Essential Role of IL-21 in B Cell Activation, Expansion, and Plasma Cell Generation during CD4+ T Cell-B Cell Collaboration

Abstract

During T cell-B cell collaboration, plasma cell (PC) differentiation and Ig production are known to require T cell-derived soluble factors. However, the exact nature of the cytokines produced by activated T cells that costimulate PC differentiation is not clear. Previously, we reported that costimulation of purified human B cells with IL-21 and anti-CD40 resulted in efficient PC differentiation. In this study, we addressed whether de novo production of IL-21 was involved in direct T cell-induced B cell activation, proliferation, and PC differentiation. We found that activated human peripheral blood CD4+ T cells expressed mRNA for a number of cytokines, including IL-21, which was confirmed at the protein level. Using a panel of reagents that specifically neutralize cytokine activity, we addressed which cytokines are essential for B cell activation and PC differentiation induced by anti-CD3-activated T cells. Strikingly, neutralization of IL-21 with an IL-21R fusion protein (IL-21R-Fc) significantly inhibited T cell-induced B cell activation, proliferation, PC differentiation, and Ig production. Inhibition of PC differentiation was observed even when the addition of IL-21R-Fc was delayed until after initial B cell activation and expansion had occurred. Importantly, IL-21 was found to be involved in PC differentiation from both naive and memory B cells. Finally, IL-21R-Fc did not inhibit anti-CD3-induced CD4+ T cell activation, but rather directly blocked T cell-induced B cell activation and PC differentiation. These data are the first to document that B cell activation, expansion, and PC differentiation induced by direct interaction of B cells with activated T cells requires IL-21.

Aiolos Overexpression in Systemic Lupus Erythematosus B Cell Subtypes and BAFF-Induced Memory B Cell Differentiation Are Reduced by CC-220 Modulation of Cereblon Activity

“…1). As shown in this and other studies, CD40L costimulation with IL-21 induces robust plasmablast differentiation from both naive and memory B cells (19,27,114). Stimulation of naive B cells with BAFF or anti-IgM alone or each in the presence of IL-2 and IL-21, however, does not induce significant proliferation or differentiation.…”

B Cell Receptor-ERK1/2 Signal Cancels PAX5-Dependent Repression of BLIMP1 through PAX5 Phosphorylation: A Mechanism of Antigen-Triggering Plasma Cell Differentiation

“…BCR stimulation with Ag is not the only stimulation required for plasma cell differentiation. Stimulation with cytokines, such as IL-2, IL-4, IL-10, and IL-21, and contact-dependent engagement of CD40 on B cells by CD40L (CD154), expressed by activated CD4 + T cells, are required for plasma differentiation (22)(23)(24)(25)(26). Costimulation with these cytokines and T cells might prolong and enhance ERK1/2 phosphorylation and PAX5 phosphorylation and enable enough BLIMP1 expression to initiate plasma cell differentiation.…”

IL-21 Stimulates Human Myeloma Cell Growth through an Autocrine IGF-1 Loop

“…Numerous studies have documented that IL-21 stimulates B cell differentiation and IgG production, and a recent study demonstrated that IL-21 is required in B cell activation expansion and plasma cell generation during CD4 ϩ T cell-B cell interaction (15)(16)(17). Although, IL-21 has been shown to be a growth and survival factor in MM several years ago, no subsequent study has been devoted to the biological significance of the IL-21/IL-21R system in MM.…”

“…Indeed, IL-21 induces the differentiation of B cells into plasma cells through up-regulation of BLIMP1 (15). Moreover, a recent study demonstrated the requirement of IL-21 in B cell activation expansion and plasma cell differentiation induced by direct interaction of B cells with activated T cells (16). The role of IL-21 in regulating Ig production is supported by knockout mouse models.…”