Amelioration of Autoimmunity in a Lupus Mouse Model by Modulation of T‐Bet –Promoted Energy Metabolism in Pathogenic Age/ Autoimmune‐Associated B Cells

作者：Xiaxia Han, Shuangshuang Gu, Soon‐Min Hong, Yang Jiang, Jinsong Zhang, Chao Yao, Zhihua Yin, Zhizhong Ye, Huihua Ding, Sheng Chen, Dai Dai, Nan Shen · 发表于：Arthritis & Rheumatology · 年份：2022 · DOI：10.1002/art.42433 · 被引用次数：25 · 研究领域：Systemic Lupus Erythematosus Research、Liver Diseases and Immunity、T-cell and B-cell Immunology

OBJECTIVE: Emerging evidence indicates that a distinct CD11c+T-bet+ B cell subset, termed age/autoimmune-associated B cells (ABCs), is the major pathogenic autoantibody producer in lupus. Human lupus is associated with significant metabolic alterations, but how ABCs orchestrate their typical transcription factors and metabolic programs to meet specific functional requirements is unclear. We undertook this study to characterize the metabolism of ABCs and to identify the regulators of their metabolic pathways in an effort to develop new therapies for ABC-mediated autoimmunity. METHODS: We developed a T-bet-tdTomato reporter mouse strain to trace live T-bet+ B cells and adoptively transferred CD4+ T cells from bm12 mice to induce lupus. We next sorted CD11c+tdTomato+ B cells and conducted RNA sequencing and an extracellular flux assay. A metabolic restriction to constrain ABC formation was tested in human and mouse B cells. We used a bm12-induced lupus mouse model to conduct the metabolic intervention. RESULTS: ABCs exhibited a hypermetabolic state with enhanced glycolytic capacity. The increased glycolytic rate in ABCs was promoted by interferon-γ (IFNγ) signaling. T-bet, a downstream transcription factor of IFNγ, regulated the gene program of the glycolysis pathway in ABCs by repressing the expression of Bcl6. Functionally, glycolysis restriction could impair ABC formation. The engagement of glycolysis promoted survival and terminal differentiation of antibody-secreting cells....