Amelioration of Autoimmunity in a Lupus Mouse Model by Modulation of T‐Bet–Promoted Energy Metabolism in Pathogenic Age/Autoimmune‐Associated B Cells
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 transcri...
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Veröffentlicht in: | Arthritis & rheumatology (Hoboken, N.J.) N.J.), 2023-07, Vol.75 (7), p.1203-1215 |
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Sprache: | eng |
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Zusammenfassung: | 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. Administration of a glycolysis inhibitor ameliorated ABC accumulation and autoantibody production in the lupus‐induced bm12 mouse model.
Conclusion
T‐bet can couple immune signals and metabolic programming to establish pathogenic ABC formation and functional capacities. Modulation of ABCs favored a metabolic program that could be a novel therapeutic approach for lupus. |
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ISSN: | 2326-5191 2326-5205 |
DOI: | 10.1002/art.42433 |