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T Cells Regulatory + CD25 + T Cell Targets by CD4 + Distinct Molecular Distinct Molecular Program Imposed on CD4 + T Cell Targets by CD4+CD25+ Regulatory T Cells This information is current as Teresa L. Sukiennicki and Deborah J. Fowell of September 28, 2021. J Immunol 2006; 177:6952-6961; ; doi: 10.4049/jimmunol.177.10.6952 http://www.jimmunol.org/content/177/10/6952 Downloaded from References This article cites 52 articles, 25 of which you can access for free at: http://www.jimmunol.org/content/177/10/6952.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 28, 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 © 2006 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Distinct Molecular Program Imposed on CD4؉ T Cell Targets by CD4؉CD25؉ Regulatory T Cells1 Teresa L. Sukiennicki and Deborah J. Fowell2 CD4؉CD25؉ regulatory T cells (Tregs) are key modulators of immunity, but their mechanism of action is unclear. To elucidate the molecular consequences of Treg encounter, we analyzed changes in gene expression in CD4؉ T cell targets activated in the presence or absence of CD4؉CD25؉ Tregs. Tregs did not alter the early activation program of CD4؉ T cells, but had reversed many of the activation-induced changes by 36 h. It is not known whether Tregs simply induce a set of transcriptional changes common to other nonproliferative states or whether instead Tregs mediate a distinct biological activity. Therefore, we compared the gene profile of T cells following Treg encounter with that of T cells made anergic, TGF-␤-treated, or IL-2-deprived; all possible modes of Treg action. Strikingly, all genes down-regulated in suppressed cells were indeed common to these nonproliferative states. In contrast, Treg encounter led to elevated expression of a unique set of genes in the target T cells. Although different from Downloaded from the nonproliferative states tested, the Treg-imposed gene program is exemplified by expression of many genes associated with growth arrest or inhibition of proliferation. We suggest that Tregs function by the induction of a distinct set of negative regulatory factors that initiate or maintain target T cells in a nonproliferative state. The Journal of Immunology, 2006, 177: 6952–6961. aturally occurring regulatory T cells (Tregs)3 are impor- via Treg-produced granzyme B and/or perforin (21, 22) have been tant modulators of immune responses. Initially demon- proposed as additional modes of Treg action. Thus, Tregs may http://www.jimmunol.org/ N strated to prevent autoimmunity, they have since been as- have multiple ways in which to disable a developing immune re- sociated with the regulation of immune responses to pathogens, sponse, and the mode of action may depend on the context of both tumors, and transplantation Ags (1–3). Their influence on CD4ϩ T the target and Treg activation signals. cells has been studied best, although direct or indirect effects on Tregs cause a block in proliferation, differentiation, and effector CD8ϩ T cells, B cells, and innate cell types including dendritic cells T cell function, but beyond this the molecular changes in target T also have been reported. Tregs suppress many activities of target cells cell biology following Treg encounter are ill-defined. IL-2 tran- including proliferation, IL-2 production (4, 5), T cell differentiation, scription is down-regulated in the target T cells (4, 5, 12) but it is and effector T cell migration and cytokine secretion (6–8). not known whether the IL-2 gene modulation is the primary target, Little is known about how Tregs mediate their suppressive ef- or a downstream consequence, of Treg suppression. The strength by guest on September 28, 2021 fects. They require activation through their TCR to acquire full of the target T cell activation signal appears to play a role in their functional competence and, in vitro, must be in close proximity to susceptibility to suppression, with increased costimulation (5, 23) their targets (or APC) to mediate suppression (4, 5). The expres- and/or Ag concentration (24) rendering the target T cells refractory sion of CD25 at high levels on Tregs suggests that they may work to Treg suppression. It is unclear how these additional signals pro- through competitive consumption of IL-2 (9), although the ability tect against Treg action. Recent data suggest that the NFAT and of Tregs to suppress IL-2R-deficient T cells (10) and in the pres- Cbl-b pathways in the target population are important for Treg ence of excess exogenous IL-2 (11, 12) suggests that IL-2 com- action, since Tregs were unable to block the proliferation of CD4ϩ petition is not essential for suppression. IL-10 and TGF-␤ are key T cell targets