|
|
| Cytokine Database |
|
INTERLEUKIN 21
LATEST LITERATURE
1: Journal of immunology (Baltimore, Md. : 1950), 2010 Jul 16, 16(8)
Regulation of the IL-21 Gene by the NF-{kappa}B Transcription Factor c-Rel.
[Abstract]IL-21 is a member of the common gamma-chain-dependent cytokine family and is a key modulator of lymphocyte development, proliferation, and differentiation. IL-21 is highly expressed in activated CD4(+) T cells and plays a critical role in the expansion and differentiation of the Th cell subsets, Th17 and follicular helper T (T(FH)) cells. Because of its potent activity in both myeloid and lymphoid cell immune responses, it has been implicated in a number of autoimmune diseases and has also been used as a therapeutic agent in the treatment of some cancers. In this study, we demonstrate that c-Rel, a member of the NF-kappaB family of transcription factors, is required for IL-21 gene expression in T lymphocytes. IL-21 mRNA and protein levels are reduced in the CD4(+) cells of rel(-/-) mice when compared with rel(+/+) mice in both in vitro and in vivo models. A c-Rel binding site identified in the proximal promoter of il21 is confirmed to bind c-Rel in vitro and in vivo and to regulate expression from the il21 promoter in T cells. Downstream of IL-21 expression, Th17, T(FH), and germinal center B cell development are also impaired in rel(-/-) mice. The administration of IL-21 protein rescued the development of T(FH) cells but not germinal center B cells. Taken together, c-Rel plays an important role in the expression of IL-21 in T cells and subsequently in IL-21-dependent T(FH) cell development.
2: Expert review of clinical immunology, 2010 Jul, 6(4)
Role of IL-21 in inflammatory bowel disease.
[Abstract]IL-21 was first described as a critical regulator of T- and B-cell functions. More recently, it has become apparent that IL-21 controls the activity of both immune and nonimmune cells and, depending on the timing and context analyzed, it can promote either inflammatory or counter-regulatory effects. IL-21 participates in the immune responses against tumor cells and chronic viral infections, but excessive production of IL-21 has been associated with the development of immune-inflammatory diseases in various organs. In this article, we focus on data supporting the pathogenic role of IL-21 in human inflammatory bowel diseases and discuss preclinical studies that suggest that neutralization of IL-21 in vivo could be a new strategy to counteract the inflammatory bowel disease-related, tissue damaging immune response.
3: Nan fang yi ke da xue xue bao = Journal of Southern Medical University, 2010 Jun, 30(6)
[Expression, purification and bioactivity evaluation of streptavidin-tagged human interleukin- 21 fusion protein.]
[Abstract]OBJECTIVE: To obtain streptavidin-tagged human interleukin-21 (hIL21) fusion protein and evaluate its bioactivities. METHODS: hIL21-SA-pET21 and pET24a-SA- hIL21 plasmids were constructed and expressed in BL21(DE3) host bacteria. The hIL21-SA and SA- hIL21 fusion protein were purified through Ni-NTA affinity chromatography and refolded by dialysis. Flow cytometry was used to detect hIL21-SA and SA- hIL21 fusion protein on the biotinylated MB49 tumor cells. MTT assay was used to evaluate the effect of the fusion protein on the proliferation of human peripheral blood lymphocytes (PBLs) stimulated by Anti-CD3. RESULTS: The recombinant fusion proteins were highly expressed in BL21(DE3) at about 30% of the total bacterial proteins. The two fusion proteins exhibited bifunctional activities, i.e. both biotin-binding property and hIL21 activity and SA-mediated high-affinity binding to biotinylated cell surfaces (with anchoring modified rate of about 95.18% and 96.91%). CONCLUSION: We have successfully obtained bifunctional fusion protein hIL21-SA and SA- hIL21,which will provide a basis for further study of tumor biotherapy using the proteins.
4: Clinical immunology (Orlando, Fla.), 2010 May 5, 59(6)
Donor CD8 T cell activation is critical for greater renal disease severity in female chronic graft-vs.-host mice and is associated with increased splenic ICOS(hi) host CD4 T cells and IL-21 expression.
[Abstract]Lupus-like renal disease in DBA/2-into-F1 (DBA --> F1) mice is driven by donor CD4 T cells and is more severe in females. Donor CD8 T cells have no known role. As expected, we observed that females receiving unfractionated DBA splenocytes (CD8 intact --> F1) exhibited greater clinical and histological severities of renal disease at 13 weeks compared to males. Surprisingly, sex-based differences in renal disease severity were lost in CD8 depleted --> F1 mice due to an improvement in females and a worsening in males. CD8 intact --> F1 female mice exhibited significantly greater donor and host effector (CD44(hi), CD62L(lo)) CD4 T cells and ICOS(hi) CD4 T follicular helper cells than males. CD8 depleted --> F1 female mice exhibited a reduction in the absolute numbers of host, but not donor CD4 Tfh cells and lost the significant increase in host CD4 effector cells vs. males. Greater female IL-21 expression, a product of Tfh cells, was seen in CD8 intact --> F1 and although reduced was still greater than male CD8 depleted --> F1 mice. Thus, donor CD8 T cells have a critical role in mediating sex-based differences in lupus renal disease severity possibly through greater host ICOS(hi) CD4 T cell involvement.
5: Journal of immunotherapy (Hagerstown, Md. : 1997), 2010 Apr, 33(3)
Intratumoral interleukin-21 increases antitumor immunity, tumor-infiltrating CD8+ T-cell density and activity, and enlarges draining lymph nodes.
[Abstract]Interleukin (IL)-21 is a novel cytokine in clinical development for the treatment of cancer. In this study, we have compared the efficacy of subcutaneous and intratumoral (IT) administration of IL-21 protein in two syngeneic mouse tumor models, RenCa renal cell carcinoma and B16 melanoma, and investigated the mechanisms by which IL-21 enhances CD8 T-cell-mediated antitumor immunity. We found that in comparison to subcutaneous administration, IT administration of IL-21 more potently inhibited tumor growth and increased survival. This correlated with increased densities of tumor-infiltrating CD8 and CD4CD25 T cells, but not CD4CD25FoxP3 T cells. Furthermore, IT administration of IL-21 increased degranulation, and expression of interferon-gamma and granzyme B in tumor-infiltrating CD8 T cells. Tumors injected with IL-21 grew slower than contralateral tumors, suggesting that the increased efficacy of IT administration of IL-21 was due to a local rather than systemic effect. IT administration of IL-21 led to enlarged tumor-draining lymph nodes (LNs), with increased naive lymphocyte numbers and proliferation of activated lymphocytes, suggesting that local administration of IL-21 generally benefits the tumor microenvironment and activates tumor-draining LNs. Overall, our data suggest that IL-21 augments CD8 T-cell-mediated antitumor immunity through increased proliferation and effector function and acts both on tumor-infiltrating CD8 T cells as well as on the draining LNs. IT administration led to superior CD8 T-cell proliferation, effector function, and antitumor efficacy, suggesting that IT administration of IL-21 may be clinically useful in patients with unresectable tumors.
6: Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology, 2010 May, 26(5)
[The detection of anti-nuclear antibody and IL-21 in patients infected with hepatitis C virus.]
[Abstract]AIM: To detect the serum anti-nuclear antibody (ANA) and interleukin-21 (IL-21) levels in patients infected with hepatitis C virus (HCV), and study their impact on the liver function of HCV patients. METHODS: Enzyme-linked immunosorbent(ELISA) assays were used to detect the serum ANA and IL-21 levels in 96 cases of HCV-IgG positive sera, as well as 30 cases of HCV-IgG negative sera. Hitachi 7600 biochemical analyzer was used to test the ALT, AST and ALB of all sera samples. RESULTS: HCV patients have abnormal liver function significantly and their average IL-21 level was much lower than the control group. While the liver function of most ANA positive HCV patients was well-balanced. The IL-21 level of HCV patients with ALT40 U/L were markedly reduced. CONCLUSION: The production of ANA and IL-21 do help to control the progress of hepetitis and reduce the damage to liver cells in HCV patients.
