR) story and reveals an unexpected requirement of TLR signalling in B cells for optimal antibody responses to T-cell-dependent antigens.

It is now well established that TLRs induce the dendritic-cell maturation required for activation and differentiation of T helper (TH) cells, which can then provide help to B cells for the generation of specific antibody responses. Indeed, the observation that mice deficient in the crucial TLR-signalling adaptor protein MyD88 (myeloid differentiation primary-response gene 88) have defective T-cell activation and impaired antibody responses to T-cell-dependent antigens favours this indirect role of TLRs in the induction of antibody responses. However, restoration of the T-cell defect in these MyD88-deficient mice did not restore the B-cell response. So, the authors set out to investigate whether TLRs expressed by B cells have a direct role in antibody responses.

To address this, B cells were transferred from wild-type, MyD88-deficient or TLR4-deficient mice to mice that lack mature B cells (μMT mice). Following immunization with a T-cell-dependent antigen (human serum albumin) and the TLR4 ligand lipopolysaccharide (LPS), CD4+ T-cell responses were induced in all of the recipient μMT mice. Although mice that received wild-type B cells developed antigen-specific IgM and IgG responses, the production of antibodies was markedly impaired in mice that received TLR4- or MyD88-deficient B cells.

Next, the authors asked whether TLR signalling in B cells was also required to induce antibody responses to T-cell-independent antigen. For this, they used flagellin, which functions as both a T-cell-dependent antigen (to induce IgG1) and a T-cell-independent antigen (to induce IgG3), and also binds TLR5 on B cells. Accordingly, μMT mice that received wild-type B cells induced strong IgM, IgG1 and IgG3 responses to flagellin. However, μMT mice that received MyD88-deficient cells failed to induce IgM and IgG1, although their IgG3 response was comparable to that in the control mice, indicating that responses to T-cell-independent antigens do not require TLR signalling in B cells.

Further analysis was then carried out to determine at what stage in the B-cell response to T-cell-dependent antigen — antigen processing and presentation or B-cell differentiation into antibody-producing cells — TLR signalling is involved. Using B cells expressing a transgenic B-cell receptor (BCR) specific for hen-egg lysozyme (HEL), it was shown that BCR-mediated uptake of HEL was increased in the presence of LPS. In addition, differentiation into germinal-centre B cells also seemed to depend on TLR signalling, as 12 days after immunization, μMT mice that received MyD88- or TLR4-deficient B cells had fewer germinal-centre B cells than mice that received wild-type cells. This differentiation defect was also reflected in the mRNA levels of key regulators that are involved in B-cell differentiation, such as BCL-6 and BLIMP1 (B-lymphocyte-induced maturation protein 1).

So, TLR signalling affects multiple stages of B-cell activation and is required for optimal antibody responses to T-cell-dependent antigens. Such direct activation of B cells might have implications for autoimmune responses following inappropriate TLR-mediated activation of self-reactive B cells.