The National Institutes of Health reports that > 23 million (~5-8%) of Americans suffer from chronic inflammatory conditions, many of which involve the pathogenic functions of autoreactive B lymphocytes and the autoantibodies they produce. Chronic inflammatory conditions also predispose to the subsequent development of malignancies, such as B cell lymphoma, in the affected cells and tissues. There is thus a critical window of opportunity in which alleviation of autoimmunity and chronic inflammation can also reduce future risk of malignancies. However, many of the current treatments for B cell-mediated autoimmunity globally deplete B cells, which can alleviate symptoms but result in immunosuppression. There is thus an ongoing need for development and refinement of therapies that target the pathogenic function of autoreactive B cells. The adapter protein TNF Receptor Associated Factor 3 (TRAF3) acts in a cell-type-specific manner to suppress B cell signaling pathways contributing to both autoimmunity and malignancy, and loss of TRAF3 protein in B cells by inflammation-induced degradation creates chronic B cell TRAF3 deficiency. This deficiency in turn predisposes to abnormally enhanced B cell survival and function, leading to autoimmunity in young adults in a preclinical mouse model, and development of B cell lymphoma in these mice as they age. This highlights a critical need to define how TRAF3 regulates B cell functions, the long-term goal of this work. The objective of this project is to address the knowledge gap of how TRAF3 regulates signals via the B cell antigen receptor (BCR) and the innate Toll-like Receptors (TLR) that are involved in autoimmunity, via the following Specific Aims: (1) Identify the molecular mechanisms by which TRAF3 restrains BCR signaling and BCR contributions to autoimmunity. (2) Define how TRAF3 inhibits B cell signals and functions of innate immune Toll-like receptors (TLRs). (3) Determine how inhibition of TRAF3-regulated BCR and TLR signaling pathways impacts development of autoimmunity in B cell-specific TRAF3-deficient mice (B-Traf3-/-). The expected outcome of these studies is a detailed knowledge of how a deficiency in TRAF3, which is associated with both aging and chronic B cell activation, contributes to B cell-mediated autoimmunity. This knowledge will be valuable in selection and development of pathway-targeted therapies for autoimmune conditions.