Vaccination is a critical public health measure for the prevention of infectious diseases. By establishing immunity against a given pathogen, its circulation and prevalence can be mitigated and limited to the point of local elimination (e.g., measles) and, in some cases, global eradication (e.g., smallpox). Such an effect of vaccination is underpinned by the inherent ability of the immune system to maintain lifelong, Ab-mediated immunity, even for decades after the initial Ag encounter (1). Although it was established in the early 1940s that Abs are produced by a specialized subset of lymphocytes called plasma cells (PCs), the exact mechanisms of lifelong, Ab-mediated immunity remained unclear and contentious for decades. In this Pillars of Immunology commentary, we discuss the foundational discovery of PC longevity by Ahmed and colleagues (2) from 1998, which overturned the contemporary dogma of how humoral immunity is maintained.
Although it was accepted that PCs were the source of Abs and long-term humoral immunity, the prevailing model at the time considered Ab-secreting PCs to be short lived, with a half-life of a few days (3, 4) to a few weeks (5). Under that model, Ag persisting on follicular dendritic cells in lymphoid tissues was required to continuously stimulate memory B cell (MBC) proliferation and differentiation into PCs. Presumably, this periodic process repeatedly replenished the pool of short-lived PCs and consequently maintained serum Abs over prolonged periods of time. Yet, evidence was emerging that PCs may be long lived and maintain constant numbers in the bone marrow (BM) without exhibiting any signs of proliferation (6).
Slifka et al. (2) reinvestigated this hypothesis using a mouse model of an acute viral infection: lymphocytic choriomeningitis virus (LCMV). LCMV-specific PCs were initially found in the spleen but only transiently, with ∼5% of day 8 PCs persisting in the spleen on day 30 and thereafter. Instead, as PCs declined in the spleen, the BM was populated with LCMV-specific PCs that were stably maintained for at least 300 d. By depleting MBCs, Slifka et al. (2) established that PCs can persist in the BM without repopulation from MBCs for at least 8 mo. Similarly, LCMV-specific serum Abs were maintained for at least 500 d after MBC depletion. Consistently, the adoptive transfer of BM PCs from infected donor mice engendered LCMV-specific serum Abs to naive recipient mice, which were maintained for at least 4 mo. Overall, the elegant experiments by Slifka et al. (2) indicated an impressive ability of BM PCs to not only survive without replenishment from MBCs but also to continuously produce Abs for the lifetime of a mouse.
The findings of Slifka et al. (2) in the murine model of LCMV instigated seminal studies in other models, including nonhuman primates (7), and eventually of BM PC longevity in humans and their relationship to sustained humoral immunity. Highlighting the relevance of the discoveries by Slifka et al. (2), it was recently demonstrated that severe acute respiratory syndrome coronavirus 2 infection elicits a population of PCs that stably persist in the BM for at least 11 mo, and this persistence correlates with virus-specific IgG Ab maintenance in serum (8). Furthermore, PCs specific for Ags encountered in childhood, like those from measles or mumps, can be found in the BM of adults ≥40 y later (9), indicating the longevity of these cells in humans. Critically, overlap between the sequences of virus-specific IgGs in serum and BCRs of BM PCs identifies these cells as the source of long-lived serum Abs in humans (9, 10). In addition, in lymphoma and rheumatoid arthritis patients treated with an anti-CD20 Ab, which results in B cell (CD20+), but not PC (CD20−), depletion, pathogen-specific Ab titers are sustained in serum (11, 12), indicating maintenance of serological memory in the absence of MBCs, similar to the findings of Slifka et al. (2) in mice.
The demonstration of BM PC longevity and continuous Ab production for the lifetime of the host by Ahmed and colleagues (2) raised important questions about the intriguing biology of long-lived BM PCs. As a result, we now understand many of the key factors that regulate PC differentiation from activated B cells, as well as the signals and pathways that mediate BM PC survival (13). BM PCs have intrinsic traits that are key to their survival, like the expression of adhesion receptors, abundance of antiapoptotic molecules, and elevated respiratory capacity (13). Similarly, their ability to continuously produce Abs is tightly linked to active unfolded protein response and autophagy pathways that counterbalance the endoplasmic reticulum stress associated with strenuous protein production (13). These traits may be epigenetically and transcriptionally determined during differentiation down the PC lineage or imparted and maintained by exogenous cues of the BM microenvironment (13). Specifically, BM PCs rely on numerous exogenous cues derived from immune and stromal cells in the BM for their survival (13). Impressively, such a phenomenon was envisaged by Slifka et al. (2) in the concluding remarks of their 1998 study where they hypothesized that “it is possible that the anatomical microenvironment plays a role in determining the lifespan of plasma cells.”
In summary, the study by Slifka et al. (2) demonstrated the existence of a long-lived population of PCs in the BM that could produce Abs for the lifetime of a mouse without replenishment from MBCs. We now understand that these BM PCs constitute the cellular basis of lifelong, Ab-mediated immunity to pathogens that is provided by vaccination or prior infection. Although we have come a long way in understanding the fundamental aspects of long-lived PCs in both animals and humans, further investigation of these cells may be able to improve the outcomes of suboptimal vaccination strategies and fully harness their immunological potential.
The authors have no financial conflicts of interest.