Parrish-Novak, J., Dillon, S.R., Nelson, A., Hammond, A., Sprecher, C., Gross, J.A. et al. Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature 408, 57-63

Department of Functional Cloning, ZymoGenetics, Inc., Seattle, Washington 98102, USA.
Nature (Impact Factor: 41.46). 12/2000; 408(6808):57-63. DOI: 10.1038/35040504
Source: PubMed


Cytokines are important in the regulation of haematopoiesis and immune responses, and can influence lymphocyte development. Here we have identified a class I cytokine receptor that is selectively expressed in lymphoid tissues and is capable of signal transduction. The full-length receptor was expressed in BaF3 cells, which created a functional assay for ligand detection and cloning. Conditioned media from activated human CD3+ T cells supported proliferation of the assay cell line. We constructed a complementary DNA expression library from activated human CD3+ T cells, and identified a cytokine with a four-helix-bundle structure using functional cloning. This cytokine is most closely related to IL2 and IL15, and has been designated IL21 with the receptor designated IL21 R. In vitro assays suggest that IL21 has a role in the proliferation and maturation of natural killer (NK) cell populations from bone marrow, in the proliferation of mature B-cell populations co-stimulated with anti-CD40, and in the proliferation of T cells co-stimulated with anti-CD3.

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    • "IL-21, first identified as a product of activated human T cells, is a pleiotropic cytokine which has diverse effects on the immune response through its ability to modulate the activity of many immune cell types [23]–[25]. Primarily produced by activated CD4+ T cell (in particular, TFH effector cells), IL-21 regulates B cell responses within the B cell follicular germinal center (GC) [25]. NKT cells are an additional potential major source of IL-21 and produce even higher level of this cytokine than activated conventional CD4+ T cells when appropriately stimulated [22]. "
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    ABSTRACT: IL-21 is a type-I cytokine that has pleiotropic immuno-modulatory effects. Primarily produced by activated T cells including NKT and TFH cells, IL-21 plays a pivotal role in promoting TFH differentiation through poorly understood cellular and molecular mechanisms. Here, employing a mouse model of influenza A virus (IAV) infection, we demonstrate that IL-21, initially produced by NKT cells, promotes TFH differentiation by promoting the migration of late activator antigen presenting cell (LAPC), a recently identified TFH inducer, from the infected lungs into the draining lymph nodes (dLN). LAPC migration from IAV-infected lung into the dLN is CXCR3-CXCL9 dependent. IL-21-induced TNF-α production by conventional T cells is critical to stimulate CXCL9 expression by DCs in the dLN, which supports LAPC migration into the dLN and ultimately facilitates TFH differentiation. Our results reveal a previously unappreciated mechanism for IL-21 modulation of TFH responses during respiratory virus infection.
    Full-text · Article · Sep 2014 · PLoS ONE
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    • "Previous studies have shown that IL-21 is also produced by Th17 cells and by natural killer T cells, and that IL-21 mRNA can be detected in stromal cells in the lymph nodes. All these studies indicate the significance of IL-21 in innate and adaptive immune responses (1–3). "
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    ABSTRACT: Interleukin 21 (IL-21) and its receptor, IL-21R, play a key role in innate and adaptive immunity. In the present study, the effect of IL-21 and IL-21R on the pathogenesis of diffuse large B-cell lymphoma (DLBCL) was investigated. The serum levels of IL-21 were detected by enzyme-linked immunosorbent assay, and the expression of IL-21R on CD8(+) T cells was examined through flow cytometry. The data showed that the serum level of IL-21 was significantly decreased in the patients with DLBCL compared with the healthy controls (P<0.001), whereas the expression of IL-21R was clearly elevated on the CD8(+) T cells in the patients with DLBCL. Further analyses revealed that the downregulation of the IL-21 serum level was correlated with an increased tumor stage of DLBCL, while the expression of IL-21R on the CD8(+) T cells was positively correlated with the tumor stage. Also, the serum level of IL-21 and the proportion of IL-21R on the CD8(+) T cells were negatively correlated in the patients. Notably, it was identified that the proportion of IL-21R on the CD8(+) T cells, but not the serum level of IL-21, was significantly upregulated in the patients with bone-marrow involvement and B symptoms. These results indicate that IL-21 and IL-21R may be involved in the pathogenesis of DLBCL, in which IL-21R may reflect the progression of the disease more accurately than the serum level of IL-21.
    Full-text · Article · Jul 2014 · Oncology letters
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    • "IL-21 is an IL-2 family member that enhances the Th17 differentiation of naïve Th cells. Importantly, the major sources of IL-21 are activated T cells and NKT cells, but not antigen presenting cells (Parrish-Novak et al., 2000), and the largest amounts of IL-21 are produced by Th17 cells, which appear to use IL-21 as a positive feedback loop for maintaining and amplifying the frequency of Th17 precursors when the supply of IL-6 is limited (Korn et al., 2007). Based on this, IL- 21 has been suggested as an important player in chronic inflammatory disorders such as inflammatory bowel disease and rheumatoid arthritis (Fina et al., 2008, Niu et al., 2010). "
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    ABSTRACT: Aim: Variations in the expression of cytokines during the progression of periodontitis remain ill-defined. We evaluated the expression of 19 cytokine genes related to T-cell phenotype/function during initiation, progression and resolution of periodontitis, and related these to the expression of soft and bone tissue destruction genes (TDGs). Materials and methods: A ligature-induced periodontitis model was used in rhesus monkeys (M. mulatta) (n = 18). Gingival tissues were taken at baseline pre-ligation, 2 weeks and 1 month (Initiation) and 3 months (progression) post ligation. Ligatures were removed and samples taken 2 months later (resolution). Total RNA was isolated and the Rhesus Gene 1.0 ST (Affymetrix) used for gene expression analysis. Significant expression changes were validated by qRT-PCR. Results: Disease initiation/progression was characterized by overexpression of Th17/Treg cytokine genes (IL-1β, IL-6, TGFβ and IL-21) and down-regulation of Th1/Th2 cytokine genes (IL-18 and IL-25). Increased IL-2 and decreased IL-10 levels were seen during disease resolution. Several Th17/Treg cytokine genes positively correlated with TDGs, whereas most Th1/Th2 genes exhibited a negative correlation. Conclusion: Initiation, progression and resolution of periodontitis involve over- and underexpression of cytokine genes related to various T-helper subsets. In addition, variations in individual T-helper response subset/genes during disease progression correlated with protective/destructive outcomes.
    Full-text · Article · Jun 2014 · Journal Of Clinical Periodontology
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