7: Immunology and cell biology, 2010 Apr 27, 26(5)
Regulation of human Th9 differentiation by type I interferons and IL-21.
[Abstract]Interleukin (IL)-9-producing CD4(+) T cells are a novel subset of T helper (Th) cells that develops independently of the Th1, Th2, Th17 and regulatory T-cell lineages. Similar to the murine model, transforming growth factor (TGF)-beta and IL-4 directed human naive CD4(+) T cells to produce IL-9. Whereas IL-4 suppressed TGF-beta-induced Foxp3 expression, TGF-beta failed to inhibit IL-4-mediated upregulation of the Th2 transcription factor GATA-3. Addition of IL-1beta, IL-6, IL-10, interferon (IFN)-alpha, IFN-beta or IL-21 to Th9-polarizing conditions augmented Th9 differentiation, while the Th1-associated cytokines IFN-gamma and IL-27 partially suppressed IL-9 production. Given that T cells are a primary source of IL-21, IL-21 expression was analyzed under Th9-polarizing conditions in the context of inflammatory cytokines. Surprisingly, type I IFNs induced elevated levels of IL-21, and blockade of IL-21 abrogated their ability to enhance Th9 differentiation. Taken together, these data indicate a complex cytokine network in the regulation of human IL-9-producing CD4(+) T cells.Immunology and Cell Biology advance online publication, 27 April 2010; doi:10.1038/icb.2010.53.
8: Journal of immunology (Baltimore, Md. : 1950), 2010 Apr 5, 11(5)
Cutting Edge: IL-21 and TLR Signaling Regulate Germinal Center Responses in a B Cell-Intrinsic Manner.
[Abstract]IL-21 produced by follicular Th (Tfh) cells is an important regulator of Tfh cell development and B cell responses, including germinal center (GC) formation. However, whether defective GC formation and Ab responses are a consequence of impaired Tfh cells development or a B cell-intrinsic defect in IL-21-deficient mice requires clarification. To address this question, we generated chimeric mice lacking IL-21R exclusively on B cells. In this study, we demonstrate that GC reaction and B cell responses induced by immunization with virus-like particles were strongly reduced in both global and B cell-specific IL-21R-deficient mice. Interestingly, the presence of TLR7 ligand within virus-like particles largely restored defective GC reaction and Ab responses in global as well as in B cell-specific IL-21R-deficient mice. Hence, IL-21 acts directly on B cells and cooperates with TLR signaling for optimal B cell responses.
9: Molecular immunology, 2010 Mar 17, 71(4)
TCR gene-engineered T cell: Limited T cell activation and combined use of IL-15 and IL-21 ensure minimal differentiation and maximal antigen-specificity.
[Abstract]Clinical TCR gene therapy of melanoma represents a feasible and promising treatment rationale yet is currently challenged by objective response rates that stay behind those observed with conventional adoptive T cell therapy. Here, the phenotype and function of TCR-transduced T cells, considered to determine the efficacy of TCR gene therapy, were studied in relation to T cell activation and cytokine treatments. We observed that the lectin Concanavalin A (ConA), and to a lesser extent anti-CD3 and CD28 mAbs (soluble CD3/CD28), resulted in functional surface expression of the TCRalphabeta transgenes and enhanced fractions of CD62L(hi), CD44(lo) naive T cells. T cell functions and limited T cell differentiation were most significant when T cells were treated with a combination of IL-15 and IL-21 rather than IL-2. In comparison, anti-CD3 and CD28 mAbs coated to either latex or polystyrene beads (polystyrene or latex CD3/CD28) resulted in improved TCR expression levels and enhanced T cell differentiation irrespective of cytokine treatment, with effects most pronounced for polystyrene CD3/CD28. T cells demonstrated enhanced cytotoxic activity and IFNgamma production when activated with CD3/CD28 beads and treated with IL-15 and IL-21, but at the same time displayed non-specific T cell responses. In contrast, ConA and soluble CD3/CD28 activations resulted in antigen-specific T cell responses. In short, we show that retroviral TCR engineering of primary T cells benefits from activation with ConA or soluble CD3/CD28 rather than immobilized anti-CD3 and CD28 mAbs with respect to T cell differentiation and antigen-specificity of T cell responses.
10: The Journal of biological chemistry, 2010 Feb 18,
Rational design of Interleukin-21 antagonist through selective elimination of {gamma}C binding epitope.
[Abstract]The cytokine Interleukin (IL)-21 exerts pleiotropic effects acting through innate as well as adaptive immune responses. The activities of IL-21 are mediated through binding to its cognate receptor complex composed of the IL-21 receptor private chain (IL-21Ralpha) and the common gamma-chain (gammaC), the latter being shared by IL-2, IL-4, IL-7, IL-9, and IL-15. The binding energy of the IL-21 ternary complex is predominantly provided by the high affinity interaction between IL-21 and IL-21Ralpha, while the interaction between IL-21 and gammaC, albeit essential for signalling, is rather weak. The design of IL-21 analogues, which have lost most or all affinity towards the signalling gammaC chain, while simultaneously maintaining a tight interaction with the private chain, would in theory represent candidates for IL-21 antagonists. We predicted the IL-21 residues which compose the gammaC binding epitope using homology modelling and alignment with the related cytokines, IL-2 and IL-4. Next we systematically analyzed the predicted binding epitope by a mutagenesis study. Indeed two mutants which have significantly impaired gammaC affinity, while undiminished IL-21Ralpha affinity were successfully identified. Functional studies confirmed that these two novel hIL-21 double-mutants do act as hIL-21 antagonists.
11: Vaccine, 2010 Feb 11, 207(2)
Enhancing therapy of B16F10 melanoma efficacy through tumor vaccine expressing GPI-anchored IL-21 and secreting GM-CSF in mouse model.
[Abstract]In the present study, we developed the tumor vaccine expressing IL-21 in the GPI-anchored form together with secreting GM-CSFs and investigated its antitumor efficacy in C57BL/6 mouse model. The fusion genes containing IL-21 and the GPI anchor signal sequence were acquired by overlaping PCR, inserted into the downstream of two multi-clone sites in recombinant plasmid pRSC/GM-CSFs to form pRSC/IL-21-gpi-GM-CSFs that was transfected into the B16F10 cells. The tumor cell vaccine B16F10/IL-21-gpi-GM-CSFs was identified by reverse transcription PCR, IFA and FCM, respectively. The results showed that the pRSC/IL-21-gpi-GM-CSFs had no cell cycle and proliferative state impact on the B16F10 cells after transfected, and that the tumor vaccine B16F10/IL-21-gpi-GM-CSFs increased the cytotoxicities of NK cells and CD8(+)CTL, enhanced the level of serum IFN-gamma, augmented therapy of tumor effect and prolonged survival time in the tumor-bearing mice immunized with the tumor vaccine B16F10/IL-21-gpi-GM-CSFs. The data that we presented here provided a rationale and practical platform for clinical testing of enhancing cell therapy of B16F10 melanoma efficacy by modified tumor vaccine expressing GPI-anchored IL-21 and secreting GM-CSF.
12: The Journal of experimental medicine, 2010 Feb 8,
IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses.
[Abstract]During T cell-dependent responses, B cells can either differentiate extrafollicularly into short-lived plasma cells or enter follicles to form germinal centers (GCs). Interactions with T follicular helper (Tfh) cells are required for GC formation and for selection of somatically mutated GC B cells. Interleukin (IL)-21 has been reported to play a role in Tfh cell formation and in B cell growth, survival, and isotype switching. To date, it is unclear whether the effect of IL-21 on GC formation is predominantly a consequence of this cytokine acting directly on the Tfh cells or if IL-21 directly influences GC B cells. We show that IL-21 acts in a B cell-intrinsic fashion to control GC B cell formation. Mixed bone marrow chimeras identified a significant B cell-autonomous effect of IL-21 receptor (R) signaling throughout all stages of the GC response. IL-21 deficiency profoundly impaired affinity maturation and reduced the proportion of IgG1(+) GC B cells but did not affect formation of early memory B cells. IL-21R was required on GC B cells for maximal expression of Bcl-6. In contrast to the requirement for IL-21 in the follicular response to sheep red blood cells, a purely extrafollicular antibody response to Salmonella dominated by IgG2a was intact in the absence of IL-21.
