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Program in Human CD45RA Regulated Cellular − B Κ TNF Activat TNF Activates a NF-κB−Regulated Cellular Program in Human CD45RA− Regulatory T Cells that Modulates Their Suppressive Function This information is current as of September 26, 2021. Meital Nagar, Jasmine Jacob-Hirsch, Helly Vernitsky, Yackov Berkun, Shomron Ben-Horin, Ninette Amariglio, Ilan Bank, Yoel Kloog, Gideon Rechavi and Itamar Goldstein J Immunol 2010; 184:3570-3581; Prepublished online 24 Downloaded from February 2010; doi: 10.4049/jimmunol.0902070 http://www.jimmunol.org/content/184/7/3570 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2010/02/22/jimmunol.090207 Material 0.DC1 References This article cites 46 articles, 20 of which you can access for free at: http://www.jimmunol.org/content/184/7/3570.full#ref-list-1 by guest on September 26, 2021 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 *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 © 2010 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology TNF Activates a NF-kB–Regulated Cellular Program in Human CD45RA– Regulatory T Cells that Modulates Their Suppressive Function Meital Nagar,*,† Jasmine Jacob-Hirsch,* Helly Vernitsky,*,† Yackov Berkun,‡ Shomron Ben-Horin,x Ninette Amariglio,* Ilan Bank,x Yoel Kloog,† Gideon Rechavi,* and Itamar Goldstein*,x Emerging data suggest that regulatory T cell (Treg) dysfunction and consequent breakdown of immunological self-tolerance in autoimmunity can be mediated by factors that are not Treg-intrinsic (e.g., cytokines). Indeed, recent studies show that in rheumatoid arthritis the proinflammatory cytokine TNF reduces the suppressive function of Tregs, whereas in vivo TNF blockade restores this function and accordingly self-tolerance. However, until now a coherent mechanism by which TNF regulates the Treg has not been Downloaded from described. In this paper, we show that TNF induces preferential and significant activation of the canonical NF-kB pathway in human Tregs as compared with CD25– conventional T cells. Furthermore, TNF induced primarily in CD45RA– Tregs a transcription program highly enriched for typical NF-kB target genes, such as the cytokines lymphotoxin-a and TNF, the TNFR superfamily members FAS, 4-1BB, and OX-40, various antiapoptotic genes, and other important immune-response genes. FACS analysis revealed that TNF also induced upregulation of cell surface expression of 4-1BB and OX40 specifically in CD45RA–FOXP3+ Tregs. In contrast, TNF had only a minimal effect on the Treg’s core transcriptional signature or on the intracellular levels of the http://www.jimmunol.org/ FOXP3 protein in Tregs. Importantly, TNF treatment modulated the capacity of Tregs to suppress the proliferation and IFN-g secretion by conventional T cells, an effect that was fully reversed by cotreatment with anti-TNFR2 mAbs. Our findings thus provide new mechanistic insight into the role of TNF and TNFR2 in the pathogenesis of autoimmunity. The Journal of Immu- nology, 2010, 184: 3570–3581. umor necrosis factor (TNF-a) is a prototype member of iopathic arthritis (JIA), ankylosing spondylitis, and psoriatic ar- the TNF superfamily (TNFSF) of ligands. It binds the thritis (3). Nevertheless, little is known at the molecular level T corresponding TNFR superfamily (TNFRSF) members about the specific effects of TNF on the various T cell subsets, and by guest on September 26, 2021 TNFR1 (TNFRSF1A; p55) and TNFR2 (TNFRSF1B; p75). TNF is consequently the fine details of the mechanism of action of TNF generated and expressed by many types of cells, including lym- blockade, in vivo, remain somewhat obscure. phocytes, and can induce a plethora of immune responses (1). VariousstudiesinbothmiceandhumanssuggestthatTNFblockade Several lines of evidence suggest that TNF has a central role in the has the potential to augment regulatory T cell (Treg) numbers and pathogenesis of a variety of human inflammatory disorders (2). function. For example, in RA patients treated with anti-TNF mAbs Moreover, TNF blockade has a notable therapeutic efficacy in there is an increase in the quantity of circulating CD25HI Tregs as well a number of T cell-dependent human autoimmune disorders, such as restoration of their partly impaired suppressive function (4, 5). as inflammatory bowel disease, rheumatoid arthritis, juvenile id- Moreover, TNF blockade during the in vitro activation and expansion of unselected human T cells results in augmented