CD28 induces mitochondrial respiration through Slp-76 in long-lived plasma cells for reactive oxygen species dependent survival. (LYM2P.737)

Abstract

Abstract Sustained humoral immunity is dependent upon bone marrow (BM) resident long-lived plasma cells (LLPC). We have shown that CD28 signaling in LLPCs is necessary for their survival and antibody production; however, the mechanistic basis for this is unclear. In T cells, CD28 induces glycolysis at the expense of mitochondrial respiration. Surprisingly, CD28 activation drives mitochondrial respiration in LLPCs but not short-lived plasma cells (SLPC) through PLCγ1. Paradoxically, respiration dependent production of reactive oxygen species is required for CD28 mediated survival. Mechanistically, CD28 provides a pro-survival signal in LLPCs through Slp-76, an adaptor protein known to be upstream of PLCγ1 in T cells. CD28 itself drives Slp-76 transcription and subsequent protein expression. Additionally, at the mRNA level Slp-76 is highly expressed in human BM PCs (LLPCs) when compared to splenic PCs (SLPCs). Furthermore, CD28 upregulates the APRIL/BAFF receptor BCMA in LLPCs but not SLPCs. Due to the high levels of Slp-76 seen in LLPCs, but not in SLPCs, we propose a model wherein CD28 induces a longevity program through Slp-76 during plasma cell differentiation that facilitates plasma cell responsiveness to extrinsic survival signals in the bone marrow niche, allowing for a plasma cell to become long-lived. By doing so, CD28 may regulate LLPC induction, function and survival. CD28 therefore represents a novel signaling axis to exploit for the augmentation of vaccine design.