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Cytokine Expression on Thymocyte Apoptosis and Th1/Th2 Synergistic

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Cytokine Expression on Thymocyte Apoptosis and Th1/Th2 Synergistic Synergistic Effect of IL-2, IL-12, and IL-18 on Thymocyte Apoptosis and Th1/Th2 Cytokine Expression This information is current as Maria Cecilia Rodriguez-Galán, Jay H. Bream, Andrew Farr of September 23, 2021. and Howard A. Young J Immunol 2005; 174:2796-2804; ; doi: 10.4049/jimmunol.174.5.2796 http://www.jimmunol.org/content/174/5/2796 Downloaded from References This article cites 48 articles, 19 of which you can access for free at: http://www.jimmunol.org/content/174/5/2796.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 23, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2005 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Synergistic Effect of IL-2, IL-12, and IL-18 on Thymocyte Apoptosis and Th1/Th2 Cytokine Expression1,2 Maria Cecilia Rodriguez-Gala´n,* Jay H. Bream,† Andrew Farr,‡ and Howard A. Young3* In the periphery, IL-18 synergistically induces the expression of the Th1 cytokine IFN-␥ in the presence of IL-12 and the Th2 cytokines IL-5 and IL-13 in the presence of IL-2. Although the expression of these cytokines has been described in the thymus, their role in thymic development and function remains uncertain. We report here that freshly isolated thymocytes from C57BL/6 and BALB/c mice stimulated in vitro with IL-2-plus-IL-18 or IL-12-plus-IL-18 produce large amounts of IFN-␥ and IL-13. Analysis of the thymic subsets, CD4؊CD8؊ (DN), CD4؉CD8؉, CD4؉CD8؊, and CD4؊CD8؉ revealed that IL-18 in combination with IL-2 or IL-12 induces IFN-␥ and IL-13 preferentially from DN cells. Moreover, DN2 and DN3 thymocytes contained more IFN-␥؉ cells than cells in the later stage of maturation. Additionally, IL-18 in combination with IL-2 induces CCR4 (Th2- associated) and CCR5 (Th1-associated) gene expression. In contrast, IL-18-plus-IL-12 specifically induced CCR5 expression. The Downloaded from IL-2-plus-IL-18 or IL-12-plus-IL-18 effect on IFN-␥ and IL-13 expression is dependent on Stat4 and NF-␬B but independent of Stat6, T-bet, or NFAT. Furthermore, IL-12-plus-IL-18 induces significant thymocyte apoptosis when expressed in vivo or in vitro, and this effect is exacerbated in the absence of IFN-␥. IL-12-plus-IL-18-stimulated thymocytes can also induce IA-IE expression on cortical and medullary thymic epithelial cells in an IFN-␥-dependent manner. Thus, the combination of IL-2, IL-12, and IL-18 can induce phenotypic and functional changes in thymocytes that may alter migration, differentiation, and cell death of immature T cells inside the thymus and potentially affect the Th1/Th2 bias in peripheral immune compartments. The Journal of Immu- http://www.jimmunol.org/ nology, 2005, 174: 2796–2804. he development of T lymphocytes occurs primarily in the thymus and play a role during thymocyte proliferation, differenti- thymus, and this process is dependent, at least in part, on ation, and thymus involution (4–8). Interestingly, IL-18 is not T cytokines (1–3). The thymic epithelial cells (TEC)4 are strictly associated with Th1 responses and has also been shown to the principal source of these immunoregulatory molecules (3), and have the potential of inducing the Th2 cytokines IL-4 (9), IL-5, in addition to IL-7, TEC can produce proinflammatory cytokines and IL-13 (10, 11). Our group previously reported that, in NK cell such as IL-1␣, IL-1␤, and TNF-␣. Considering that no inflamma- and T cells, IL-18 can synergize with IL-2 for the induction of IL-5 tory reactions occur in the thymus, the function of these cytokines and IL-13 as well for IFN-␥ (10). Therefore, IL-18 can induce both by guest on September 23, 2021 in the thymus can differ considerably from that in the peripheral Th1 and/or Th2 responses depending on its surrounding cytokine immune system (1–3). Although known for their role in Th1 cell milieu (11, 12). polarization and for their strong synergism in IFN-␥ production, Based on the fact that IL-2 (13), IL-12 (5–7), and IL-18 (4, 8) IL-12 and IL-18 have recently been reported to be expressed in the have been previously reported to be expressed and also to play a role in intrathymic T cell development, we investigated the effects of IL-18-plus-IL-12 or IL-18-plus-IL-2 on the induction of Th1 *Laboratory of Experimental Immunology, Center for Cancer Research, National and Th2 cytokines from fresh thymocytes and on the specific T cell † Cancer Institute, Frederick, MD 