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Differentiation IL-27 Limits IL-2 Production During IL-27 Limits IL-2 Production during Th1 Differentiation Alejandro V. Villarino, Jason S. Stumhofer, Christiaan J. M. Saris, Robert A. Kastelein, Frederic J. de Sauvage and This information is current as Christopher A. Hunter of September 28, 2021. J Immunol 2006; 176:237-247; ; doi: 10.4049/jimmunol.176.1.237 http://www.jimmunol.org/content/176/1/237 Downloaded from References This article cites 66 articles, 30 of which you can access for free at: http://www.jimmunol.org/content/176/1/237.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 28, 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 © 2006 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology IL-27 Limits IL-2 Production during Th1 Differentiation1 Alejandro V. Villarino,* Jason S. Stumhofer,* Christiaan J. M. Saris,‡ Robert A. Kastelein,§ Frederic J. de Sauvage,† and Christopher A. Hunter2* Although the ability of IL-27 to promote T cell responses is well documented, the anti-inflammatory properties of this cytokine remain poorly understood. The current work demonstrates that during infection with Toxoplasma gondii, IL-27R-deficient mice generate aberrant IL-2 responses that are associated with the development of a lethal inflammatory disease. Because in vivo depletion of IL-2 prolongs the survival of infected IL-27R؊/؊ mice, these data suggest that IL-27 curbs the development of immunopathology by limiting parasite-induced IL-2 production. Consistent with this hypothesis, IL-27R؊/؊ CD4؉ T cells produce more IL-2 than wild-type counterparts during in vitro differentiation, and when rIL-27 is introduced, it can suppress the expres- sion of IL-2 mRNA and protein by the latter group. Additionally, these studies reveal that, like IL-27, IL-12 can inhibit IL-2 production, and although each employs distinct mechanisms, they can synergize to enhance the effect. In contrast, this property is not shared by closely related cytokines IL-6 and IL-23. Thus, while traditionally viewed as proinflammatory agents, the present Downloaded from findings establish that IL-27 and IL-12 cooperate to limit the availability of IL-2, a potent T cell growth and survival factor. Moreover, because the current studies demonstrate that both can induce expression of suppressor of cytokine signaling 3, a protein that tempers cytokine receptor signaling, they also suggest that IL-27 and IL-12 share additionally inhibitory properties. The Journal of Immunology, 2006, 176: 237–247. nterleukin-27 is a member of the IL-6/IL-12 family of cyto- tive (low), the importance of IL-27R expression is evidenced by http://www.jimmunol.org/ kines that, like IL-12 (IL-12p35/IL-12p40) and IL-23 (IL- the unique CD4ϩ T cell phenotypes noted in IL-27R-deficient (IL- I 23p19/IL-12p40), is secreted as a helical protein (IL-27p28) 27RϪ/Ϫ) mice and the heterogeneous Jak/STAT family signaling bound to a soluble receptor-like subunit (EBI3) (1). Produced by cascade that this receptor can propagate (Jak 1 and Jak 2; STAT1, APCs in response to host- and pathogen-derived inflammatory 3, 4, and 5) (9–11, 14). Moreovoer, IL-27 can be secreted by the cues (2), IL-27 mediates its cellular effects through a high affinity same APCs that provide the impetus for T cell activation and IL- receptor complex that includes a unique subunit (IL-27R, WSX-1, 27R expression (TCR ligation), thus placing this cytokine-receptor TCCR) and gp130 (3), a component shared by several cytokines pairing in an ideal position to influence Th cell responses. including IL-6, IL-11, OSM, G-CSF, and LIF (4). Although gp130 When present during primary stimulation of naive CD4ϩ T by guest on September 28, 2021 is present on a range of immune and nonimmune cells (5), the cells, IL-27 enhances proliferation and promotes differentiation highest levels of IL-27R are found on the surface of resting NK into type I (Th1) effector cells that secrete IFN-␥ (1). By inducing cells, resting NKT cells, regulatory T cells, effector T cells, and expression of T-bet, a transcription factor whose target genes in- memory T cells, suggesting that IL-27 is directed at key elements clude IFN-␥ and IL-12R␤2, IL-27 directly promotes effector cy- of innate and adaptive immunity (6). Accordingly, IL-27R-defi- tokine production (IFN-␥) and sensitizes activated CD4ϩ T cells to cient mice (IL-27RϪ/Ϫ) develop aberrant inflammatory responses IL-12, a dominant factor in the polarization of Th1 responses (9– following infection with various pathogens (7). 