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Which Modulates T Cell Activation Adapter, Expressed by Regulatory T Cells, MS4A4B Is a GITR-Associated Membrane MS4A4B Is a GITR-Associated Membrane Adapter, Expressed by Regulatory T Cells, Which Modulates T Cell Activation This information is current as Duncan Howie, Kathleen F. Nolan, Stephen Daley, Emma of October 3, 2021. Butterfield, Elizabeth Adams, Hugo Garcia-Rueda, Claire Thompson, Nigel J. Saunders, Stephen P. Cobbold, Yukiko Tone, Masahide Tone and Herman Waldmann J Immunol 2009; 183:4197-4204; Prepublished online 14 September 2009; doi: 10.4049/jimmunol.0901070 Downloaded from http://www.jimmunol.org/content/183/7/4197 Supplementary http://www.jimmunol.org/content/suppl/2009/09/14/jimmunol.090107 http://www.jimmunol.org/ Material 0.DC1 References This article cites 36 articles, 19 of which you can access for free at: http://www.jimmunol.org/content/183/7/4197.full#ref-list-1 Why The JI? Submit online. by guest on October 3, 2021 • 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 © 2009 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology MS4A4B Is a GITR-Associated Membrane Adapter, Expressed by Regulatory T Cells, Which Modulates T Cell Activation1 Duncan Howie,2* Kathleen F. Nolan,* Stephen Daley,* Emma Butterfield,* Elizabeth Adams,* Hugo Garcia-Rueda,* Claire Thompson,* Nigel J. Saunders,* Stephen P. Cobbold,* Yukiko Tone,† Masahide Tone,† and Herman Waldmann* In the aftermath of thymic negative selection, natural and adaptive regulatory T cells (Tregs) must acknowledge peripheral, “danger-free” self-Ag to ensure their sustained activity. In this paper, we show that natural and adaptive Tregs or T cells transduced with cDNA for Foxp3, just like Th1 cells, express members of the MS4A family of transmembrane molecules. Naive T cells transduced with MS4A4B become able to respond to lower levels of Ag. Using two family members, MS4A4B and MS4A6B, as baits in a yeast split-ubiquitin Treg library screen, we demonstrate their interaction with each other and with GITR, Orai1, and other surface receptors. Interaction of 4B with GITR augments GITR signaling and T cell IL-2 production in response to Downloaded from triggering with GITR ligand or anti-GITR Abs. This interaction provides a mechanism whereby MS4A family members, through lateral coassociation with costimulatory molecules, may amplify Ag signals. We propose that T cells preoccupied with immune defense use this MS4A family to enhance sensitivity to extrinsic Ag stimulation, ensuring its elimination, while Tregs use these adaptors to allow low level Ag signals to sustain regulatory function. The Journal of Immunology, 2009, 183: 4197–4204. ␤ mmune tolerance is an essential aspect of the immune system which TGF is experienced by T cells likely governs the outcome http://www.jimmunol.org/ and has evolved multiple mechanisms to ensure that host for the cell. I tissues are spared damage while pathogens are eradicated ef- Using serial analysis of gene expression (SAGE) and DNA mi- ficiently. Its major mechanisms are deletion of autoreactive cells croarrays, we investigated whether there were any genes shared by and the generation of regulatory T cells (Tregs)3. Tregs are func- Tregs induced by over-expression of Foxp3 and by TGF␤.We tionally characterized as T lymphocytes that have acquired the identified a family of four-pass membrane receptors, the MS4A ability to inhibit both T cell-mediated and innate immune re- family, with transcription up-regulated by both Foxp3 and TGF␤. sponses (1). Multiple routes by which Tregs can acquire this ca- Using a split-ubiquitin genetic screen, we showed interactions be- pacity have been described, including central education in the thy- tween MS4A4B and MS4A6B, the most Treg cell-specific MS4A ϩ ϩ ϩ mus, giving rise to the CD4 CD25 Foxp3 natural Tregs (2–4), members with multiple surface receptors, including the costimu- by guest on October 3, 2021 and peripheral induction through exposure to chronic, incomplete latory receptor GITR (TNFRSF18). One of these tetraspan family signals, along with the immunomodulatory cytokines TGF␤ or members has already been described in Th1 cells but their func- IL-10 (5–7). tional relevance to T cells has not been resolved. We show that TGF␤ has an essential role in immune homeostasis and is ca- transduction of MS4A4B into naive T cells can heighten their sen- pable, depending on the tissue-specific context, of inducing anti- sitivity