CD28 Regulates Metabolic Fitness for Long-Lived Plasma Cell Survival

Abstract

SUMMARY 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.

CRTC2 regulates plasma cell metabolism and survival

“…A recent report found that differential expression of Lcp2, which encodes the CD28 adaptor protein SLP76, linked CD28 signaling in LLPCs to increased Irf4 expression and an IRF4-mediated increase in mitochondrial mass and oxidative phosphorylation. This increase in metabolic fitness was proposed as a mechanism for LLPC survival in the bone marrow niche (Utley, Chavel et al, 2020). However, a previous study failed to identify Lcp2 as differentially expressed between ASCs and follicular B cells (Shi et al, 2015) and our own RNA-seq analysis showed no significant difference in Lcp2 expression between TG PCs and WT PCs.…”

“…The metabolism of LLPCs differs from SLPCs (Lam et al, 2016, Utley et al, 2020, although the mechanism(s) underlying differences in lifespan remain largely unknown.…”

ARS2-directed alternative splicing mediates CD28 driven T cell glycolysis and effector function

“…We recently reported that signaling through the CD28 PYAP ICD is required for enhanced glycolysis in T cells activated for 24 hours 46 . Earlier studies found that PI3K activation by CD28 induced GLUT1 expression and enhanced glycolysis over the same 24 hour activation period 3,47 , indicating that the signaling initiated by the membrane proximal YMNM and membrane distal PYAP domains of CD28 cooperate to induce glycolytic metabolism during T cell priming.…”

Metabolic Swifts Govern Normal and Malignant B Cell Lymphopoiesis

“…These are the long-lived PC (LLPC). In contrast to their SL brothers, LLPCs secrete much higher amounts of Ab and can live for decades inside the BM, where they migrate without dividing [ 52 , 53 ].…”