21702; Lymphocyte and Cell Biology Section, Mo- populations that arise during thymic ontogeny. lecular Immunology and Inflammation Branch, National Institute of Musculoskeletal Diseases, Bethesda, MD 20892; and ‡Departments of Biological Structure and Im- Typically, T cells require prior activation signals to be optimally munology, University of Washington, Seattle, WA 98195 responsive to cytokine stimulation. In this report, we demonstrate Received for publication August 17, 2004. Accepted for publication December that freshly isolated thymocytes can produce large amounts of 23, 2004. IFN-␥ and IL-13 after stimulation with IL-18 in combination with The costs of publication of this article were defrayed in part by the payment of page IL-2 or IL-12, independent of other external stimuli (PMA, iono- charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. mycin, CD3, Con A, TCR engagement, etc.). This cytokine gene 1 This project has been funded in whole or in part with federal funds from the National induction is effective even at concentrations of IL-12 and IL-18 Cancer Institute, National Institutes of Health, under Contract No. N01-CO-12400. lower than that present during certain microbial infections (14). Fur- The TE-71 and ANV 41.2 cell lines were created under National Institute of Allergy thermore, IL-2-plus-IL-18 also induces CCR4 (Th2 phenotype) and and Infectious Diseases Grants AI 59575 and AI 24137 (to A.F.). CCR5 (Th1 phenotype) expression, whereas IL-12-plus-IL-18 trig- 2 The publisher or recipient acknowledges right of the U.S. Government to retain a nonexclusive, royalty-free license in and to copyright covering the article. The content gers the expression of only CCR5. Considering that CCR4 and CCR5 of this publication does not necessarily reflect the views or policies of the Department are constitutively expressed in the thymus, the up-regulation of these of Health and Human Services, nor does mention of trade names, commercial prod- chemokine receptors expression could alter the natural environment ucts, or organizations imply endorsement by the U.S. Government. of this organ through changes in migration pattern (15), negative se- 3 Address correspondence and reprint requests to Dr. Howard A. Young, National Cancer Institute-Frederick, Building 560, Room 31-23, Frederick, MD 21702-1201. lection (16), as well as potentially releasing cells to the peripheral E-mail address: [email protected] immune compartment with a Th1 or Th2 pre-established bias. 4 Abbreviations used in this paper: TEC, thymic epithelial cell; ATOC, adult thymic Interestingly, distinct thymocyte subsets exhibit specific cytokine organ culture; m, mouse; LN, lymph node; RPA, RNase protection assay; DN, production profiles, suggesting a different capacity for cytokine ex- CD4ϪCD8Ϫ double negative; DP, CD4ϩCD8ϩ double positive; CD4ϩ, CD4ϩCD8Ϫ single positive; CD8ϩ, CD4ϪCD8ϩ single positive; 7AAD, 7-aminoactinomycin D; pression by these subsets during T cell maturation. Furthermore, using KO, knockout. mice deficient in Stat family members, T-bet, the NF-␬B p50 subunit, Copyright © 2005 by The American Association of Immunologists, Inc. 0022-1767/05/$02.00 The Journal of Immunology 2797 and NFAT, we were able to identify the transcription factors essential tion assay (RPA), 5 ␮g of total cytoplasmic RNA were analyzed using the for the production of IFN-␥ and IL-13 by thymocytes. IL-12-plus- RiboQuan kits (BD Pharmingen) and [33P]UTP-labeled riboprobes as de- IL-18 induces cell death in adult thymic organ culture (ATOC) but not scribed previously (21). in suspension cultures, demonstrating that the thymic microenviron- ment is important during apoptosis induction triggered by these cy- Cytokine assays tokines. This effect is also seen in IL-12-plus-IL-18 cDNA-injected ␥ Supernatants from cells treated in vitro were collected and assayed for mice in vivo and is exacerbated in the absence of IFN- . Finally cytokine production by ELISA. The kits used were as follows: mouse IL-12-plus-IL-18-stimulated thymocytes induce IA-IE expression in IFN-␥ and mouse IL-13 (R&D Systems). cortical and medullary epithelial cell lines in an IFN-␥-dependent manner, demonstrating that the synergistic effect of IL-2, IL-12, and Flow cytometry analysis and cell sorting IL-18 may not only influence Th1/Th2 polarization and apoptosis induction in thymocytes but also may influence the thymic microen- Up to six-color analysis was performed on a BD Biosciences FACSort flow vironment in an indirect way.
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