PDF(Pubmed)
Abstract：
Toll-like receptors are pattern recognition receptors that bridge the innate and adaptive immune responses and are critical for host defense. Most studies of Toll-like receptors have focused upon their roles in myeloid cells. B lymphocytes express most Toll-like receptors and are responsive to Toll-like receptor ligands, yet Toll-like receptor-mediated signaling in B cells is relatively understudied. This is an important knowledge gap, as Toll-like receptor functions can be cell type specific. In striking contrast to myeloid cells, TRAF3 inhibits TLR-mediated functions in B cells. TRAF3-deficient B cells display enhanced IRF3 and NFκB activation, cytokine production, immunoglobulin isotype switching, and antibody production in response to Toll-like receptors 3, 4, 7, and 9. Here, we address the question of how TRAF3 impacts initial B-cell Toll-like receptor signals to regulate downstream activation. We found that TRAF3 in B cells associated with proximal Toll-like receptor 4 and 7 signaling proteins, including MyD88, TRAF6, and the tyrosine kinase Syk. In the absence of TRAF3, TRAF6 showed a greater association with several Toll-like receptor signaling proteins, suggesting that TRAF3 may inhibit TRAF6 access to Toll-like receptor signaling complexes and thus early Toll-like receptor signaling. In addition, our results highlight a key role for Syk in Toll-like receptor signaling in B cells. In the absence of TRAF3, Syk activation was enhanced in response to ligands for Toll-like receptors 4 and 7, and Syk inhibition reduced downstream Toll-like receptor-mediated NFκB activation and proinflammatory cytokine production. This study reveals multiple mechanisms by which TRAF3 serves as a key negative regulator of early Toll-like receptor signaling events in B cells.
摘要：
Toll样受体是模式识别受体,其桥接先天和适应性免疫应答并且对于宿主防御是关键的。对Toll样受体的大多数研究都集中在它们在骨髓细胞中的作用上。B淋巴细胞表达大多数Toll样受体，对Toll样受体配体有反应，然而,对Toll样受体介导的B细胞信号传导的研究相对不足.这是一个重要的知识差距，Toll样受体功能可以是细胞类型特异性的。与骨髓细胞形成鲜明对比，TRAF3抑制B细胞中TLR介导的功能。TRAF3缺陷B细胞显示增强的IRF3和NFκB激活，细胞因子产生，免疫球蛋白同种型转换，和响应Toll样受体3、4、7和9的抗体产生。这里,我们解决了TRAF3如何影响初始B细胞Toll样受体信号以调节下游激活的问题.我们发现，B细胞中的TRAF3与近端Toll样受体4和7信号蛋白相关，包括MyD88、TRAF6和酪氨酸激酶Syk。在没有TRAF3的情况下，TRAF6与几种Toll样受体信号蛋白有更强的相关性，这表明TRAF3可能会抑制TRAF6对Toll样受体信号复合物的访问，从而抑制早期Toll样受体信号传导。此外,我们的结果强调了Syk在B细胞Toll样受体信号传导中的关键作用.在不存在TRAF3的情况下,响应于Toll样受体4和7的配体,Syk活化增强,并且Syk抑制降低下游Toll样受体介导的NFκB活化和促炎细胞因子产生。这项研究揭示了TRAF3作为B细胞早期Toll样受体信号传导事件的关键负调节因子的多种机制。