11). In turn, because CD4ϩ T cells from IL-27RϪ/Ϫ mice produce Although IL-27R mRNA can be detected in several immune less IFN-␥ than wild-type (WT)3 counterparts during acute infec- lineages (3, 8), initial studies have focused on the role of IL-27 in tion with Leishmania major (8), a consensus emerged that IL-27 is directing (CD4ϩ) Th cell responses (1, 9–11). Similar to the IL- critical for rapid induction of type I inflammation (15–18). How- 12R (IL-12R␤2), the ligand-specific component of the IL-27R is ever, during chronic leishmaniasis, IL-27RϪ/Ϫ or EBI3Ϫ/Ϫ mice present at low levels on the surface of naive CD4ϩ T cells, while are able to develop protective Th1 responses that, while delayed, the shared subunit (IL-12R␤1/gp130) is more abundant (6, 12, 13). are sufficient to control parasite replication (19, 20). Furthermore, Conversely, activated CD4ϩ T cells express high levels of IL-27R when challenged with an avirulent mycobacterium (bacillus in vivo and in vitro, an effect shown to be mediated through a Calmette-Guerin) (8) or during chronic infection with Mycobac- TCR-dependent process (6). Whether induced (high) or constitu- terium tuberculosis (21, 22), IL-27RϪ/Ϫ mice generate Th1 re- sponses that are comparable to those of WT counterparts and, fol- lowing infection with Trypanosoma cruzi, their production of *Department of Pathobiology, University of Pennsylvania School of Veterinary Med- ␥ icine, Philadelphia, PA 19104; †Department of Molecular Biology, Genentech, South IFN- is enhanced (23). Thus, while it can augment the production ϩ San Francisco, CA 94080; ‡Department of Inflammation Research, Amgen, Thousand of IFN-␥ by CD4 T cells, these in vivo findings demonstrate that § Oaks, CA 91320; and DNAX Research Institute, Palo Alto, CA 94304 IL-27 is not required for the development of type I immunity. Received for publication June 9, 2005. Accepted for publication October 12, 2005. Studies with IL-27R-deficient mice suggest that IL-27 does not The costs of publication of this article were defrayed in part by the payment of page determine the polarity (Th1 vs Th2) of CD4ϩ T cell responses, but, charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. instead, regulates the intensity of pathogen-induced inflammation. 1 This work was supported by the State of Pennsylvania, Grant NIH42334 (AI41158 with a minority supplement to A.V.V.; A10662). 2 Address correspondence and reprint requests to Dr. Christopher A. Hunter, 3800 Spruce Street (Rosenthal Building), Room 226, Philadelphia, PA 19104. E-mail ad- 3 Abbreviations used in this paper: WT, wild type; BFA, brefeldin A; FasL, Fas dress: [email protected] ligand; SOCS, suppressor of cytokine signaling. Copyright © 2005 by The American Association of Immunologists, Inc. 0022-1767/05/$02.00 238 IL-27 LIMITS Th CELL IL-2 PRODUCTION During infection with the intestinal helminth Trichuris muris, IL- were then labeled with CFSE (5 ␮g/ml; Sigma-Aldrich), stimulated with 27RϪ/Ϫ mice display accelerated type II (Th2) responses that, soluble anti-CD3 Ab (1 ␮g/ml) and soluble anti-CD28 Ab (1 ␮g/ml), and when compared with WT cohorts, mediate enhanced worm expul- cultured in complete RPMI 1640 (10% heat-killed FBS, 100 U/ml peni- cillin, 1 mg/ml streptomycin, nonessential amino acids, and 2-ME). In all sion (24). Similarly, after challenge with the intracellular eu- experiments, cells were cultured at 2 ϫ 106 cells/ml in tissue culture- Ϫ/Ϫ karyote Toxoplasma gondii, IL-27R mice develop appropri- treated 96- or 48-well plates (200 or 500 ␮l/well). For Th1-polarizing ately polarized Th1 responses that limit parasite replication at the conditions, cultures were supplemented with rIL-12 (5 ng/ml; Genetics site of infection. However, although WT animals are able to con- Institute). IL-27 (200 ng/ml) was provided by F. DeSauvage (Genentech, Ϫ/Ϫ South San Francisco, CA), and IL-23 (100 ng/ml) by R. Kastelein (DNAX, tract T cell responses once acute infection is abated, IL-27R Palo Alto, CA). Recombinant IL-6 (10 ng/ml) and IFN-␥ (100 U/ml) were mice develop a lethal inflammatory disease that is characterized by purchased from eBioscience and BD Pharmingen, respectively. To assay ϩ escalating CD4 T cell proliferation and IFN-␥ production (25). the amount of IL-2 and IFN-␥ secreted during culture, supernatants were Therefore, because IL-27R is required to suppress pathological T harvested after 48 and 72 h (before PMA/ionomycin/BFA), respectively, cell responses during infection with T.
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