IL-21 Induces the Functional Maturation of Murine NK Cells

Brady, Jason; Hayakawa, Yoshihiro; Smyth, Mark J.; Nutt, Stephen L.

doi:10.4049/jimmunol.172.4.2048

Cited by 273 publications

(279 citation statements)

References 58 publications

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“…In contrast, we isolated B cell subsets by sorting such that the purity was usually Ͼ97%. Thus, because IL-21 has pleiotropic effects on other cell types, such as T cells and NK cells (23,25,60,61) that would still be present in these cultures, the apparent increase in anti-CD40 mAb-induced B cell proliferation observed in the presence IL-4, IL-10, or IL-13 may result from an indirect effect of IL-21 on T cells and NK cells. Similarly, IL-4, IL-10, and IL-13 can all influence the behavior of monocytes, with respect to phenotype and cytokine secretion (62).…”

Section: Discussionmentioning

confidence: 99%

Kinetics of Human B Cell Behavior and Amplification of Proliferative Responses following Stimulation with IL-21

Good

Bryant

Tangye

2006

The Journal of Immunology

250

237

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Although recent studies indicated that IL-21 is an important regulator of human B cell activation, detailed comparison of the effects of IL-21 on distinct B cell subsets have not been performed. Our studies revealed that IL-21R is expressed by naive and germinal center B cells, but not memory or plasma cells. IL-21R was increased on naive and memory B cells following in vitro activation. Investigation into the kinetics and magnitude of responses of human B cells to IL-21 revealed that IL-21 potently augmented proliferation of CD40L-stimulated neonatal, splenic naive, and memory and tonsil germinal center B cells. This response exceeded that induced by IL-4, IL-10, and IL-13, cytokines that also induce B cell proliferation. Remarkably, CD40L/IL-21-stimulated naive B cells underwent the same number of divisions as memory cells and exhibited a greater enhancement in their response compared with CD40L alone than memory B cells. Therefore, IL-21 is a powerful growth factor for naive B cells. This may result from the higher expression of IL-21R on naive, compared with memory, B cells. Stimulation of human B cells with CD40L/IL-21 also induced IL-10 production and activation of STAT3. We propose that IL-21 may have therapeutic application in conditions of immunodeficiency where it could expand naive B cells, the predominant B cell subset in such patients. Conversely, because IL-21 is increased in murine models of lupus, dysregulated IL-21 production may contribute to perturbed B cell homeostasis observed in systemic lupus erythematosus. Thus, antagonizing IL-21 may be a novel strategy for treating Ab-mediated autoimmune diseases.

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Section: Discussionmentioning

confidence: 99%

Kinetics of Human B Cell Behavior and Amplification of Proliferative Responses following Stimulation with IL-21

Good

Bryant

Tangye

2006

The Journal of Immunology

250

237

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“…The induction of type I immune responses, as well as the terminal differentiation of NK cells, therefore appear relevant to an effective antitumor activity. To this regard, IL-21, a promising cytokine able to build up NK cell antitumor activity (59), has been found to promote both the expression of genes associated with type I response and the terminal differentiation of the highly cytotoxic CD56 dim / CD16 ϩ NK cell subset, which can potentially direct ADCC against tumor cells via CD16-Fc ligation (18,19,60). NK cellmediated ADCC response against tumor targets can be promoted by administration of mAbs to tumor-associated Ags (61, 62) (Fig.…”

Section: Nk Cell-based Immunotherapeutic Strategies Against Cancermentioning

confidence: 99%

“…IFN-␥ induces type I immune response and directly acts on cancer cells. Finally, IL-21, another cytokine binding the common ␥-chain (shared with IL-2, IL-4, IL-7, IL-9, and IL-15), has been demonstrated to favor the onset of the most cytotoxic CD56 dim CD16 ϩ NK cell subset and to enhance its cytotoxicity (18,19).…”

mentioning

confidence: 99%

NK Cells and Cancer

Zamai

Ponti

Mirandola

et al. 2007

The Journal of Immunology

260

199

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In this review, we overview the main features and functions of NK cells, focusing on their role in cell-mediated immune response to tumor cells. In parallel, we discuss the information available in the field of NK cell receptors and offer a wide general overview of functional aspects of cell targeting and killing, focusing on the recent acknowledgments on the efficacy of NK cells after cytokine and mAb administration in cancer therapy. Since efficacy of NK cell-based immunotherapy has been proven in KIR-mismatch regimens or in TRAIL-dependent apoptosis, the ability to manipulate the balance of activating and inhibitory receptors on NK cells and of their cognate ligands, as well as the sensitivity of tumor cells to apoptosis, opens new perspectives for NK cell-based immunotherapy.

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“…115,116 IL-21 promotes the differentiation of CD56 dim CD16 1 NK-cell subset, which can potentially direct ADCC. 117,118 Combining the TLR agonist CpG with Rituximab increased antitumor NK cell ADCC in a mouse model. 119 Activated NK cells by an agonistic antibody to the activating 4-1BB receptor completely regressed subcutaneous murine lymphoma tumors during Rituximab treatment.…”

Section: Allogeneic Nk Cellsmentioning

confidence: 99%

NK cell-based immunotherapy for malignant diseases

et al. 2013

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Natural killer (NK) cells play critical roles in host immunity against cancer. In response, cancers develop mechanisms to escape NK cell attack or induce defective NK cells. Current NK cell-based cancer immunotherapy aims to overcome NK cell paralysis using several approaches. One approach uses expanded allogeneic NK cells, which are not inhibited by self histocompatibility antigens like autologous NK cells, for adoptive cellular immunotherapy. Another adoptive transfer approach uses stable allogeneic NK cell lines, which is more practical for quality control and large-scale production. A third approach is genetic modification of fresh NK cells or NK cell lines to highly express cytokines, Fc receptors and/or chimeric tumor-antigen receptors. Therapeutic NK cells can be derived from various sources, including peripheral or cord blood cells, stem cells or even induced pluripotent stem cells (iPSCs), and a variety of stimulators can be used for large-scale production in laboratories or good manufacturing practice (GMP) facilities, including soluble growth factors, immobilized molecules or antibodies, and other cellular activators. A list of NK cell therapies to treat several types of cancer in clinical trials is reviewed here. Several different approaches to NK-based immunotherapy, such as tissue-specific NK cells, killer receptor-oriented NK cells and chemically treated NK cells, are discussed. A few new techniques or strategies to monitor NK cell therapy by non-invasive imaging, predetermine the efficiency of NK cell therapy by in vivo experiments and evaluate NK cell therapy approaches in clinical trials are also introduced.

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IL-21 Induces the Functional Maturation of Murine NK Cells

Cited by 273 publications

References 58 publications

Kinetics of Human B Cell Behavior and Amplification of Proliferative Responses following Stimulation with IL-21

Kinetics of Human B Cell Behavior and Amplification of Proliferative Responses following Stimulation with IL-21

NK Cells and Cancer

NK cell-based immunotherapy for malignant diseases

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