Plasma cell survival: The intrinsic drivers, migratory signals, and extrinsic regulators

Abstract

Antibody-secreting cells (ASC) are the effectors of protective humoral immunity and the only cell type that produces antibodies or immunoglobulins in mammals. In addition to their formidable capacity to secrete massive quantities of proteins, ASC are terminally differentiated and have unique features to become long-lived plasma cells (LLPC). Upon antigen encounter, B cells are activated through a complex multistep process to undergo fundamental morphological, subcellular, and molecular transformation to become an efficient protein factory with lifelong potential. The ASC survival potential is determined by factors at the time of induction, capacity to migration from induction to survival sites, and ability to mature in the specialized bone marrow microenvironments. In the past decade, considerable progress has been made in identifying factors regulating ASC longevity. Here, we review the intrinsic drivers, trafficking signals, and extrinsic regulators with particular focus on how they impact the survival potential to become a LLPC.

Keywords: antibody-secreting cell; bone marrow; immunoglubulin secretion; long-lived plasma cell; maturation; survival niche.

Fig. 1.. On becoming a LLPC: The inducers, intrinsic drivers, trafficking signals, and extrinsic regulators.

Antigen exposure induces B-cell activation and differentiation. ASC differentiation is driven by a sophisticated transcriptional network aided by posttranscriptional and epigenetic controls and metabolic programs. ASC survival is influenced by the quality of their niche, predominantly the BM. In-between is the trafficking of newly-minted ASC to the niche from their site of induction, which, in turn, affect ASC longevity by the nature of the immune response at the time and the location ASC are formed (which is affected by the host status and the antigen nature and property).

Fig. 2.. Induction and recall of humoral immunity.

Upon primary antigen encounter, naïve B cells are activated and then either immediately differentiate into ASC by extrafollicular (EF) reactions or enter a germinal center (GC) response where they undergo class-switch recombination (CSR) and somatic hypermutation (SHM), ultimately leading to the generation of BCR with higher affinity. Once selected during the GC reaction, the cells further differentiate either into ASC/SLPC/LLPC or memory B cells. Upon secondary or subsequent antigen exposure, memory B cells are activated and then follow either a secondary EF response or re-enter a secondary GC response. ASC originated from both GC and memory B cells can migrate to the BM.

Fig. 3.. From BCR to secretory Ig: Intracellular transport for Ig secretion.

Initiation of Ig synthesis and production upon the recognition of membrane-bound antigen by BCR (and other co-receptors) of activated B cells (1). Translation, folding, and assembly (ie. maturation) of Ig peptides into Ig molecules at the ER membrane (the ER lumen) (2). Modification (including glycosylation) and transportation of properly folded Ig molecules through the Golgi network to the cell surface for secretion (3). Ig molecules are embedded in the plasma membrane or secreted (4). To achieve high-rate Ig synthesis, newly-minted ASC increase the size and functional capacity of their secretory pathway organelles, ER and the Golgi.

Fig. 4.. The UPR signaling in ASC.

The UPR constitutes a dynamic and complex network of signals and is mediated by three main classes of ER stress sensors, which localize in the ER lumen: PERK, IRE1α, and ATF6α. In unstressed conditions, these sensors remain inactive. Upon ER stress induction, the two enzymatic arms, PERK and IRE1α, become self-activated, while ATF6α is transited to the Golgi apparatus. In the cytosol, activation of PERK leads to reduction of global protein synthesis – mainly through promoting the selective translation of transcription factor ATF4, which, in turn, drives the expression of genes involved in amino acid metabolism, autophagy, and apoptosis. Self-activation of IRE1α results in initiation of its endoribonuclease activity, which processes and splices the mRNA encoding XBP1 into splicing XBP1 (sXBP1), the more active and stable isoform of the transcription factor. sXBP1 upregulates a subset of UPR-affiliated genes (including those driving protein folding, quality control, and ER-associated degradation). Under ER stress conditions, transcription factor ATF6α transits from the ER lumen into the Golgi network for downstream processing. Here, ATF6α cytosolic domain is released to the cytosol and subsequently, translocated into the nucleus to guide the expression of some ER-affiliated genes including XBP1. Resolution of ER stress results in ASC homeostasis and survival. However, unresolved ER stress triggers the pro-apoptotic programs that induce apoptosis – the so-called ER stress-induced cell death. This outcome is mainly regulated by PERK and IRE1α, the two enzymatic branches of the UPR, and often through downregulating the expression of anti-apoptotic proteins, particularly Mcl-1 and Bcl-2.