IL-21 Induces Differentiation of Human Naive and Memory B Cells into Antibody-Secreting Plasma Cells

Abstract

IL-21 is a type I cytokine that influences the function of T cells, NK cells, and B cells. In this study, we report that IL-21 plays a major role in stimulating the differentiation of human B cells. When human B cells were stimulated through the BCR, IL-21 induced minimal proliferation, IgD down-modulation, and small numbers of plasma cells. In contrast, after CD40 engagement, IL-21 induced extensive proliferation, class switch recombination (CSR), and plasma cell differentiation. Upon cross-linking both BCR and CD40, IL-21 induced the largest numbers of plasma cells. IL-21 drove both postswitch memory cells as well as poorly responsive naive cord blood B cells to differentiate into plasma cells. The effect of IL-21 was more potent than the combination of IL-2 and IL-10, especially when responsiveness of cord blood B cells was examined. IL-21 costimulation potently induced the expression of both B lymphocyte-induced maturation protein-1 (BLIMP-1) and activation-induced cytidine deaminase as well as the production of large amounts of IgG from B cells. Despite the induction of activation-induced cytidine deaminase and CSR, IL-21 did not induce somatic hypermutation. Finally, IL-2 enhanced the effects of IL-21, whereas IL-4 inhibited IL-21-induced plasma cell differentiation. Taken together, our data show that IL-21 plays a central role in CSR and plasma cell differentiation during T cell-dependent B cell responses.

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

“…IL-21 is a member of the common g-chain cytokine family shown to play a central role in plasmablast and plasma cell differentiation during T cell-dependent B cell responses (19,20). In humans, IL-21 is mainly produced by activated peripheral CD4 + T cells and follicular Th cells (21,22).…”

IL-21 accelerates xenogeneic graft-versus-host disease correlated with increased B-cell proliferation

“…It is well accepted that the frequency of plasma cells generally is correlated with the amount of Ig production in vivo (Ettinger et al, 2005), so the capacity of IL-21 to induce plasma cells differentiation was explored. 7 days after plasmid administration, fl ow cytometric analysis of hu-PBMC-BRG mouse splenocytes was performed.…”

“…The impact of IL-21 on human B-cell responsiveness was addressed in vitro, and all of the experiments were carried out, in which human B cells were isolated and stimulated with IL-21 in combination with anti-CD40 and/or anti-IgM, which mimic the BCR-antigen and B cell-T cell interaction (Ettinger et al, 2008;Konforte et al, 2009). Notably, IL-21 was found to induce proliferation and differentiation of human B cells isolated from PBMCs and spleen (Ettinger et al, 2005;Good et al, 2006). In our xenogeneic GVHD model, B cells were activated and proliferated after engaging mouse tissues with the help of human T cells.…”

Eliciting protective immune responses against murine myeloma challenge in lymphopenia mice through adoptive transfer of tumor antigen-specific lymphocytes and immunization of tumor vaccine secreting mIL-21

“…Moreover, IL-21 functions as a co-stimulator for lymphocyte proliferation, for enhancing memory lymphocyte responses, and for modulating immunological homeostasis. 7,11,12 Furthermore, the murine myeloma vaccine secreting murine IL-21 (mIL-21-Sp2/0) induced potent antitumor effects in mice. 13 These studies support the use of IL-21 in the ex vivo generation of potent-specific CTLs for adoptive therapy or as an adjuvant cytokine during in vivo immunization against tumor Ag.…”