13: Journal of leukocyte biology, 2010 Jan 26, 62(2)
IL-21 enhances NK cell functions and survival in healthy and HIV-infected patients with minimal stimulation of viral replication.
[Abstract]IL-21 plays an important role in regulating immune response and controlling chronic viral infections. Recently, we reported its decreased serum concentrations and their immunological consequences in HIV-infected persons. In this study, we have investigated how exogenous IL-21 enhances NK cell responses in these persons. We show that the cytokine receptors are expressed equally on all NK cell subsets defined by expression of CD16 and CD56; the cytokine activates STAT-3, MAPK, and Akt to enhance NK cell functions; the STAT-3 activation plays a key role in constitutive and IL-21-mediated enhancement of NK cell functions; the cytokine increases expression of antiapoptotic proteins Bcl-2 and Bcl-XL and enhances viability of NK cells but has no effect on their proliferation; the cytokine enhances HIV-specific ADCC, secretory, and cytotoxic functions, as well as viability of NK cells from HIV-infected persons; it exerts its biological effects on NK cells with minimal stimulation of HIV-1 replication; and the cytokine-activated NK cells inhibit viral replication in cocultured, HIV-infected, autologous CD4(+) T cells in a perforin- and LFA-1-dependent manner. These data suggest that IL-21 may serve as a valuable therapeutic tool for enhancing NK cell responses and inhibiting viral replication in HIV-infected patients.
14: Cancer immunology, immunotherapy : CII, 2010 Jan 26, 62(2)
Combination of IL-21 and IL-15 enhances tumour-specific cytotoxicity and cytokine production of TCR-transduced primary T cells.
[Abstract]IL-21, and to a lesser extent IL-15, inhibits differentiation of antigen-primed CD8 T cells and promotes their homeostasis and anti-tumour activity. Here, we investigated molecular mechanisms behind tumour-specific responses of primary murine T lymphocytes engineered to express a TCR directed against human gp100/HLA-A2 following short-term exposure to IL-15 and/or IL-21. We demonstrated that IL-15 + IL-21, and to a lesser extent IL-21, enhanced antigen-specific T-cell cytotoxicity, which was related to enhanced expression of granzymes A and B, and perforin 1. Furthermore, IL-15 + IL-21 synergistically enhanced release levels and kinetics of T-cell IFNgamma and IL-2, but not IL-10. Enhanced secretion of IFNgamma was accompanied by increased gene expression and cytosolic protein content, and was restricted to effector memory T cells. To summarize, we show that IL-15 + IL-21 improves antigen-specific responses of TCR-transduced effector T cells at multiple levels, which provides a rationale to treat T cells with a combination of these cytokines prior to their use in adoptive TCR gene therapy.
15: Immunity, 2009 Dec 18, 31(6)
Analysis of interleukin-21-induced Prdm1 gene regulation reveals functional cooperation of STAT3 and IRF4 transcription factors.
[Abstract]Interleukin-21 (IL-21) is a pleiotropic cytokine that induces expression of transcription factor BLIMP1 (encoded by Prdm1), which regulates plasma cell differentiation and T cell homeostasis. We identified an IL-21 response element downstream of Prdm1 that binds the transcription factors STAT3 and IRF4, which are required for optimal Prdm1 expression. Genome-wide ChIP-Seq mapping of STAT3- and IRF4-binding sites showed that most regions with IL-21-induced STAT3 binding also bound IRF4 in vivo and furthermore revealed that the noncanonical TTCnnnTAA GAS motif critical in Prdm1 was broadly used for STAT3 binding. Comparing genome-wide expression array data to binding sites revealed that most IL-21-regulated genes were associated with combined STAT3-IRF4 sites rather than pure STAT3 sites. Correspondingly, ChIP-Seq analysis of Irf4(-/-) T cells showed greatly diminished STAT3 binding after IL-21 treatment, and Irf4(-/-) mice showed impaired IL-21-induced Tfh cell differentiation in vivo. These results reveal broad cooperative gene regulation by STAT3 and IRF4.
16: Journal of leukocyte biology, 2009 Dec 30, 184(1)
c-Maf activates the promoter and enhancer of the IL-21 gene, and TGF-{beta} inhibits c-Maf-induced IL-21 production in CD4+ T cells.
[Abstract]Previous studies have shown that IL-6 potently induces IL-21 production in CD4(+) T cells, whereas TGF-beta inhibits IL-6-induced IL-21 production in CD4(+) T cells. In this study, we addressed the mechanisms underlying the transcriptional regulation of IL-21 production in CD4(+) T cells. We found that IL-6 induced c-Maf expression in CD4(+) T cells and that the enforced expression of c-Maf induced IL-21 production in CD4(+) T cells without IL-6, IL-4/STAT6 signaling, or an autocrine effect of IL-21. Moreover, we found that c-Maf directly bound to and activated IL-21P and the CNS-2 enhancer through MARE sites. On the other hand, we also found that although TGF-beta up-regulated IL-6-induced c-Maf expression in CD4(+) T cells, TGF-beta inhibited c-Maf-induced IL-21 production in CD4(+) T cells. Finally, we found that Foxp3 bound to IL-21P and the CNS-2 enhancer and inhibited c-Maf-induced IL-21 production modestly but significantly in CD4(+) T cells. Taken together, these results suggest that c-Maf induces IL-21 production directly in CD4(+) T cells by activating IL-21P and the CNS-2 enhancer and that TGF-beta suppresses c-Maf-induced IL-21 production in CD4(+) T cells.
17: International journal of cancer. Journal international du cancer, 2009 Dec 28, 184(1)
Transient depletion of CD4(+) T cells augments IL-21-based immunotherapy of disseminated neuroblastoma in syngeneic mice.
[Abstract]IL-21 is a member of the IL-2 cytokine family, produced by CD4+ T cells. We previously showed that immunotherapy (IT) with IL-21-transduced neuroblastoma cells (Neuro2a/IL-21) cured 33% of syngeneic mice bearing systemic NB. Here we studied whether the removal of Treg cells could potentiate the therapeutic efficacy of Neuro2a/IL-21 vaccine. The administration of anti-CD25 mAb, which targets Treg cells, slightly potentiated the effect of vaccine IT (50% cure rate), but anti-CD4 mAb had a more potent effect leading to 80% cure rate. Anti-CD25 mAb, indeed, only partially depleted CD4+CD25+FoxP3+ Treg cells, while anti-CD4 mAb was more effective in this respect, leading to 90% depletion of Treg cells. In mice receiving vaccine+anti-CD4 mAb, which developed systemic immunity to NB, CD4+ T cells counts completely recovered in 90 days. Depletion of CD8+ T cells abrogated the effect of the combined IT, indicating a predominant role of these cells in driving the immune response. In addition, CD8+ T cells from cured mice co-injected with Neuro2a/parental cells (pc) in NOD-SCID mice completely inhibited tumor growth. Spleen cells from mice receiving Neuro2a/IL-21 vaccination showed increased expression of IFN-alpha2, -beta1, and -gamma mRNA. Moreover, mice receiving vaccine therapy alone or vaccine+anti-CD4 mAb showed increased IFN-gamma serum levels and IFN-gamma-producing CD8+ T cells were found in spleen cells.In conclusion, anti-CD4 mAb potentiated IL-21-based IT by removing Treg cells and/or their precursors and other potentially immunesuppressive CD4+ cell subsets, thus allowing the development of an IL-21-driven CD8+ T cell response, which mediates NB rejection. (c) 2009 UICC.
18: British journal of cancer, 2009 Dec 22, 184(1)
Interleukin-21 can efficiently restore impaired antibody-dependent cell-mediated cytotoxicity in patients with oesophageal squamous cell carcinoma.
