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

Ettinger, Rachel; Sims, Gary P.; Fairhurst, Anna‐Marie; Robbins, RC; Silva, Yong Sing Da; Spolski, Rosanne; Leonard, Warren J.; Lipsky, Peter E.

doi:10.4049/jimmunol.175.12.7867

Cited by 584 publications

(691 citation statements)

References 56 publications

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“…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).…”

mentioning

confidence: 99%

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

Nakayama¹,

Kosek²,

Capone³

et al. 2017

The Journal of Immunology

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BAFF is a B cell survival and maturation factor implicated in the pathogenesis of systemic lupus erythematosus (SLE). In this in vitro study, we describe that soluble BAFF in combination with IL-2 and IL-21 is a T cell contact-independent inducer of human B cell proliferation, plasmablast differentiation, and IgG secretion from circulating CD27+ memory and memory-like CD27−IgD− double-negative (DN) B cells, but not CD27−IgD+ naive B cells. In contrast, soluble CD40L in combination with IL-2 and IL-21 induces these activities in both memory and naive B cells. Blood from healthy donors and SLE patients have similar circulating levels of IL-2, whereas SLE patients exhibit elevated BAFF and DN B cells and reduced IL-21. B cell differentiation transcription factors in memory, DN, and naive B cells in SLE show elevated levels of Aiolos, whereas Ikaros levels are unchanged. Treatment with CC-220, a modulator of the cullin ring ligase 4-cereblon E3 ubiquitin ligase complex, reduces Aiolos and Ikaros protein levels and BAFF- and CD40L-induced proliferation, plasmablast differentiation, and IgG secretion. The observation that the soluble factors BAFF, IL-2, and IL-21 induce memory and DN B cell activation and differentiation has implications for extrafollicular plasmablast development within inflamed tissue. Inhibition of B cell plasmablast differentiation by reduction of Aiolos and Ikaros may have utility in the treatment of SLE, where elevated levels of BAFF and Aiolos may prime CD27+ memory and DN memory-like B cells to become Ab-producing plasmablasts in the presence of BAFF and proinflammatory cytokines.

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mentioning

confidence: 99%

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

Nakayama¹,

Kosek²,

Capone³

et al. 2017

The Journal of Immunology

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“…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.…”

Section: Il-21 Enhanced the Differentiation Of Human B Cells Into Plamentioning

confidence: 99%

“…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.…”

Section: Protein Cellmentioning

confidence: 99%

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

Tan

Xing

et al. 2013

Protein Cell

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Graft-versus-host disease (GVHD) is a prevalent and potential complication of hematopoietic stem cell trans-plantation. An animal model, xenogeneic GVHD (X-GVHD), that mimics accurately the clinical presentation of GVHD would provide a tool for investigating the mechanism involved in disease pathogenesis. Murine models indicated that inhibiting IL-21 signaling was a good therapy to reduce GVHD by impairing T cell functions. We sought to investigate the effect of exogenous human IL-21 on the process of X-GVHD. In this study, human IL-21 was expressed by hydrodynamic gene delivery in BALB/cRag2 −/− IL-2Rγc −/− (BRG) immunodeficient mice which were intravenously transplanted human peripheral blood mononuclear cells (hPBMCs). We found that human IL-21 exacerbated X-GVHD and resulted in rapid fatality. As early as 6 days after hPBMCs transplanted to BRG mice, a marked expansion of human CD19 + B cells, but not T cells, was observed in spleen of IL-21-treated mice. Compared with control group, IL-21 induced robust immunoglobulin secretion, which was accompanied by increased accumulation of CD19 + CD38 high plasma cells in spleen. In addition, we demonstrated that B-cell depletion was able to ameliorate X-GVHD. These results are the fi rst to fi nd in vivo expansion and differentiation of human B cells in response to IL-21, and reveal a correlation between the expansion of B cells and the exacerbation of xenogeneic GVHD. Our fi ndings show evidence of the involvement of B cells in X-GVHD and may have implications in the treatment of the disease.

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Dou

Wang

et al. 2010

Cancer Gene Ther

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Previous studies have indicated that the cytokine interleukin (IL)-21 may induce both innate and adaptive immune responses against tumors. The goal of this study was to evaluate a new adoptive immunotherapy strategy that combined lymphocytes from mice immunized with a murine myeloma vaccine secreting murine IL-21 (mIL-21-Sp2/0) in lymphopenic mice induced by cyclophosphamide. The data indicate that effective antitumor immunity was induced in mice receiving syngeneic murine lymphocytes from the mice immunized with the mIL-21-Sp2/0. More importantly, the efficacy against the Sp2/0 cell challenge was enhanced after the lymphocytes were activated and proliferated ex vivo before administration into the lymphopenic mice. We conclude that the adoptive transfer of tumor antigen-specific lymphocytes into mice immunized with mIL-21-Sp2/0 induced protective immune responses against myeloma challenge.

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

Cited by 584 publications

References 56 publications

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

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

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

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