Increased mitochondrial metabolism profile is required for immunologic function in age associated B cells

Abstract

Abstract Specific metabolic programs are activated by immune cells to fulfill their functional roles. Age-associated B cells (ABCs) are a subset of B cells that are identified by expression of non-canonical B lineage marker, CD11c. An expansion of ABCs has been identified in various autoimmune diseases, including systemic lupus erythematosus (SLE). They have many distinct properties, such as capacity to stimulate T cells and the ability to secrete autoreactive antibodies when they are stimulated in vitro. The metabolic pathways that support these functions are unknown. Using mouse models of human SLE, we confirmed ABCs induce T cell activation effectively and these activated T cells acquire follicular helper T (Tfh) cell phenotypes, including BCL6 expression, up-regulation of surface expression of CXCR5 and PD-1 and IL-21 production. Metabolically, ABCs are bioenergetically more active than follicular (FO) B cells, with higher rates of glycolysis and oxidative phosphorylation. They have increased mitochondrial activation with an increased production of reactive oxygen species (mtROS). Treatment of ABCs with mitochondrial complex I inhibitor or mtROS scavenger leads to a selective loss of their capacity to induce Tfh differentiation but not T cell activation or proliferation. The aberrant activation of mitochondrial metabolism and mtROS production was also consistently observed in ABCs from SLE patients as well. Therefore, ABCs have evolved a distinct metabolism adapted to their specific functional properties. Supported by NIH NIAMS R01 AR075565 NIH NIAMS U19 AI144306