CD28 Regulates Metabolic Fitness for Long-Lived Plasma Cell Survival
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Sustained humoral immunity depends on the survival of bone marrow (BM) resident long-lived plasma cells (LLPC). However, the mechanisms governing LLCP survival are not completely understood. We have previously shown that CD28, the prototypic T cell costimulatory molecule, is essential for the survival of LLPC but not SLPC through its activation by CD80/CD86 expressing dendritic cells (DC) in the bone marrow microenvironment. We have also demonstrated that CD28 signaling provides a pro-survival signal in the malignant counterpart of LLPC known as multiple myeloma (MM). How CD28 is able to provide a pro-survival signal specifically in LLPC but not SLPC is unknown. Recent data also distinguish increased glucose uptake and mitochondrial metabolism as required for LLPC longevity, distinct from the metabolic program of short-lived plasma cells (SLPC). Extrinsic interactions in the BM survival niche are known to regulate LLPC survival; however, the mechanism by which intrinsic metabolic programing is regulated in LLPC compared to SLPC is unclear. We now show that CD28 transduces a pro-survival signal in LLPC but not SLPC through differential expression of the adaptor protein SLP-76. CD28 signaling increased LLPC glucose uptake, mitochondrial mass, and maximal respiratory capacity. In MM, CD28 activation was also able to increase glucose uptake, mitochondrial mass, and spare respiratory capacity. CD28 activation also increased reactive oxygen species (ROS) in LLPC, a byproduct of mitochondrial respiration. Unexpectedly, the CD28-mediated enhancement of respiratory capacity and LLPC/MM survival was dependent on ROS suggesting a role for ROS in supporting CD28-mediated signaling. Consistent with a role for ROS in CD28-mediated signaling, CD28-induced NF-kB activation was abrogated by ROS inhibition. IRF4, a pro-survival transcription factor for PC and target of NF-kB, has been shown to be downstream of CD28 in MM. Here we show that IRF4 was upregulated by CD28 activation in LLPC. The importance of upregulated IRF4 expression in mediating metabolic reprogramming was demonstrated in LLPC from IRF4+/- heterozygous mice having lower glucose uptake, mitochondrial mass and ROS. Altogether, these data demonstrate that CD28 signaling is a key mediator of the intrinsic metabolic program underlying LLPC longevity and survival.