CD28 induces mitochondrial respiration through Slp-76 in Long-Lived Plasma Cells for ROS-dependent survival.

Sustained humoral immunity is dependent upon bone marrow (BM) resident long-lived plasma cells (LLPCs). We have shown that CD28 signaling in LLPCs is necessary for their survival and antibody production; however, the mechanistic basis for this is unclear. In T cells, CD28 induces glycolysis at the expense of mitochondrial respiration. To our great surprise, CD28 induces mitochondrial respiration and increases the spare respiratory capacity in LLPCs, but not in short lived plasma cells (SLPCs), through Slp-76. While not affecting glycolysis, CD28 does increase the glycolytic capacity and glycolytic reserve specifically in LLPCs. Paradoxically, the mitochondrial respiration dependent production of reactive oxygen species (ROS) is required for CD28 mediated survival. Mechanistically, ROS dependent activation of NFkB drives Irf4 expression, which itself upregulates myc, both of which have been described as central regulators of metabolism in T cells. In addition, CD28 drives myc-dependent mitochondrial biogenesis in LLPCs, thereby sustaining mitochondrial respiration-dependent ROS. This leads to a self-reinforcing model wherein CD28 induces mitochondrial respiration for ROS-dependent activation of Irf4 and myc, which then drive further mitochondrial biogenesis and enhanced metabolic fitness for LLPC survival. Our work suggests that CD28, by increasing metabolic fitness, may provide a qualitatively distinct program of longevity that allows greater competitive advantage for survival in the BM microenvironment. CD28 may therefore regulate LLPC induction, survival, and function, making it an attractive target for the augmentation of vaccine design as well as in the alleviation of antibody mediated autoimmunity.