CD28 induces mitochondrial respiration in long lived plasma cells for reactive oxygen species dependent survival and NFκB-mediated Blimp1 expression. (LYM6P.771)

Abstract

Abstract Sustained humoral immunity is dependent upon bone marrow resident long-lived plasma cells (LLPCs). We have shown that CD28 signaling in LLPCs is necessary for their survival and antibody production; however, the signaling pathways that define LLPC survival and function are not completely understood. In T cells, CD28 is known to induce glycolysis at the expense of mitochondrial respiration. To our great surprise, CD28 induces mitochondrial respiration-dependent reactive oxygen species (ROS) through PLCγ1 in LLPCs but not splenic short lived plasma cells (SLPCs). Paradoxically, inhibition of ROS kills LLPCs while promoting survival of SLPCs. In LLPCs, CD28-mitochondrial ROS activates NFκB, which in turn binds directly to the Blimp1 promoter, the master regulator of plasma cell identity. Furthermore, CD28 induces Blimp1 expression in LLPCs but not SLPCs. These data suggest a model wherein CD28-induced mitochondrial respiration drives survival of LLPCs through mitochondrial ROS-dependent activation of NFκB and subsequent Blimp1 upregulation. By understanding CD28 regulation of LLPC metabolism, new therapeutic targets arise for antibody-mediated autoimmune disease and vaccine design.