How intrinsic and extrinsic regulators of plasma cell survival might intersect for durable humoral immunity

Plasma cells (PC) are key to protective immunity because they secrete antibodies. Surviving for periods ranging from days to decades in mammals, PC possess varying survival times that cannot be entirely stochastic or extrinsically set, as presumed half-lives vary with antigenic specificity. Here, we review the signals that impart survival potential to PC. These include signals provided during formation, and signals experienced once generated and embedded in the so-called long-lived niche. These signals all feed into survival by maintaining PC expression of MCL1, potentially synergistically with influences of other BCL2 family members. Herein, we propose that each formed PC has a capacity to respond to extrinsic cues that sets an upper maximum to its lifespan, but survival is also affected by variable availability of signals provided in BM survival niches. PC survival thus becomes a function of immunogen characteristics and niche anatomy, determined by the weighted survival benefit ascribed to each involved factor. Most factors, such as supporting cell types and secreted proteins, are predicted to influence survival times varying temporally by orders of magnitude, rather than absolute PC abundances measured at a single time, which may account for the variation in PC lifespan evident in the literature.