Regulation of B cell lymphocyte responses by TLR10

描述（由申请人提供）：toll样受体（TLRs）通过感知微生物和诱导T细胞反应激活所需的树突状细胞成熟事件，在先天免疫系统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，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，但由于缺乏可识别的信号反应和激活配体，TLR10在B细胞中高表达的功能仍然未知。TLR10在小鼠中是一种不活跃的假基因，这一事实加剧了这种知识差距。本研究通过开发和使用包括激活抗TLR10抗体和TLR10转基因小鼠模型在内的研究工具来克服这些障碍。该建议的总体目标是表征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)充分表征TLR10在人类B细胞谱系中的表达特征和调控；2)表征TLR10在体外调节B细胞活性的功能；3)定义TLR10在调制类开关重组中的作用；4)研究TLR10在调节抗原特异性适应性免疫应答中的作用。这些研究对于开发对人类和自身免疫性疾病（如狼疮）有效的疫苗具有重要意义，其中TLR活性失调明显起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. PUBLIC HEALTH RELEVANCE: Toll-like receptor 10 is an uncharacterized immune receptor that is highly expressed on human B cells. This proposal aims to understand the function of this receptor in regulating B cell responses leading to antibody production. This research is relevant to vaccine design and autoimmune disease.