TLR Signaling in Adaptive Immune Responses

Science's STKE  22 Nov 2005:
Vol. 2005, Issue 311, pp. tw413
DOI: 10.1126/stke.3112005tw413

Toll-like receptors (TLRs), which recognize pathogen-associated motifs and play a key role in initiating innate immune responses, have also been implicated in maturation of dendritic cells and thereby in T helper (TH) cell activation. Whether TLRs play a direct role in B cell activation has been unclear. Pasare and Medzhitov found that mice lacking the TLR signaling adaptor MyD88 (myeloid differentiation primary response gene 88) showed impaired immunoglobulin (Ig) G1 and IgG2 antibody responses to T-dependent antigens and lower steady-state levels of IgM, IgG1, IgG2c, and IgG3 than those in wild-type mice. Because impaired B cell responses could result from inadequate TH activation, the authors tested the direct role of TLR signaling in B cells by transferring B cells from wild-type or knockout mice into a strain of mice that lack mature B cells. Antigen-specific production of IgG and IgM was impaired in mice that received B cells lacking MyD88 or TLR4 compared with that in mice receiving wild-type B cells and, following immunization, these mice had a lower percentage of B cells that were positive for a germinal center marker. Furthermore, immunization of transgenic mice that expressed MyD88 in dendritic cells but not in B cells led to functional TH1 responses but not to antigen-specific antibody production. Moreover, TLR ligation enhanced the processing of antigen taken up through B cell receptor-mediated endocytosis. Thus, TLR signaling appears to play a direct role in T-dependent antigen-specific B cell responses in addition to its effects on TH activation and thus T cell help. The IgE response (which is initiated by parasites) was similar in mice receiving B cells lacking MyD88 to that in mice receiving wild-type B cells, which suggests that TLR signaling in B cells may help identify the microbial origin of antigens and thereby direct the B cell response.

C. Pasare, R. Medzhitov, Control of B-cell responses by Toll-like receptors. Nature 438, 364-368 (2005). [PubMed]