CD28 Regulates Metabolic Fitness for Long-Lived Plasma Cell Survival

• Type of Material: Article
• Authors: Adam Utley, Roswell Park Comprehensive Cancer Center; Colin Chavel, Roswell Park Comprehensive Cancer Center; Shivana Lightman, Roswell Park Comprehensive Cancer Center; G. Aaron Holling, Roswell Park Comprehensive Cancer Center; James Cooper, Roswell Park Comprehensive Cancer Center; Peng Peng, Roswell Park Comprehensive Cancer Center; Wensheng Liu, Roswell Park Comprehensive Cancer Center; Benjamin Barwick, Emory University; Catherine M. Gavile, Emory University; Orla Maguire, Roswell Park Comprehensive Cancer Center; Megan Murray-Dupuis, Roswell Park Comprehensive Cancer Center; Cheryl Rozanski, Roswell Park Comprehensive Cancer Center; Martha S. Jordan, University of Pennsylvania; Taku Kambayashi, University of Pennsylvania; Scott H. Olejniczak, Roswell Park Comprehensive Cancer Center; Kelvin P. Lee, affiliation; Lawrence Boise, Emory University
• Language: English
• Date: 2020-06-23
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2020 The Author(s).
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.celrep.2020.107815
• Title of Journal or Parent Work: Cell Reports
• Volume: 31
• Issue: 12
• Grant/Funding Information: This research was supported by NIH grants CA121044 (K.P.L.), T32CA085183 (A.U.), CA127910, CA192844 (L.H.B.), and AI100157 (S.H.O.).
• Keywords: humoral immunity; longevity; metabolic programs; short-lived plasma cells; long-lived plasma cells; CD28; epidemic infectious disease

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.