TFEB and age-associated B cells in autoimmunity

Project summary Age-associated B cells (ABCs) is a recently described B cell subset that accumulate during aging or development of systemic autoimmunity. They contribute to dysregulation of humoral immunity during aging and production of autoantibodies in autoimmune diseases. They are particularly responsive to TLR signaling and can be generated in both T cell dependent and T cell independent manner. Its metabolic and transcriptional regulation remain poorly understood. The MiTF/TFE transcription family member TFEB is a key modulator of lysosomal biogenesis, autophagy and lipid metabolism. We present preliminary evidence suggesting a potential contribution of TFEB transcription factor to the metabolic fitness of ABCs. TFEB overactivation leads to abnormal mitophagy and impaired mitochondrial metabolism in B cells, and dampened humoral immunity against T cell independent antigens. ABCs from aged mice, aged human donors and patients with systemic lupus erythematosus (SLE) exhibit elevated TFEB expression and its associated transcriptional signature. Our central hypothesis is that TFEB modulates systemic autoimmunity partly by controlling the mitochondrial metabolism and function of ABCs. Specifically, increased TFEB activity will reduce mitochondrial metabolism of ABCs, reduce autoantibody production and ameliorate SLE pathology, whereas reduced TFEB activity will have the opposite effects. In Aim 1, we will perform metabolic assays, transcriptomics and metabolomics to define the functions of TFEB in ABC generation, mitochondrial metabolism and function using novel genetic gain-of-function, loss-of-function, and reporter models. In Aim 2, we will test how TFEB may contribute to SLE pathogenesis using a TLR7 ligand induced lupus model on TFEB gain-of-function and loss-of-function mouse models. Our research will establish the first metabolic metabolism controlling ABCs.