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

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.