[Abstract]Background:We previously reported that Trastuzumab- and Cetuximab-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) in cancer patients was impaired in comparison with that in healthy donors because of NK-cell dysfunction. In this study, we evaluated whether IL-21 could improve the impairment of ADCC in patients with oesophageal squamous cell carcinoma (ESCC), as IL-21 was reported to have the ability to activate NK cells.Methods:We examined Trastuzumab- and Cetuximab-mediated ADCC of peripheral blood mononuclear cells (PBMCs) or of enriched NK cells derived from ESCC patients (n=20) and healthy donors (n=16) in the presence of IL-21. We further analysed ADCC-related molecules (perforin, granzyme-B, and CD247) on NK cells in response to IL-21.Results:Trastuzumab- and Cetuximab-mediated ADCC of PBMCs or of enriched NK cells was enhanced by the addition of IL-21 in a dose-dependent manner and the levels of ADCC enhanced by IL-21 in patients were high enough in comparison with those in healthy donors, paralleling the upregulation of CD247 on NK cells.Conclusion:IL-21 could efficiently restore impaired ADCC in ESCC patients with the upregulation of CD247 molecules.British Journal of Cancer advance online publication, 22 December 2009; doi:10.1038/sj.bjc.6605502 www.bjcancer.com.
19: Current drug targets, 2009 Dec 8, 114(26)
Targeting Interleukin-21 in Immune-Mediated Pathologies.
[Abstract]Interleukin (IL)-21, a cytokine mostly produced by activated CD4+ T cells, has been reported to play an important role in the tissue-damaging immune response in various organs. This pathogenic effect is strictly linked to the ability of IL-21 to control the functional activities of multiple immune and non-immune cells. For instance, IL-21 regulates the differentiation and function of effector CD4+ T helper cells; controls activation, proliferation, and survival of B cells; enhances the cytotoxic activity of CD8+ T cells and NK cells; inhibits the differentiation of inducible regulatory T cells (Tregs) and makes effector CD4+ T cells resistant to the Tregs-mediated immunesuppression; stimulates epithelial cells and fibroblasts to make chemokines and extracellular matrix proteases respectively. Consistently, studies from various laboratories have documented the beneficial effect of IL-21 neutralization on the progression of inflammatory diseases in mice. Here we review the present knowledge on the expression and role of IL-21 in immune-mediated pathologies.
20: Inflammatory bowel diseases, 2009 Dec 8,
Interleukin 21 expression is increased in rectal biopsies from patients with ulcerative colitis.
[Abstract]BACKGROUND: Interleukin-21 (IL-21) is critical in the development of autoimmune diseases. The role of IL-21 in the pathogenesis of immune thrombocytopenia (ITP) remains unknown. MATERIALS AND METHODS: We examined the expression of IL-21, IL-17, and interferon (IFN)-gamma in ITP patients and controls by enzyme-linked immunosorbent assay and flow cytometry. Detection of specific anti-platelet GPIIb/IIIa and/or GPIb/IX autoantibodies was measured by modified monoclonal antibody specific immobilization of platelet antigens. RESULTS: IL-21 was expressed on both CD3(+)CD8(-) T cells and CD3(+)CD8(+) T cells by flow cytometry. Plasma IL-21 level and the percentage of CD3(+)CD8(-)IL-21(+) T cells and CD3(+)CD8(+)IL-21(+) T cells were significantly elevated in ITP patients compared to controls. The percentage of CD3(+)CD8(-)IL-17(+) T (Th17), CD3(+)CD8(-)IFN-gamma(+) T (Th1), and CD3(+)CD8(+)IFN-gamma(+) T (Tc1) cells also significantly increased in ITP patients. Moreover, we found a significant positive correlation between CD3(+)CD8(-)IL-21(+) T cells and Th17 cells. In addition, a positive correlation between CD3(+)CD8(-)IL-21(+) T cells and Th1 cells was also found. CONCLUSION: Together, our results indicated a possible role of IL-21 in ITP patients correlated to Th17 and Th1 cells, and blockade of IL-21 may be a reasonable therapeutic strategy for ITP especially those with active disease.
21: Journal of clinical immunology, 2009 Dec 10,
Elevated Interleukin-21 Correlated to Th17 and Th1 Cells in Patients with Immune Thrombocytopenia.
[Abstract]BACKGROUND: Interleukin-21 (IL-21) is critical in the development of autoimmune diseases. The role of IL-21 in the pathogenesis of immune thrombocytopenia (ITP) remains unknown. MATERIALS AND METHODS: We examined the expression of IL-21, IL-17, and interferon (IFN)-gamma in ITP patients and controls by enzyme-linked immunosorbent assay and flow cytometry. Detection of specific anti-platelet GPIIb/IIIa and/or GPIb/IX autoantibodies was measured by modified monoclonal antibody specific immobilization of platelet antigens. RESULTS: IL-21 was expressed on both CD3(+)CD8(-) T cells and CD3(+)CD8(+) T cells by flow cytometry. Plasma IL-21 level and the percentage of CD3(+)CD8(-)IL-21(+) T cells and CD3(+)CD8(+)IL-21(+) T cells were significantly elevated in ITP patients compared to controls. The percentage of CD3(+)CD8(-)IL-17(+) T (Th17), CD3(+)CD8(-)IFN-gamma(+) T (Th1), and CD3(+)CD8(+)IFN-gamma(+) T (Tc1) cells also significantly increased in ITP patients. Moreover, we found a significant positive correlation between CD3(+)CD8(-)IL-21(+) T cells and Th17 cells. In addition, a positive correlation between CD3(+)CD8(-)IL-21(+) T cells and Th1 cells was also found. CONCLUSION: Together, our results indicated a possible role of IL-21 in ITP patients correlated to Th17 and Th1 cells, and blockade of IL-21 may be a reasonable therapeutic strategy for ITP especially those with active disease.
22: International immunology, 2009 Nov 23, 183(11)
IL-21 and T follicular helper cells.
[Abstract]Upon encounter with antigen, CD4(+) T cells differentiate into effector T(h) subsets with distinctive functions that are related to their unique cytokine profiles and anatomical locations. One of the most important T(h) functions is to provide signals to developing B cells that induce specific and appropriate antibody responses. The major CD4(+) T cell subset that helps B cells is the T follicular helper (T(FH)) cell, whose expression of the chemokine receptor CXCR5 [chemokine (C-X-C motif) receptor 5] serves to localize this cell to developing germinal centers (GCs) where it provides instructive signals leading to Ig class switching and somatic mutation. T(FH) cells produce high levels of IL-21, a cytokine that is critical for GC formation and also for the generation of T(FH) cells. Although T(FH) cells have been found to produce cytokines characteristic of other T(h) subsets, they represent a distinct lineage whose development is driven by the transcription factor B-cell CLL lymphoma-6 (BCL6). Consistent with their critical role in the generation of antibody responses, dysregulated T(FH) function has been associated with the development of systemic autoimmunity. Here, we review the role of IL-21 in the regulation of normal T(FH) development and function as well as in progression of autoimmune responses.
23: Cell cycle (Georgetown, Tex.), 2009 Nov 31, 8(22)
Pathogenic role of interleukin-21 in psoriasis.
[Abstract]Interleukin-21 (IL-21) is a class I cytokine with antitumor properties due to enhanced proliferation and effector function of CD8(+) T cells and natural killer (NK) cells. Here we have explored the magnitude and time-course of cytostatics-induced lymphopenia in mice and investigated whether treatment with cytostatics influences the antitumor effect of IL-21 in mouse tumor models. We show that pegylated liposomal doxorubicin (PLD), irinotecan and oxaliplatin induced transient lymphopenia, whereas 5-fluorouracil (5-FU) transiently increased lymphocyte counts. B cells were more sensitive than T cells towards irinotecan and oxaliplatin. Additive antitumor effects were observed after combining IL-21 with PLD, oxaliplatin and to less extent 5-FU but not irinotecan, and larger effect was observed when IL-21 administration was postponed relative to chemotherapy, suggesting that these agents may transiently impair immune function. However, the chemotherapies did not significantly alter the levels of circulating regulatory T cells and only marginally affected the ability of CD8(+) T cells to respond to IL-21 measured as increased granzyme B mRNA. Our results show that IL-21 therapy can be successfully combined with agents from different chemotherapeutic drug classes, i.e. topoisomerase II inhibitors (PLD), anti-metabolites (5-FU) and platinum analogs (oxaliplatin) provided that IL-21 therapy is delayed relative to chemotherapy.
