CD28 Regulates Metabolic Fitness for Long-Lived Plasma Cell Survival

Cell Rep. 2020 Jun 23;31(12):107815. doi: 10.1016/j.celrep.2020.107815.


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.

Keywords: CD28; IRF4; ROS; SLP76; metabolism; mitochondria; plasma cell.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Bone Marrow Cells / cytology
  • CD28 Antigens / metabolism*
  • Cell Respiration
  • Cell Survival
  • Female
  • Glucose / metabolism
  • Humans
  • Interferon Regulatory Factors / metabolism
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mitochondria / metabolism
  • Plasma Cells / cytology*
  • Plasma Cells / metabolism*
  • Reactive Oxygen Species / metabolism
  • Signal Transduction
  • Spleen / cytology


  • CD28 Antigens
  • Interferon Regulatory Factors
  • Reactive Oxygen Species
  • interferon regulatory factor-4
  • Glucose