T follicular helper (TFH) cells are critical for the development of protective antibodies via germinal center B cell responses; however, uncontrolled TFH cell expansion activates autoreactive B cells to produce antibodies that cause autoimmunity. Yet, relatively little is known about the biology of TFH cells in SLE and the signals that lead to their abnormal accumulation and helper activity of autoreactive B cells. The long-range goal of this application is to understand the signaling pathways that are activated by antigen and cytokine receptors on lymphocytes, and how they regulate outcomes such as cell growth, differentiation, and effector functions. This proposal focuses on the BAFF cytokine receptor B cell maturation antigen (BCMA) in the development and function of TFH cells to control autoantibody production in lupus. Although increased circulating level of BAFF has been linked to the loss of B cell tolerance in systemic autoimmunity, the potential role for BAFF in TFH cell homeostasis is not known. BCMA is a receptor for BAFF and is critical for the development and survival of bone marrow plasma cells (PCs) that secrete protective antibodies. Paradoxically, BCMA deficiency exacerbates the formation of autoantibody-secreting PCs in spleens of lupus-prone mice. We show preliminary evidence that, in lupus-prone mice, TFH cells uniquely express BCMA and that the absence of BCMA in CD4+ T cells enhances TFH cell numbers and responsiveness to BAFF through the BAFF receptor BR3. These results identify a new BCMA-BAFF axis in controlling TFH cell homeostasis and suggest that the balance between BCMA and BR3 signaling in TFH cells serves as an additional checkpoint of immune tolerance. Taken together, the proposed studies should help test a novel hypothesis that BCMA signaling may contribute to immune tolerance in SLE by restraining TFH cell expansion and B cell helper activity, and if BCMA signaling is lacking then BR3 signaling promotes TFH cell differentiation and accumulation. Identifying the factors that drive BCMA expression in CD4+ T cells in autoimmunity may provide key insights into the interplay between BCMA and BR3 to regulate TFH cell responses that could be used therapeutically to treat SLE.