24: Tissue antigens, 2009 Oct 21, 285(1)
IL-21: roles in immunopathology and cancer therapy.
[Abstract]Abstract Cytokines are secreted signalling molecules with decisive effects on haematopoiesis, innate and adaptive immunity, and immunopathology. Interleukin (IL)-21 is a novel cytokine produced by activated CD4(+) T cells and natural killer T (NKT) cells. IL-21 is part of a family of cytokines which include IL-2, -4, -7, -9 and -15 that all share the common IL-2 receptor gamma chain (gamma(c)) in their individual receptor complexes. IL-21 receptor (IL-21R) is widely expressed on both myeloid and lymphoid cell lineages and IL-21 actions include co-stimulation of B cell differentiation and immunoglobulin (Ig) production, co-mitogen of T cells, and stimulation of NK and CD8(+) T cell cytotoxic function. Initially, IL-21 was recognized for its anti-tumour effects in several preclinical tumour models, warranting its currently ongoing clinical development as a cancer immunotherapeutic. More recently, IL-21 has been associated with the development of a panel of autoimmune and inflammatory diseases, where neutralization of IL-21 has been suggested as a potential new therapy. In this review, we will cover the latest discoveries of IL-21 as a cancer therapy and its implications in immunopathologies.
25: Blood, 2009 Oct 20, 285(1)
IL-21 blockade reduces graft-versus-host-disease mortality by supporting inducible T regulatory cell generation.
[Abstract]IL-21 is a pleiotropic cytokine produced by CD4(+) T-cells and NKT-cells that enhances Th1 and Th17 differentiation while inhibiting the conversion of inducible Tregs from naive T-cells. To determine the role of IL-21 in GVHD, anti-IL-21 Ab was given to recipients of CD25(-)CD4(+) or CD4(+) and CD8(+) T-effectors. IL-21 neutralization attenuated GVHD-related weight loss and prolonged survival. Likewise, a majority of mice receiving IL-21(-/-) CD25(-) T-effectors survived long-term, while those receiving wild-type T cells died. The latter recipients had higher grades of GVHD-related tissue damage in the ileum and colon. Surprisingly, disruption of IL-21 signaling did not affect IL-17 production, although colon-infiltrating T-effector cells had decreased IFNgamma and increased IL-4 production. FoxP3(+) Tregs were increased in colons of anti-IL-21 Ab-treated recipients of FoxP3(-) IL-21(-/-) T-cells, indicating Treg conversion. Recipients of congenic FoxP3-deficient T-effectors isolated from chimeras and used as donor T-cells were resistant to the GVHD protective effects of IL-21 blockade. Whereas graft-versus-leukemia (GVL) can occur in the absence of IL-21, loss of both IL-21 and perforin expression abrogated GVL. Together, these data indicate that IL-21 suppresses iTreg conversion and further suggest that IL-21 blockade is an attractive strategy to reduce GVHD-induced injury.
26: Discovery medicine, 2009 Oct, 8(42)
Interleukin-21 in T cell-mediated diseases.
[Abstract]Interleukin-21 (IL-21), a cytokine produced by activated CD4+ T cells, activated natural killer T cells, and T follicular cells, has been reported to play a crucial role in the tissue-damaging T cell response in various organs, such as gut, skin, pancreas, and joints. This pathogenic effect is strictly linked to the ability of IL-21 to enhance the functional activities of multiple immune and non-immune cells. Consistently, studies from various laboratories have shown that blockade of IL-21 limits the progression of T cell-mediated inflammatory diseases in mice. Here we review the present knowledge on the expression and role of IL-21 in T cell-mediated pathologies.
27: Journal of leukocyte biology, 2009 Oct 1, 183(7)
IL-21 preferentially enhances IL-15-mediated homeostatic proliferation of human CD28+ CD8 memory T cells throughout the adult age span.
[Abstract]An age-related decline in human immune response is marked by the accumulation of CD28(-) CD8 T cells, which is attributed to repeated antigenic stimulation and to homeostatic proliferation mediated by cytokines such as IL-15. However, the identity of the cytokines that are responsible for the maintenance of CD28 expression is less known. Here, we report the role of IL-21 in the regulation of IL-15-mediated growth and CD28 expression of CD8 memory T cells of young and old donors. We showed that IL-21 drives more IL-15-stimulated cells to enter cell division and to undergo apoptosis. Furthermore, IL-21 preferentially enhanced IL-15-induced proliferation of CD28(+) CD8 memory T cells over their CD28(-) counterparts, as CD28(+) cells expressed higher levels of IL-15R and IL-21R and greater pSTAT5 upon IL-15 and IL-21 stimulation. In addition, IL-21 reduced IL-15-induced CD28 down-regulation in CD8 memory T cells. Finally, the ability of proliferation and survival in response to homeostatic cytokines IL-15 and IL-21 of CD28(+) CD8 memory T cells was well-maintained with age. Together, these findings suggest that IL-21 enhances IL-15-mediated proliferation of CD8 memory T cells, particularly CD28(+) memory T cells, and also serves as an antagonist to the IL-15-induced increase of CD28(-) CD8 T cells.
28: World journal of gastroenterology : WJG, 2009 Oct 7, 15(37)
Involvement of interleukin-15 and interleukin-21, two gamma-chain-related cytokines, in celiac disease.
[Abstract]Celiac disease (CD), an enteropathy caused by dietary gluten in genetically susceptible individuals, is histologically characterized by villous atrophy, crypt cell hyperplasia, and increased number of intra-epithelial lymphocytes. The nature of CD pathogenesis remains unclear, but recent evidence indicates that both innate and adaptive immune responses are necessary for the phenotypic expression and pathologic changes characteristic of CD. Extensive studies of molecules produced by immune cells in the gut of CD patients have led to identification of two cytokines, namely interleukin (IL)-15 and IL-21, which are thought to play a major role in orchestrating the mucosal inflammatory response in CD. Here we review the current knowledge of the expression and function of IL-15 and IL-21 in CD.
29: Journal of leukocyte biology, 2009 Sep 17, 284(38)
IL-21 and IL-10 have redundant roles but differential capacities at different stages of plasma cell generation from human germinal center B cells.
[Abstract]The GC is the anatomical site where antigen-activated B cells differentiate into PC, producing high-affinity antibodies in physiological and pathological states. PC differentiation is regulated by multiple factors within the GC microenvironment, including cytokines. IL-21, a recently identified type I cytokine produced by GC-Th cells, promotes differentiation of human B cells into ISC. In this study, we investigated in detail the functional role of IL-21 in the course of GC-B cell differentiation into terminally differentiated PC compared with that of IL-10, a well-known PC differentiation factor. IL-21 had a greater capacity to initiate PC differentiation from CD77(+) centroblasts than IL-10 by strongly inducing PC transcription factors through activation of STAT3; however, IL-10 was more potent than IL-21 in generating CD138(+) PC from CD20(-)CD38(++) plasmablasts in the terminal stage of GC-B cell differentiation. This differential effect of IL-21 and IL-10 was reflected in receptor expression on B cell subsets emerging in the course of differentiation. Our studies have revealed that IL-21 is a critical decision-maker for driving initial PC differentiation at the stage of CD77(+) centroblasts, yet IL-10 is more effective in producing IgG by generating terminally differentiated CD138(+) PC at the later stage of PC differentiation in the GC.
30: Journal of immunology (Baltimore, Md. : 1950), 2009 Oct 1, 183(7)
TLR3 ligand polyinosinic:polycytidylic acid induces IL-17A and IL-21 synthesis in human Th cells.
