IL-21 and IL-10 have redundant roles but differential capacities at different stages of plasma cell generation from human germinal center B cells

Abstract

The GC is the anatomical site where antigen-activated B cells differentiate into PC, producing high-affinity antibodies in physiological and pathological states. PC differentiation is regulated by multiple factors within the GC microenvironment, including cytokines. IL-21, a recently identified type I cytokine produced by GC-Th cells, promotes differentiation of human B cells into ISC. In this study, we investigated in detail the functional role of IL-21 in the course of GC-B cell differentiation into terminally differentiated PC compared with that of IL-10, a well-known PC differentiation factor. IL-21 had a greater capacity to initiate PC differentiation from CD77(+) centroblasts than IL-10 by strongly inducing PC transcription factors through activation of STAT3; however, IL-10 was more potent than IL-21 in generating CD138(+) PC from CD20(-)CD38(++) plasmablasts in the terminal stage of GC-B cell differentiation. This differential effect of IL-21 and IL-10 was reflected in receptor expression on B cell subsets emerging in the course of differentiation. Our studies have revealed that IL-21 is a critical decision-maker for driving initial PC differentiation at the stage of CD77(+) centroblasts, yet IL-10 is more effective in producing IgG by generating terminally differentiated CD138(+) PC at the later stage of PC differentiation in the GC.

A Recombinant G Protein Plus Cyclosporine A–Based Respiratory Syncytial Virus Vaccine Elicits Humoral and Regulatory T Cell Responses against Infection without Vaccine-Enhanced Disease

“…Help for B cells might be a consequence of IL-10 production by induced Treg cells. Although IL-10 is considered to be an anti-inflammatory cytokine, its enhancement of B cell activation and Ab production has been known for decades (97,(107)(108)(109)(110). Induced Treg cells produce high levels of IL-10, and this has been suggested to lead to B cell maturation (108,111,112).…”

IL-21–Dependent B Cell Death Driven by Prostaglandin E2, a Product Secreted from Follicular Dendritic Cells

“…including LPS and CpG oligonucleotides (11,12). In human B cells stimulated via CD40, IL-21 further augments their proliferation and plasma cell differentiation, whereas the same cytokine suppresses their proliferation induced by anti-IgM plus IL-4 (13)(14)(15)(16). In contrast, IL-21 that is administered into mice in vivo has been shown to cause apoptosis in resting B cells while promoting differentiation of Ag-stimulated B cells into plasma and memory cells (10).…”

IL-21 acts as a promising therapeutic target in systemic lupus erythematosus by regulating plasma cell differentiation

“…Moreover, another study investigated the effect of IL-21 and IL-10 on the different PC development stages in the GC. IL-21 preferentially converted CD77 1 centroblasts into CD20 2 CD38 high plasmablasts in the early stage; however, IL-10 had a more potent effect on the terminal differentiation of CD20 2 CD38 high plasmablasts into CD138 1 PC in the later stage 54 (Figure 1). …”