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Commitment to the Th17 Lineage IL-23 Promotes Maintenance But IL-23 Promotes Maintenance but Not Commitment to the Th17 Lineage Gretta L. Stritesky, Norman Yeh and Mark H. Kaplan This information is current as J Immunol 2008; 181:5948-5955; ; of September 27, 2021. doi: 10.4049/jimmunol.181.9.5948 http://www.jimmunol.org/content/181/9/5948 Downloaded from References This article cites 31 articles, 14 of which you can access for free at: http://www.jimmunol.org/content/181/9/5948.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • 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 *average by guest on September 27, 2021 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 © 2008 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology IL-23 Promotes Maintenance but Not Commitment to the Th17 Lineage1 Gretta L. Stritesky,2 Norman Yeh,2 and Mark H. Kaplan3 IL-23 plays a critical role establishing inflammatory immunity and enhancing IL-17 production in vivo. However, an understand- ing of how it performs those functions has been elusive. In this report, using an IL-17-capture technique, we demonstrate that -IL-23 maintains the IL-17-secreting phenotype of purified IL-17؉ cells without affecting cell expansion or survival. IL-23 main tains the Th17 phenotype over multiple rounds of in vitro stimulation most efficiently in conjunction with IL-1␤. However, in contrast to Th1 and Th2 cells, the Th17 phenotype is not stable and when long-term IL-23-stimulated Th17 cultures are exposed to Th1- or Th2-inducing cytokines, the Th17 genetic program is repressed and cells that previously secreted IL-17 assume the cytokine secreting profile of other Th subsets. Thus, while IL-23 can maintain the Th17 phenotype, it does not promote commit- ment to an IL-17-secreting lineage. The Journal of Immunology, 2008, 181: 5948–5955. Downloaded from he cytokine environment generated in an immune re- inflammation (1, 2). The initial descriptions of Th17 cells were sponse to self or foreign Ags directs the development of based on cultures stimulated with IL-23, although only a small T discrete Th cell subsets that mediate specific types of in- percentage of cells within these cultures were IL-17-positive (6, 7). flammation as a mechanism for combating pathogens, with Th1 This resulted from the inability of IL-23 to prime naive cells to cells mediating immunity to intracellular bacteria and parasites, become Th17 cells, largely due to a lack of IL-23R on naive cells http://www.jimmunol.org/ Th2 cells mediating immunity to extracellular parasites, and Th17 (8). In short-term cultures, IL-23 maintains a population of IL-17- cells involved in resistance to extracellular bacteria and fungal secreting T cells, which has been interpreted as a function of pro- infections (1, 2). Cytokines promote the development of effector moting Th17 cell expansion or survival (9). However, this has not subsets by activating STAT proteins that, in concert with lineage been extensively tested and in some early experiments IL-23 func- specific transcription factors, initiate a subset-specific effector pro- tion was compared with control cultures incubated with IL-2, a gram. Thus, IL-12-activated Stat4, and IFN-␥-stimulated induction cytokine now known to inhibit the Th17 phenotype (10). IL-23 of T-bet, promote Th1 differentiation, and IL-4 activated Stat6, induces the expression of IL-22 (11, 12), and most recently, IL-23 which induces GATA-3 expression, promotes Th2 development has also been shown to maintain a pathogenic Th17 phenotype (3). Although rapid progress has been made in understanding Th17 compared with cells cultured in TGF-␤ and IL-6 due to an inability by guest on September 27, 2021 biology, and there are many parallels with Th1 and Th2 cells, of IL-23 to induce IL-10 production (13). However, the long-term many aspects of Th17 development and function are still unclear. effects of IL-23 on Th17 cells, and whether IL-23 mediates com- TGF-␤ and IL-6, through the induction of IL-21, promote the de- mitment to the Th17 phenotype, as defined by the ability of these velopment the IL-17-secreting phenotype (1, 2) by activating Stat3 cells to maintain the Th17 phenotype in the presence of a Th1 or and inducing Th17 lineage defining transcription factors including Th2 promoting environment, remain unclear. In this study, we de- ROR␥t