[Abstract]TLR3 and TLR9 recognize the pathogen-associated microbial patterns dsRNA and unmethylated DNA, respectively. The recent discovery that these receptors also recognize endogenous ligands from necrotic material has drawn increased attention to their involvement in autoimmunity. Th cell cytokines IL-17A and IL-21 have been assigned with pivotal roles in the regulation of such autoimmune diseases. IL-17A is the hallmark cytokine of the recently discovered proinflammatory Th cell subset T(H)17. By contrast, the expression of IL-21 does not seem to be limited to a single distinct Th cell subset. We investigated the expression of IL-17A and IL-21 in human CD4+ T cells in response to stimulation with the TLR3 ligand polyinosinic:polycytidylic acid (poly(I:C)) and the TLR9 ligand CpG. We discovered that poly(I:C) induced synthesis of both IL-17A and IL-21. Moreover, we found that poly(I:C) was able to drive the differentiation of naive Th cells into an IL-21 but not into an IL-17A-producing phenotype and did this without affecting the levels of transcription factors T-bet, GATA-3, or retinoic acid receptor-related orphan receptor C. Finally, we found that the IL-21-producing cells that were differentiated in response to poly(I:C) expressed the chemokine receptor CXCR3, which is important in the recruitment of T cells into inflamed joints in rheumatoid arthritis. This is the first report to show that the TLR3 ligand poly(I:C) can directly induce the synthesis of IL-17A and IL-21 and drive differentiation of human naive CD4+ T cells.
31: Blood, 2009 Sep 8, 284(38)
Interleukin-21 restores immunoglobulin production ex vivo in patients with common variable immunodeficiency and selective IgA deficiency.
[Abstract]Interleukin-21 (IL-21) is an important promoter for differentiation of human B cells into Ig-secreting cells. The objective of this study was to evaluate an IL-21 based approach to induce immunoglobulin production in B cells from patients with common variable immunodeficiency (CVID) or selective IgA deficiency (IgAD). We show that a combination of IL-21, IL-4 and anti-CD40 stimulation induces class switch recombination to IgG and IgA and differentiation of Ig-secreting cells, consisting of both sIgG(+) and sIgA(+) B cells and CD138(+) plasma cells, in patients with CVID or IgAD. Stimulation with IL-21 was far more effective than stimulation with IL-4 or IL-10. Moreover, spontaneous apoptosis of CD19(+) B cells from patients with CVID or IgAD was prevented by a combination of IL-21, IL-4 and anti-CD40 stimulation. Analysis of IL-21 and IL-21R mRNA expression upon anti-CD3 stimulation of T cells, however, showed no evidence for defective IL-21 expression in CVID patients and sequencing of the coding regions of the IL-21 gene did not reveal any mutations, suggesting a regulatory defect. Thus, our work provides an initial basis for a potential therapeutic role of IL-21 to reconstitute immunoglobulin production in CVID and IgAD.
32: Bone marrow transplantation, 2009 Aug 31, 144(1-2)
IL-21 is critical for GVHD in a mouse model.
[Abstract]Immunological effects of IL-21 on T, B and natural killer (NK) cells have been reported, but the role of IL-21 in GVHD remains obscure. Here, we demonstrate that morbidity and mortality of GVHD was significantly reduced after BMT with splenocytes from IL-21R(-/-) mice compared with those from wild type mice. To further confirm our observation, we generated a decoy receptor for IL-21. GVHD was again less severe in mice receiving BM cells transduced with the IL-21 decoy receptor than control mice These results suggest that IL-21 critically regulates GVHD, and that blockade of the IL-21 signal may represent a novel strategy for the prophylaxis for GVHD.Bone Marrow Transplantation advance online publication, 31 August 2009; doi:10.1038/bmt.2009.223.
33: BMC immunology, 2009, 10(1-2)
Interleukin-21 induces the differentiation of human umbilical cord blood CD34-lineage- cells into pseudomature lytic NK cells.
[Abstract]BACKGROUND: Umbilical cord blood (UCB) is enriched with transplantable CD34+ cells. In addition to CD34-expressing haematopoietic stem cells (HSC), human UCB contains a rare population of CD34-lineage- cells endowed with the ability to differentiate along the T/NK pathway in response to interleukin (IL)-15 and a stromal cell support. IL-21 is a crucial regulator of NK cell function, whose influence on IL-15-induced differentiation of CD34-lineage- cells has not been investigated previously. The present study was designed and conducted to address whether IL-21 might replace the stromal cell requirements and foster the IL-15-induced NK differentiation of human UCB CD34-lineage- cells. RESULTS: CD34-lineage- cells were maintained in liquid culture with Flt3-L and SCF, with the addition of IL-15 and IL-21, either alone or in combination. Cultures were established in the absence of feeder cells or serum supplementation. Cytokine-treated cells were used to evaluate cell surface phenotype, expression of molecular determinants of lymphoid/NK cell differentiation, secretion of IFN-gamma, GM-CSF, TNF-alpha and CCL3/MIP-1alpha, and cytolytic activity against NK-sensitive tumour cell targets. CD34-lineage- cells proliferated vigorously in response to IL-15 and IL-21 but not to IL-21 alone, and up-regulated phosphorylated Stat1 and Stat3 proteins. CD34-lineage- cells expanded by IL-21 in combination with IL-15 acquired lymphoid morphology and killer-cell immunoglobulin-like receptor (KIR)-CD56+CD16-/+ phenotype, consistent with pseudo-mature NK cells. IL-21/IL-15-differentiated cells expressed high levels of mRNA for Bcl-2, GATA-3 and Id2, a master switch required for NK-cell development, and harboured un-rearranged TCRgamma genes. From a functional standpoint, IL-21/IL-15-treated cells secreted copious amounts of IFN-gamma, GM-CSF and CCL3/MIP-1alpha, and expressed cell surface CD107a upon contact with NK-sensitive tumour targets, a measure of exocytosis of NK secretory granules. CONCLUSION: This study underpins a novel role for IL-21 in the differentiation of pseudo-mature lytic NK cells in a synergistic context with IL-15, and identifies a potential strategy to expand functional NK cells for immunotherapy.
34: Cytokine, 2009 Aug 24, 10(1-2)
In vivo antitumor efficacy of interleukin-21 in combination with chemotherapeutics.
[Abstract]Interleukin-21 (IL-21) is a class I cytokine with antitumor properties due to enhanced proliferation and effector function of CD8(+) T cells and natural killer (NK) cells. Here we have explored the magnitude and time-course of cytostatics-induced lymphopenia in mice and investigated whether treatment with cytostatics influences the antitumor effect of IL-21 in mouse tumor models. We show that pegylated liposomal doxorubicin (PLD), irinotecan and oxaliplatin induced transient lymphopenia, whereas 5-fluorouracil (5-FU) transiently increased lymphocyte counts. B cells were more sensitive than T cells towards irinotecan and oxaliplatin. Additive antitumor effects were observed after combining IL-21 with PLD, oxaliplatin and to less extent 5-FU but not irinotecan, and larger effect was observed when IL-21 administration was postponed relative to chemotherapy, suggesting that these agents may transiently impair immune function. However, the chemotherapies did not significantly alter the levels of circulating regulatory T cells and only marginally affected the ability of CD8(+) T cells to respond to IL-21 measured as increased granzyme B mRNA. Our results show that IL-21 therapy can be successfully combined with agents from different chemotherapeutic drug classes, i.e. topoisomerase II inhibitors (PLD), anti-metabolites (5-FU) and platinum analogs (oxaliplatin) provided that IL-21 therapy is delayed relative to chemotherapy.
35: Nature medicine, 2009 Sep, 15(9)
Involvement of interleukin-21 in the epidermal hyperplasia of psoriasis.
[Abstract]T cells are crucial mediators of the skin damage in psoriasis. We here show that interleukin-21 (IL-21), a T cell-derived cytokine, is highly expressed in the skin of individuals with psoriasis, stimulates human keratinocytes to proliferate and causes epidermal hyperplasia when injected intradermally into mice. In the human psoriasis xenograft mouse model, blockade of IL-21 activity resolves inflammation and reduces keratinocyte proliferation. Blocking IL-21 may represent a new therapeutic strategy in psoriasis.
36: Journal of immunology (Baltimore, Md. : 1950), 2009 Sep 1, 183(5)
Modulation of single-cell IgG secretion frequency and rates in human memory B cells by CpG DNA, CD40L, IL-21, and cell division.
