A Replicative Self-Renewal Model for Long-Lived Plasma Cells: Questioning Irreversible Cell Cycle Exit

Reuben M Tooze

doi:10.3389/fimmu.2013.00460

Abstract

Plasma cells are heterogenous in terms of their origins, secretory products, and lifespan. A current paradigm is that cell cycle exit in plasma cell differentiation is irreversible, following a pattern familiar in short-lived effector populations in other hemopoietic lineages. This paradigm no doubt holds true for many plasma cells whose lifespan can be measured in days following the completion of differentiation. Whether this holds true for long-lived bone marrow plasma cells that are potentially maintained for the lifespan of the organism is less apparent. Added to this the mechanisms that establish and maintain cell cycle quiescence in plasma cells are incompletely defined. Gene expression profiling indicates that in the transition of human plasmablasts to long-lived plasma cells a range of cell cycle regulators are induced in a pattern that suggests a quiescence program with potential for cell cycle re-entry. Here a model of relative quiescence with the potential for replicative self-renewal amongst long-lived plasma cells is explored. The implications of such a mechanism would be diverse, and the argument is made here that current evidence is not sufficiently strong that the possibility should be disregarded.

Highlights

Entry into cell cycle quiescence accompanies the final phenotypic maturation of plasma cells [1]
A REPLICATIVE SELF-RENEWAL MODEL OF LONG-LIVED PC MAINTENANCE In a replicative self-renewal model long-lived plasma cells reside in the bone marrow niche in a quiescent state, expressing a range of cell cycle regulators, but can be triggered by cellular and immunological cues into undergoing transient episodes of replicative self-renewal at a low frequency (Figure 2A)
Additional contributory mechanism, that have not been addressed here, could be envisaged from expressed oncogenes conferring apoptotic resistance leading to preferential survival of both daughter cells despite a normal self-renewal threshold

Summary

INTRODUCTION

Entry into cell cycle quiescence accompanies the final phenotypic maturation of plasma cells [1]. In contrast long-lived plasma cells may potentially survive for the lifetime of the organism [2, 3], and the mechanisms maintaining quiescence in such populations are of much greater significance. It may be timely to re-evaluate this paradigm and consider an alternate possibility: that long-lived “memory” plasma cells adopt a quiescent state, controlled by their niche environment, but maintain the potential for replicative self-renewal through cell division. The implications of such a mechanism are diverse, and the evidence against is potentially not sufficiently strong that the possibility should be disregarded.

DISCUSSION

SUMMARY AND PERSPECTIVES