that lacked expression of these signal molecules (25, immunomodulators in in vivo models of Treg suppression pro- 26). Therefore, Tregs may directly target these signaling pathways duced by the Tregs themselves or induced in other cell types by to facilitate suppression. Tregs (13–16). Modulation of APC function by Tregs (17–19), Postulating that molecular changes in the suppressed cell may anergy induction (20), and direct cytotoxicity of immune targets yield clues to the functional state induced in targets by Tregs and/or the mechanism of Treg activity, we used microarray tech- nology to determine changes in target T cell gene expression fol- Department of Microbiology and Immunology, David H. Smith Center for Vaccine Biology and Immunology, Aab Institute of Biomedical Sciences, University of Roch- lowing Treg-mediated suppression. Differences in gene expression ester, Rochester, NY 14642 in the suppressed cells evolved over time, with only 12 genes ϩ Ϫ Received for publication April 21, 2006. Accepted for publication August 25, 2006. differentially expressed between CD4 CD25 target cells cul- The costs of publication of this article were defrayed in part by the payment of page tured in the presence (suppressed) or absence (nonsuppressed) of charges. This article must therefore be hereby marked advertisement in accordance Tregs at 12 h and 242 genes at 36 h. The kinetics of expression of with 18 U.S.C. Section 1734 solely to indicate this fact. many of these genes suggested a pattern of aborted activation in 1 This work was supported by the Juvenile Diabetes Research Foundation, Research the presence of Tregs. That is, similar transcriptional changes oc- Grant 1-2000-609 (to D.J.F.) and National Institutes of Health Training Grant AI- 07169 (to T.L.S.). curred in the presence or absence of Tregs early after activation, 2 Address correspondence and reprint requests to Dr. Deborah J. Fowell, David H. but the presence of Tregs reversed many of these activation-in- Smith Center for Vaccine Biology and Immunology, Aab Institute of Biomedical duced changes by 36 h. To determine whether Tregs induced dis- Sciences, Department of Microbiology and Immunology, University of Rochester, tinct changes in target T cells, we examined cells that had been 601 Elmwood Avenue, Box 609, Rochester, NY 14642. E-mail address: ␤ [email protected] anergized, deprived of IL-2, or treated with TGF- for expression 3 Abbreviations used in this paper: Treg, regulatory T cell; 7-AAD, 7-aminoactino- of a panel of genes found to be differentially expressed following mycin D; KLF, Kruppel family; GRP1, general receptor of phosphoinositide 1. a Treg encounter. All of the down-regulated genes in suppressed Copyright © 2006 by The American Association of Immunologists, Inc. 0022-1767/06/$02.00 The Journal of Immunology 6953 cells were similarly affected under one or more of the nonprolif- Quantitative real-time PCR erative conditions tested, suggesting that Tregs do not function by Unamplified cDNA was generated from mRNA using random hexamers inhibiting a discrete panel of target T cell genes. In contrast, a and Superscript II (Invitrogen Life Technologies). cDNA was loaded in unique set of genes was more highly expressed in target T cells duplicate onto custom-designed TaqMan Low-Density Arrays (Applied following Treg encounter but not in T cells inactivated in other Biosystems). Data were analyzed using Sequence Detection System soft- ways. This global analysis of gene expression in suppressed cells ware (Applied Biosystems) with 18S ribosomal RNA as the endogenous control. supports the idea that Treg-induced suppression is a distinct mo- lecular process. Results Kinetic changes in target T cell activation in the presence Materials and Methods of Tregs Mice The timing and downstream consequences of Treg encounter for BALB/c Thy1.2ϩ mice were purchased from The Jackson Laboratory or ϩ the target T cell are poorly understood. We have recently defined the National Cancer Institute. BALB/c Thy1.1 mice were bred in house. a narrow kinetic window in which Tregs act on CD4ϩ T cell tar- Mice were housed under pathogen-free conditions and all animal protocols were approved by the University Committee for Animal Resources at the gets, occurring within the first 6–12 h of target T cell activation in University of Rochester Medical School. vitro (12). To obtain a better understanding of how the target T cell changes over time, we analyzed the expression of early activation Media, Abs, and reagents markers on CD4ϩCD25Ϫ target T cells in the presence or absence ϩ ϩ Cells were cultured in RPMI 1640 with 10% heat-inactivated FCS of allelically marked CD4 CD25 Tregs.
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