Despite the important role of B lymphocytes as a bridge between the innate and the adaptive immune system, little is known regarding lipopolysaccharide (LPS) recognition, activation of signalling networks or conceivable cooperation between LPS and the B-cell antigen receptor (BCR). Here, we show that primary B cells can efficiently discriminate between different LPS chemotypes, responding with at least 100-fold higher sensitivity to rough-form LPS compared with smooth-form LPS. Using genetically modified mice, we demonstrate that B lymphocytes recognize all LPS chemotypes via Toll-like receptor 4 (TLR4). In addition, we dissect the signalling pathways that lead to CD69 upregulation upon TLR4 and BCR activation in primary B cells. Our data suggest that TLR4 and BCR induce CD69 transcription via two distinct sets of signalling molecules, exerting quantitative and qualitative differences in B-cell activation. Finally, we show that simultaneous stimulation of TLR4 and BCR additively elevates B-cell activation. In contrast, co-engagement of TLR4 and BCR by antigen-coupled LPS synergistically enhances activation of B cells, pointing out attractive targets for signalling crosstalk in B lymphocytes.Key words: BCR Á B lymphocytes Á CD69 Á Lipopolysacharide Á TLR4 Supporting Information available online IntroductionConsiderable evidence supports an important role of B lymphocytes in immune responses against gram-negative bacteria. Lipopolysaccharide (LPS) is the main structural component of the cell wall of these pathogens and is a primary target for recognition by the immune system [1,2]. Stimulation of B cells by LPS induces B-cell proliferation, antibody secretion, and promotes B cells to function as antigen-presenting cells by enhancing expression of MHC class II and co-stimulatory molecules [3,4]. Thus, B cells are an important bridge between the innate and the adaptive immune system, due to their ability to be activated by pathogen-associated molecules like LPS and to generate antigen-specific antibodies.Toll-like receptors (TLR) are a family of transmembrane proteins responsible for recognition of pathogen-associated patterns and initiation of the respective responses [5]. Genetic experiments have shown that TLR4 is the signal-transducing receptor for LPS [6][7][8]. TLR4 requires interaction with the glycoprotein MD-2 for LPS recognition, as has been demonstrated using gene-disrupted mice [9]. TLR4 is a leucine-rich repeat protein with an intracellular signal-transducing Toll/IL-1R (TIR) [17,18]. Nevertheless, binding of LPS to the TLR4/MD-2 complex leads to the recruitment of the cytosolic adaptor proteins MyD88 and Mal, initiating a signalling cascade that culminates in nuclear translocation of the transcription factors NF-kB and AP-1 [19,20].In detail, recruitment of IL-1R-associated kinase (IRAK)-4 by MyD88 facilitates phosphorylation of IRAK-1, which dissociates from the receptor complex to interact with the TNFR-associated factor 6 (TRAF6). The IRAK-1/TRAF6 complex mediates subsequent signalling steps leadin...
The cover image was specifically designed based on an illustration provided by Minguet et al., the authors of Enhanced B‐cell activation mediated by TLR4 and BCR crosstalk (pp. 2475–2487). The authors demonstrate that while simultaneous stimulation of TLR4 and BCR activates B cells in an additive manner, antigen‐coupled LPS activates B cells synergistically. The authors proposed this image based on the idea that “science is multidimensional and will never be finished or completely understood”. The illustration was further enhanced with images taken from various studies published in this issue of the European Journal of Immunology.
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