[Abstract]During the recall response by CD27(+) IgG class-switched human memory B cells, total IgG secreted is a function of the following: 1) the number of IgG-secreting cells (IgG-SC), and 2) the secretion rate of each cell. In this study, we report the quantitative ELISPOT method for simultaneous estimation of single-cell IgG secretion rates and secreting cell frequencies in human B cell populations. We found that CD27(+) IgM(-) memory B cells activated with CpG and cytokines had considerable heterogeneity in the IgG secretion rates, with two major secretion rate subpopulations. BCR cross-linking reduced the frequency of cells with high per-cell IgG secretion rates, with a parallel decrease in CD27(high) B cell blasts. Increased cell death may account for the BCR-stimulated reduction in high-rate IgG-SC CD27(high) B cell blasts. In contrast, the addition of IL-21 to CD40L plus IL-4-activated human memory B cells induced a high-rate IgG-SC population in B cells with otherwise low per-cell IgG secretion rates. The profiles of human B cell IgG secretion rates followed the same biphasic distribution and range irrespective of division class. This, along with the presence of non-IgG-producing, dividing B cells in CpG plus cytokine-activated B memory B cell populations, is suggestive of an on/off switch regulating IgG secretion. Finally, these data support a mixture model of IgG secretion in which IgG secreted over time is modulated by the frequency of IgG-SC and the distribution of their IgG secretion rates.
37: The Journal of biological chemistry, 2009 Sep 18, 284(38)
Transcriptional activation of the interleukin-21 gene and its receptor gene by human T-cell leukemia virus type 1 Tax in human T-cells.
[Abstract]At the incipient stages of the development of adult T-cell leukemia, T-cells infected with human T-cell leukemia virus type 1 (HTLV-1) suffer disregulation in cell growth caused by aberrant expression of host genes by the HTLV-1 transactivator protein Tax (Tax1). Tax1-mediated growth promotion is thought to result from, at least in part, up-regulation of genes for growth factors and their receptors that induce T-cell growth. In the present study, we demonstrate that Tax1 transactivates the interleukin-21 (IL-21) and its receptor (IL-21R) genes in human T-cells. Introduction of Tax1 via recombinant adenoviruses induced expression of endogenous IL-21 and IL-21R. Isolated promoters of the IL-21 and IL-21R genes were activated by Tax1 in reporter assays, which further revealed that there were at least two Tax1-responsive elements in either the IL-21 promoter or the IL-21R promoter. Chromatin immunoprecipitation assay and gel mobility shift assay exhibited that the IL-21 promoter elements bound transcription factors AP-1 and NF-kappaB, and the IL-21R promoter elements were associated with AP-1 and interferon regulatory factor. Collectively, Tax1-dependent activation of these transcriptional factors presumably contributes to expression of the IL-21 gene and its receptor gene. The related virus HTLV-2 with Tax2 similar to Tax1 is known not to be pathogenic. Tax2 exhibited little, if any, or no induction of the IL-21 transcription in CD4+ T-cells, in contrast to Tax1. The study suggests insights into cytokine-dependent aberrant growth of HTLV-1-infected T-cells and the molecular basis of different pathogenicity between HTLV-1 and HTLV-2.
38: Journal of immunotherapy (Hagerstown, Md. : 1997), 2009 Sep, 32(7)
Genetic modification of T cells with IL-21 enhances antigen presentation and generation of central memory tumor-specific cytotoxic T-lymphocytes.
[Abstract]An optimized antigen-presenting cell for tumor immunotherapy should produce a robust antigen specific cytotoxic T lymphocytes (CTL) response to tumor-associated antigens, which can persist in vivo and expand on antigen reencounter. Interleukin (IL)-21 synergizes with other gamma-chain cytokines to enhance the frequency and cytotoxicity of antigen-specific CTL. As T cells themselves may serve as effective antigen-presenting cells (T antigen-presenting cells; TAPC) and may be useful in vivo as cellular vaccines, we examined whether CD8(+) T cells genetically modified to produce IL-21 could induce immune responses to tumor associated antigen peptides in healthy human leukocyte antigen-A2(+) donors. We found that IL-21 modified TAPC enhanced both the proliferation and survival of MART-1 specific CD8(+) T cells, which were enriched by >8-fold over cultures with control nontransgenic TAPC. MART-1-specific CTL produced interferon-gamma in response to cognate peptide antigen and killed primary tumor cells expressing MART-1 in a major histocompatibility complex restricted manner. IL-21 modified TAPC similarly enhanced generation of functional CTL against melanoma antigen gp100 and the B-cell chronic lymphocytic leukemia associated RHAMM antigen. Antigen-specific CTL generated using IL-21 gene-modified TAPC had a central memory phenotype characterized by CD45RA(-), CD44(high), CD27(high), CD28(high), CD62L(high), and IL-7 receptor-alpha(high), contrasting with the terminal effector phenotype of CTL generated in the absence of IL-21. Thus, TAPC stimulation in the presences of IL-21 enhances proliferation of tumor antigen-specific T cells and favors induction of a central memory phenotype, which may improve proliferation, survival, and efficacy of T-cell based therapies for the treatment of cancer.
39: Tissue antigens, 2009 Sep, 74(3)
Multiple sclerosis association study with the TENR-IL2-IL21 region in a Spanish population.
[Abstract]Polymorphisms from the TENR-IL2-IL21 block in the 4q27 chromosome were recently associated with type 1 diabetes, celiac disease, rheumatoid arthritis and psoriasis. We undertook this study to investigate the potential role of polymorphisms rs3136534, rs6822844 and rs2069762 (-330 T/G IL2) in multiple sclerosis (MS) (805 patients of Spanish Caucasian origin and 952 health controls). We did not find evidence for association with any single nucleotide polymorphisms (SNPs) tested. Allele and genotype frequencies of the SNPs, which were studied, were similar in DRB1*15-positive or DRB1*15-negative patients. After stratification of MS patients by clinical course, a weak association was observed with rs2069762 G allele and haplotype bearing this allele with secondary progressive MS, although these cases represent 22% of the MS cases. Our results did not show major influence of TENR-IL2-IL21 locus on susceptibility or disease progression in MS. However, we could not exclude completely the effect in MS for this region. Additional studies, using much larger sample sizes and analysis of additional polymorphisms in the gene and its flanking region, will be required to ascertain their contributions to MS susceptibility.
40: Cancer letters, 2009 Nov 18, 285(1)
Ex vivo expansion of tumor specific lymphocytes with IL-15 and IL-21 for adoptive immunotherapy in melanoma.
[Abstract]Although T central memory cells have been described as the most effective T-cell subtype against tumor growth, little is known about the requirements needed for their optimal ex vivo generation. Hence, our goal is to establish a protocol that will lead to consistent ex vivo generation of lymphocytes skewed toward a central memory phenotype. Antigen-specific T-cell lines were generated by ex vivo stimulation with Class-I and Class-II melanoma peptide pulsed dendritic cells in the presence of either IL-2 or IL-15 plus IL-21. Tumor specific lymphocytes of both central memory and effector characteristics were consistently generated from healthy donors and melanoma patients. IL15/IL21 cultures result in a cell population with a lower proportion of CD4(+)CD25(high)FoxP3(+) regulatory cells and higher number of CD8(+) and CD56(+) cells, and consequently render a higher yield of cells with a greater cytolytic activity and IFN-gamma production against melanoma cell lines.
41: Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K, 2009 Oct, 23(10)
Interleukin-21 effectively induces apoptosis in mantle cell lymphoma through a STAT1-dependent mechanism.
