Regulation of B cell lymphocyte responses by TLR10

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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.