and ROR␣ (4, 5). Other cytokines have been shown to fine the effects of IL-23 on IL-17-secreting T cells through mul- contribute to the Th17 phenotype, though their precise function is tiple rounds of Ag receptor stimulation. Using cytokine-capture not yet clear. assays, we demonstrate that IL-23 maintains the Th17 phenotype IL-23 is required for the in vivo function of Th17 cells. Al- without affecting proliferation or survival. Results suggest that though some Th17 cells can develop in the absence of IL-23, mice while IL-23 is a maintenance factor for the Th17 phenotype, it deficient in IL-23p19 have a greatly diminished ability to mediate does not mediate commitment to this phenotype. Departments of Pediatrics, HB Wells Center for Pediatric Research and Department Materials and Methods of Microbiology and Immunology, Indiana University School of Medicine, Indianap- Mice olis, IN 46202 Indiana University Institutional Animal Care and Use Committee approved Received for publication June 17, 2008. Accepted for publication August 28, 2008. all animal studies in this report. C57BL/6 or BALB/c mice were from The costs of publication of this article were defrayed in part by the payment of page Harlan Sprague Dawley. charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Th cell differentiation 1 This work was supported by U.S. Public Health Service Award AI45515 (to ϩ ϩ M.H.K.) from the National Institutes of Health. G.L.S. and N.Y. were supported by Naive CD4 CD62L cells isolated from spleens using a MACS isolation a Training Grant in Immunology and Infectious Disease (T32AI060519) and N.Y. system (Miltenyi Biotec) were activated with soluble anti-CD3 (4 ␮g/ml was supported by the DeVault Fellowship from the Indiana University Cancer Biol- 145–2C11) and soluble anti-CD28 (1 ␮g/ml; BD Pharmingen) in the pres- ogy Training Program. ence of CD4ϩ depleted irradiated splenocytes (1:5). These conditions were 2 G.L.S. and N.Y. contributed equally to this study. found to be optimal over plate-bound anti-CD3 for Th17 generation, par- 3 ticularly in long-term cultures. Th1 and Th2 primed cultures were activated Address correspondence and reprint requests to Dr. Mark H. Kaplan, Department of ϩ with plate bound anti-CD3 and CD4 depleted irradiated splenocytes (1:5) Pediatrics, and Microbiology and Immunology, Wells Center for Pediatric Research, ␮ Indiana University School of Medicine, 702 Barnhill Drive, RI 2600, Indianapolis, IN and cultured with anti-IL-4 (10 g/ml 11B11) and IL-12 (5 ng/ml; R&D 46202. E-mail address: [email protected] Systems) or anti-IFN-␥ (10 ␮g/ml XMG) and IL-4 (10 ng/ml; PeproTech), respectively. Th17-primed cultures were cultured with anti-IFN-␥, anti- Copyright © 2008 by The American Association of Immunologists, Inc. 0022-1767/08/$2.00 IL-4, TGF-␤1 (1 ng/ml; R&D Systems), IL-6 (100 ng/ml; PeproTech), and www.jimmunol.org The Journal of Immunology 5949 FIGURE 1. Cytokine selection of IL-17ϩ Th17 cells. A, Naive CD4ϩ T cells were activated, cultured in TGF-␤ plus IL-6 plus IL-1␤ and blocking Abs (anti- IFN-␥ and anti-IL-4) for 5 days and activated before surface staining for IL-17 using cytokine capture. Cells were then sorted into IL-17-high and low populations. B, Supernatants from IL-17-high and -low cells stimu- lated with anti-CD3 were tested for cytokines using ELISA. C, RNA was isolated from cells treated in B and gene expression was assessed using real-time PCR. Downloaded from http://www.jimmunol.org/ IL-1␤ (10 ng/ml; eBioscience). Cells were expanded on day three after min before washing and incubating 10 min with Streptavidin-PE (BD stimulation by adding half the concentration of the original cytokines in Pharmingen). IL-17 captured cells were sorted using a FACS Aria cell fresh medium. For Th1 and Th2 long-term cultures, cells on day 5 of each sorter (BD Biosciences). by guest on September 27, 2021 round of stimulation were replated (0.5 ϫ 106 cells/ml) and stimulated with ϩ plate-bound anti-CD3 (0.5 ␮g/ml) in the presence of CD4 depleted irra- Phospho-STAT protein analysis diated splenocytes (1:5) and cultured with the original concentration of cytokines and Abs. For long-term Th17 cultures, cells were replated (0.5 ϫ T cells were stimulated for 30 min with IL-23 (10 ng/ml) or IL-4 (10 106 cells/ml) and stimulated with soluble anti-CD3 (1 ␮g/ml) in the pres- ng/ml).
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