Regulation of B cell lymphocyte responses by TLR10

描述(申请人提供)：Toll样受体(TLRs)通过感知微生物并诱导激活T细胞反应所需的树突状细胞成熟事件，在先天免疫系统和获得性免疫系统之间提供了关键的联系。此外，TLR亚群在B淋巴细胞中表达，在B淋巴细胞中它们具有内在的活性，包括促进抗体产生和维持长期记忆。尽管对TLRs进行了大量研究，但在B细胞中高表达的TLR10的功能仍不清楚，这主要是因为缺乏可识别的信号反应和激活配体。TLR10在小鼠中是一个不活跃的假基因，这一事实加剧了这种知识差距。这一建议通过开发和使用研究工具克服了这些障碍，研究工具包括激活抗TLR10抗体和TLR10转基因小鼠模型。这项建议的首要目标是确定TLR10在B细胞谱系中的表达和功能。这一目标是通过以下研究来实现的：1)全面描述TLR10在人类B细胞谱系中的表达及其调控；2)确定TLR10在体外调节B细胞活性的功能；3)确定TLR10在调节类开关重组中的作用；4)研究TLR10在调节抗原特异性获得性免疫反应中的作用。这些研究对开发对人类有效的疫苗和自身免疫疾病(如狼疮)具有相当大的意义，在狼疮中，TLR活性失调发挥着明显的B细胞内在作用。

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.