Why are long-lived plasma cells long-lived?

Long-Lived Plasma Cells (LLPCs) are an integral part of long-term protective humoral immunity. They can live for decades, unlike Short-Lived Plasma Cells (SLPCs), and continuously produce antibody regardless of antigen stimulation, unlike Memory B Cells (MBCs). LLPCs are critical for the sustained protective immunity against pathogens that are only intermittently present in a population but can cause significant morbidity/mortality when active-such as epidemic diseases. What drives B cell differentiation specifically to the LLPC lineage is still not fully understood; there is conflicting information on what drives the fate decisions for MBCs vs. SLPCs vs. LLPCs. Evidence suggests that although LLPC and SLPC have similar gene transcriptional profiles they differ significantly in their metabolic profiles-likely due to the demands of prolonged continuous antibody production in LLPC. These metabolic changes include increased uptake of metabolic substrates, increased mitochondrial mass/function and enhanced fuel availability via lipophagy, and enhanced proteostasis to remove misfolded proteins. However, the possibility of repeated antigen-driven generation of a large number of highly metabolically active long-lived cells is problematic for a resource-constrained organism, and it is now clear that LLPC numbers are constrained by a limited number of specialized LLPC niches in the bone marrow and other tissues. LLPCs are not intrinsically long-lived but rely on interactions with the LLPC niche to maintain their longevity. For example, activation of the CD28 receptor on LLPC by its ligands CD80/CD86 on dendritic cells (DC) in the LLPC niche results in augmented metabolism through enhanced lipophagy, intracellular long chain fatty acid availability, oxidative phosphorylation, increased mitochondrial mass and function that are necessary for LLPC survival. CD28 activation is essential for the survival of LLPC but not for SLPC, supporting the concept that enhancement of LLPC metabolic capacity by interactions with its niche plays a key role in LLPC longevity. In human health, new insights into how LLPCs survive and differentiate will impact the development of robust and long-lasting vaccinations, as well as with treatment of autoantibody-mediate autoimmune diseases and PC malignancies such as multiple myeloma (MM)-as these malignancies remain dependent on many of the same survival pathways as their nonmalignant LLPC counterparts.