CD28 Regulates Metabolic Fitness for Long-Lived Plasma Cell Survival
Adam Utley, Colin Chavel, Shivana M. Lightman, G. Aaron Holling, James J. M. Cooper, Peng Peng, Wensheng Liu, Benjamin G. Barwick, Catherine M. Gavile, Orla Maguire, Megan Murray-Dupuis, Cheryl Rozanski, Martha S. Jordan, Taku Kambayashi, Scott H. Olejniczak, Lawrence Boise, Kelvin P. Lee
Abstract
Durable humoral immunity against epidemic infectious disease requires the survival of long-lived plasma cells (LLPCs). LLPC longevity is dependent on metabolic programs distinct from short-lived plasma cells (SLPCs); however, the mechanistic basis for this difference is unclear. We have previously shown that CD28, the prototypic T cell costimulatory receptor, is expressed on both LLPCs and SLPCs but is essential only for LLPC survival. Here we show that CD28 transduces pro-survival signaling specifically in LLPCs through differential SLP76 expression. CD28 signaling in LLPCs increased glucose uptake, mitochondrial mass/respiration, and reactive oxygen species (ROS) production. Unexpectedly, CD28-mediated regulation of mitochondrial respiration, NF-κB activation, and survival was ROS dependent. IRF4, a target of NF-κB, was upregulated by CD28 activation in LLPCs and decreased IRF4 levels correlated with decreased glucose uptake, mitochondrial mass, ROS, and CD28-mediated survival. Altogether, these data demonstrate that CD28 signaling induces a ROS-dependent metabolic program required for LLPC survival.