[Abstract]Interleukin-21 (IL-21) has been recently shown to modulate the growth of specific types of B-cell neoplasm. Here, we studied the biological effects of IL-21 in mantle cell lymphoma (MCL). All MCL cell lines and tumors examined expressed the IL-21 receptor. Addition of recombinant IL-21 (rIL-21) in vitro effectively induced STAT1 activation and apoptosis in MCL cells. As STAT1 is known to have tumor-suppressor functions, we hypothesized that STAT1 is important in mediating IL-21-induced apoptosis in MCL cells. In support of this hypothesis, inhibition of STAT1 expression using siRNA significantly decreased the apoptotic responses induced by IL-21. To further investigate the mechanism of IL-21-mediated apoptosis, we employed oligonucleotide arrays to evaluate changes in the expression of apoptosis-related genes induced by rIL-21; rIL-21 significantly upregulated three proapoptotic proteins (BIK, NIP3 and HARAKIRI) and downregulated two antiapoptotic proteins (BCL-2 and BCL-XL/S) as well as tumor necrosis factor-alpha. Using an ELISA-based assay, we demonstrated that rIL-21 significantly decreased the DNA binding of nuclear factor-kappaB, a transcriptional factor known to be a survival signal for MCL cells. To conclude, IL-21 can effectively induce apoptosis in MCL via a STAT1-dependent pathway. Further understanding of IL-21-mediated apoptosis in MCL may be useful in designing novel therapeutic approaches for this disease.
42: Virus research, 2009 Sep, 144(1-2)
Interleukin-21 regulates expression of the immediate-early lytic cycle genes and proteins in Epstein-Barr Virus infected B cells.
[Abstract]The switch between the latent and the lytic cycle of Epstein-Barr Virus (EBV) infection is characterized by the induction of viral transcriptional activators Zta and Rta. CD4(+) T cell-derived cytokines are likely to regulate expression of these proteins in EBV-infected B cells. Here we show that interleukin-21 decreases constitutive expression of Rta and its target EA-D in EBV-infected B cell lines during the first 3 days of culture. In some cell lines this is followed by a strong increase in the expression of Zta, Rta, and EA-D during prolonged culture. Additionally, we provide evidence that IL-21-mediated JAK/STAT signals regulate increase in the Zta expression.
43: Journal of immunology (Baltimore, Md. : 1950), 2009 Mar 1, 182(5)
IL-21 mediates suppressive effects via its induction of IL-10.
[Abstract]IL-21 is a pleiotropic cytokine that is required for normal Ig production. We previously showed that IL-21 was elevated in BXSB-Yaa mice with systemic lupus erythematosus. These mice also had elevated IL-10 levels, and we now show that IL-21 induces IL-10 mRNA and protein, suggesting unexpected immunosuppressive activities for IL-21. Indeed, Th1 priming with IL-21 leads to accumulation of cells with immunosuppressive activity, and IL-21 overexpression decreases specific Ab production after immunization in an IL-10-dependent fashion. Moreover, we show that IL-21 signaling is required for maximal induction of IL-10 by IL-6 or IL-27. Overall, our data indicate that IL-21 regulates immune responses at least in part by inducing IL-10 and reveal unanticipated immunosuppressive actions for this cytokine.
44: Molecular immunology, 2009 Feb 20, 182(5)
IL-21 and IL-15 cytokine DNA augments HSV specific effector and memory CD8(+) T cell response.
[Abstract]The recurrence of lesions and transmission of Herpes simplex virus is dependent on the number and function of viral specific CD8(+) T cells, especially the memory T cells. The generation, turnover and set point of this cell population is maintained by different factors like exposure to antigen, cytokines and co-stimulatory molecules. However, the contribution of these factors in the generation and maintenance of the memory CD8(+) T cell population is still controversial, since it is not clear if homeostatic proliferation driven by cytokines can overcome T cell receptor (TCR) signaling. Since, interleukin 15 (IL-15) and interleukin 21 (IL-21) are cytokines implicated in homeostatic control of CD8(+) T cell pool, we constructed and used expression plasmids coding for IL-15 (pIL-15) and IL-21 (pIL-21) to expand HSV specific CD8(+) T cells in an animal model. Our results showed that the IL-21 increased the frequency of CD8(+) T cells in the absence of antigen, although the magnitude of this response was dependent on TCR signaling. Both pIL-15 and pIL-21 boosted the numbers of antigen specific CD8(+) IFNgamma producing cells in the primary response. In the memory phase, numbers of CD8(+) CD44(high) as well as CD8(+) T cells producing IFN-gamma and TNF-alpha were increased when pIL-15 and pIL-21 were used alone or in combination, compared to vector treatment only, and association of antigen further increased the proliferative response. Our data suggest that genetic treatment with pIL-15 and pIL-21 in the presence or absence of cognate antigen can contribute to immune-enhancement against HSV.
45: Cellular immunology, 2009 Feb 20, 182(5)
Distinct response in maintenance of human naive and memory B cells via IL-21 receptor and TCL1/Akt pathways.
[Abstract]The molecular mechanisms involving in B-cell survival/proliferation are poorly understood. Here we investigated the molecules affecting the survival of human na?ve and memory B cells. Without stimulation, na?ve B cells survived longer than memory B cells. Moreover, the viability of memory B cells decreased more rapidly than that of na?ve B cells following with Staphylococcus aureus Cowan strain (SAC), anti-immunoglobulin (Ig), or anti-CD40 stimulation, but displayed the same levels of survival following CpG DNA stimulation. We analyzed the transcriptional differences between B-cell subsets by gene expression profiling, and identified 15 genes significantly correlated to survival/proliferation. Among them, IL-21 receptor (IL-21R) and T-cell leukemia 1 (TCL1) proto-oncogene were highly expressed in na?ve B cells. IL-21 induced the proliferation of both na?ve and memory B cells. Marked phosphorylation of Akt was found in na?ve B cells compared with memory B cells. This study suggests that naive and memory B cells are regulated by several distinct molecules, and the IL-21R and TCL1/Akt pathways might play crucial roles in na?ve B cells for their maintenance.
46: Diabetes, 2009 Feb 10, 182(5)
IL-21 is required for the development of type 1 diabetes in NOD mice.
[Abstract]Objective: IL-21 is a type 1 cytokine that has been implicated in the pathogenesis of type 1 diabetes (T1D) via the unique biology of the Non-Obese Diabetic (NOD) mouse strain. The aim of this study was to investigate a causal role for IL-21 in T1D. Research Design and Methods: We generated IL-21R deficient NOD mice and C57Bl/6 mice expressing IL-21 in pancreatic beta-cells, allowing the determination of the role of insufficient and excessive IL-21 signaling in T1D. Results: Deficiency in IL-21R expression renders NOD mice resistant to insulitis, production of insulin autoantibodies and onset of T1D. The lymphoid compartment in IL-21R(-/-) NOD is normal, does not contain an increased regulatory T cell fraction or diminished effector cytokine responses. However, we observed a clear defect in autoreactive effector T cells in IL-21R(-/-) NOD by transfer experiments. Conversely, over-expression of IL-21 in pancreatic beta-cells induced inflammatory cytokine and chemokines, including IL-17A, IL17F, IFN-gamma, MCP-1, MCP-2, IP-10, in the pancreas. The ensuing leukocytic infiltration in the islets resulted in destruction of beta-cells and spontaneous T1D in the normally diabetes-resistant C57Bl/6 and NOD x C57Bl/6 backgrounds. Conclusions: This work provides demonstration of the essential pro-diabetogenic activities of IL-21 on diverse genetic backgrounds (NOD and C57BL/6) and indicates that IL-21 blockade could be a promising strategy for interventions in human T1D.
47: Journal of immunology (Baltimore, Md. : 1950), 2009 Feb 15, 182(4)
IL-21: an executor of B cell fate.
[Abstract]IL-21 is a type I cytokine that shares the common receptor gamma-chain with IL-2, IL-4, IL-7, IL-9, and IL-15. B cells are one of the lymphoid cell types whose development and function are regulated by IL-21. Depending on the interplay with costimulatory signals and on the developmental stage of a B cell, IL-21 can induce proliferation, differentiation into Ig-producing plasma cells, or apoptosis in both mice and humans. Alone and in combination with Th cell-derived cytokines IL-21 can regulate class switch recombination to IgG, IgA, or IgE isotypes, indicating its important role in shaping the effector function of B cells. This review highlights the role of IL-21 in B cell development, function, and disease and provides some perspectives on the future studies in this area.