Regulation of B cell lymphocyte responses by TLR10

描述（由申请人提供）：Toll样受体（TLR）通过感知微生物和诱导T细胞应答激活所需的树突状细胞成熟事件，在先天性和适应性免疫系统之间提供关键联系。此外，TLR亚群在B淋巴细胞中表达，其中它们具有内在活性，包括促进抗体产生和维持长期记忆。尽管对TLR进行了大量研究，但在B细胞中高度表达的TLR 10的功能仍然未知，这主要是由于缺乏可识别的信号传导应答和活化配体。这种知识差距由于TLR 10在小鼠中是一种无活性的假基因而加剧。该提案通过开发和使用研究工具克服了这些障碍，这些研究工具包括激活抗TLR 10抗体和TLR 10转基因小鼠模型。该提案的首要目标是表征B细胞谱系内的TLR 10表达和功能。该目标通过旨在以下的研究来实现：1）充分表征人B细胞谱系内TLR 10表达的概况和调节; 2）表征TLR 10在调节B细胞活性中的体外功能; 3）确定TLR 10在调节类别转换重组中的作用; 4）检查TLR 10在调节抗原特异性适应性免疫应答中的作用。这些研究对于开发在人类中有效的疫苗和对于自身免疫性病症如狼疮（其中失调的TLR活性起明显的B细胞内在作用）具有相当大的意义。

DESCRIPTION (provided by applicant): Toll-like receptors (TLRs) provide a critical link between the innate and adaptive immune system by sensing microbes and inducing dendritic cell maturation events needed for the activation of T cell responses. Additionally, TLR subsets are expressed in B lymphocytes where they have intrinsic activities which include the promotion of antibody production and maintenance of long term memory. Despite considerable research on TLRs the function of TLR10, which is highly expressed in B cells, remains unknown largely due to a lack of identifiable signaling responses and activating ligands. This knowledge gap is exacerbated by the fact that TLR10 is an inactive pseudogene in mice. This proposal overcomes these barriers through the development and use of research tools which include activating anti-TLR10 antibodies and a TLR10 transgenic mouse model. The overarching goal of this proposal is to characterize TLR10 expression and function within the B cell lineage. This goal is addressed through studies which aim: 1) to fully characterize the profile and regulation of TLR10 expression within the human B cell lineage; 2) to characterize the in vitro function of TLR10 in modulating B cell activity; 3) to define the role of TLR10 in the modulating class switch recombination; 4) to examine the role of TLR10 in regulating antigen-specific adaptive immune responses. These studies have considerable implications for the development of vaccines that are effective in humans and for autoimmune conditions such as lupus where dysregulated TLR activity plays a clear B cell intrinsic role.