expansion of x + + *Sheba Cancer Research Center, ‡Division of Pediatrics, and Department of Med- FOXP3 CD4 T cells with a regulatory phenotype (6, 7). icine, The Chaim Sheba Medical Center, Tel Aviv University, Sackler Faculty of It should be noted that studies in patients with various auto- Medicine, Tel Hashomer; and †The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel immune disorders and mice models show that Treg-type cells are Received for publication June 29, 2009. Accepted for publication January 26, 2010. present at considerable numbers at the actual site of inflammation This work was supported in part by an award from the Flight Attendant Medical (8, 9). Thus, a major challenge is to define the Treg extrinsic Research Institute. factors that facilitate tissue inflammation even when Tregs are The microarray data presented in this article have been submitted to the National present in abundance. In this regard, there is controversy as to Center for Biotechnology Information Gene Expression Omnibus under accession whether TNF—a cytokine abundant at sites of inflammation—can number GSE18893. interfere with the suppressive function of the Treg (4, 8–13). Address correspondence and reprint requests to Dr. Itamar Goldstein, The Sheba – Cancer Research Center, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel. Tregs as opposed to CD25 conventional T cells (Tcons) consti- E-mail address: [email protected] tutively express high levels of TNFR2, but both subsets do not ex- The online version of this article contains supplemental material. press TNFR1 (4, 12). Whereas the downstream molecular events Abbreviations used in this paper: acTreg, activated regulatory T cell; DI, division initiated following TNFR1 ligation have been studied in great detail, index; EASE, Expression Analysis Systematic Explorer; IPA, Ingenuity Pathways there is significantly less information about signal transduction via Analysis, JIA, juvenile idiopathic arthritis; MB, microbead; MFI, mean fluorescence TNFR2 that, as opposed to TNFR1, does not contain a death domain intensity; mTNF, membrane-bound TNF; nrTreg, naı¨ve/resting regulatory T cell; PMA/Ion, PMA and ionomycin; rhIL-2, recombinant human IL-2; RTQPCR, real- (14, 15). Binding of TNF to TNFR1 activates at least three distinct time quantitative PCR; SF, synovial fluid; Tcon, conventional T cell; TNFRSF, TNF cellular pathways: IKK/NF-kB, JNK/c-Jun, and the proapoptotic receptor superfamily; TNFSF, TNF superfamily; Treg, regulatory T cell. caspases 8 and 3 (1). At present, the specific cellular program in- Copyright Ó 2010 by The American Association of Immunologists, Inc. 0022-1767/10/$16.00 duced by TNFR2 stimulation in Tregs is practically unknown. www.jimmunol.org/cgi/doi/10.4049/jimmunol.0902070 The Journal of Immunology 3571 In this study, using various complementary methods, such as gene Briefly, CFSE-labeled CD25– T cells at 1 3 105 cells per well were plated into 96-well plates (Costar) and activated by plate-bound immobilized expression microarrays, PCR-based assays, analysis of protein ex- ++ pression and/or phosphorylation by FACS, and other relevant assays OKT3 (2.5 mg/ml) in the presence of graded amounts of CD25 Tcells. Selected cultures, as indicated in the text, were supplemented with TNF (50 to test suppressive functions, we now identify the cellular program ng/ml), rhIL-2 (100 IU/ml), anti-TNFR2 mAbs (10 mg/ml), or Infliximab that mediates the inhibitory effect of TNF on the Treg suppressive (50 mg/ml) at time 0 and 72 h later. As indicated, we also activated the Treg/ function. Our data show a central role for activation of the canonical Tcon cocultures with K562 artificial APCs, engineered to stably express the NF-kB pathway—primarily in CD45RA– Tregs—that consequently FcR CD32 alone (KT32), or with 4.1BBL (KT32/4.1BBL), kindly provided by Carl H. June (University of Pennsylvania Cancer Center, Philadelphia, induces a distinctive proinflammatory cellular program. PA). To induce potent TCR activation, the KT32 cells were preincubated with OKT3 and anti-CD28 mAbs at a concentration of 1 mg/ml for 10 min Materials and Methods and then irradiated with 10,000 cGy. Regardless of the activation protocol, 5 d later the T cells were harvested and analyzed by FACS. CD4+ Tcon Human subjects proliferation was determined using the proliferation platform of FlowJo Blood samples were obtained from healthy adult blood donors.
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