Mitochondrial reactive oxygen species suppress humoral immune response through reduction of CD19 expression in B cells in mice

Abstract

Reactive oxygen species (ROS) are implicated in the modulation of diverse processes including immune responses. To evaluate the effects of metabolic ROS produced by mitochondria on B-cell function and development, we created transgenic (Tg) mice expressing a phosphorylation-defective mutant of succinate dehydrogenase A in B cells (bSDHA^Y215F ). Splenic B cells in male, but not female, bSDHA^Y215F mice produced three times more ROS than those in the control mice, and had decreased production of IgM, IgG₁ , and IgG₃ , and affinity maturation of IgG₁ against T-cell-dependent antigens. Following immunization, the male bSDHA^Y215F mice further displayed suppressed germinal center (GC) formation, and proliferation of GC B cells. Signaling analysis revealed defects in the intrinsic BCR responses, such as activation of Lyn, Btk, and PLCγ2, thus resulting in reduced intracellular Ca²⁺ mobilization. Notably, the expression levels of B-cell co-receptor CD19 and its interaction with Lyn after BCR ligation were significantly reduced in B cells from male bSDHA^Y215F mice. These results suggest that mitochondrial ROS suppress humoral immune responses through reduction of CD19 expression and resultant BCR signaling in B cells. Therefore, B-cell immunity may be more labile to oxidative stress in male mice than in female mice.

Keywords: B cells; Gender difference; Immune responses; Mitochondria; ROS.