to Ag. MS4A4B overexpression in EL4 cells results in inflammatory peripheral Foxp3-expressing Tregs, as demonstrated augmented signaling and IL-2 production in response to GITR in TGF␤1Ϫ/Ϫ and dominant negative TGF␤R mice, which develop triggering. We propose that Th1 cells (36) and Tregs use these a fatal early-onset autoimmune disease characterized by loss of adaptors to increase their ability to perceive Ag immunity and for Foxp3-positive Tregs. TGF␤ is, however, a pleiotropic cytokine ensuring adequate regulation of self-reactivity. and, in concert with IL-6, can steer T cells toward a proinflam- matory Th17 phenotype. Therefore, the physiological context in Materials and Methods Mice *Sir William Dunn School of Pathology, University of Oxford, Oxford, United King- dom; and †Department of Pathology and Laboratory Medicine, University of Penn- A1(M).RAG1null TCR-transgenic mice and CBA/Ca mice were bred and sylvania, Philadelphia, PA 19104 maintained in specific pathogen-free conditions at the Sir William Dunn Received for publication April 2, 2009. Accepted for publication July 21, 2009. School of Pathology. All procedures were conducted in accordance with the Home Office Animals (Scientific Procedures) Act of 1986. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Generation of SAGE libraries 1 This work was funded by a programme grant from the Medical Research Council ϩ and a grant from the EU FP6 RISET consortium. Four long SAGE libraries were generated from A1.RAGnull CD4 T cells. 2 Address correspondence and reprint requests to Dr. Duncan Howie, Sir William SAGE libraries were generated as previously described (33). Two li- Dunn School of Pathology, University of Oxford, Oxford, OX1 3RE, United King- braries were constructed from cells stimulated for 7 days with (DBYT) dom. E-mail address: [email protected] or without (DBY) exogenous human rTGF␤ added at 2 ng/ml. The other two libraries were identical to DBY and DBYT apart from isolation of 3 Abbreviations used in this paper: Treg, regulatory T cell; BMDC, bone marrow- derived dendritic cell; DBY, cells stimulated without exogenous human TGF␤; CD4 T cells from the bone marrow-derived dendritic cell (BMDCs) by DBYT, cells stimulated with exogenous human TGF␤; DC, dendritic cell; iTreg, Ficoll centrifugation after 7 days and reculture in IL-2 at 2000 U/ml for TGF␤-induced Tregs; nTreg, natural Treg; SAGE, serial analysis of gene expression. a further week. These libraries were named DBY.IL2 and DBYT.IL2. Data analysis was performed using the software package !SAGEClus Copyright © 2009 by The American Association of Immunologists, Inc. 0022-1767/09/$2.00 (Ref. 33; www.molbiol.ox.ac.uk/pathology/tig). www.jimmunol.org/cgi/doi/10.4049/jimmunol.0901070 4198 MS4A EXPRESSION BY REGULATORY T CELLS Microarray analysis vealed using HRP-conjugated secondary Abs using ECL (SuperSignal; Pierce Biotechnology). Abs used were anti-␤-actin (Santa Cruz Biotech- Custom microarrays with immune system-directed bias were prepared nology), rabbit anti-MS4A4B (34), GITR (YGITR 765), Thy1.2 (30H12), using 70mer probes specific for 768 genes. Each probe was printed with p42/44 MAPK (3A7), and phospho p42/44 MAPK (Thr202/Tyr204) (both four replicates on nonadjacent areas onto amine slides (Genetix). De- from Cell Signaling Technology). tails of the microarray are available from ArrayExpress (Accession Number: A-MEXP-239; www.ebi.ac.uk/microarray-as/ae/). RNA integ- Flow cytometry rity was confirmed using a 2100 BioAnalyser (Agilent). Total RNA was reverse transcribed using Superscript III reverse transcriptase and la- Cells were stained with the following Abs: anti-GITR YGITR 765.4.2 beled as directed using the Cy3 and Cy5 3 DNA 900 dendrimer labeling (produced in house), fluorochrome-conjugated anti-CD25, anti-CD4, kit (Genisphere) using a two-step hybridization protocol with on-slide and anti-CD8 (BD Biosciences), PE- or allophycocyanin-conjugated anti- mixing on a Slide Booster (Advalytix). Arrays were scanned using a Foxp3 (eBioscience), and rabbit polyclonal anti-MS4A4B (34). Surface ScanArray Express HT scanner (PerkinElmer). Image analysis was per- staining for CD4 and CD25 was performed on ice for 30 min, followed by formed using BlueFuse v 2 (BlueGnome Ltd). washing in PBS and permeabilization with 0.5% saponin before staining for MS4A4B or rabbit Ig as a control for 30 min and detection with FITC-con- Quantitative real-time RT-PCR jugated goat anti-rabbit Ig. Blocking of MS4A4B staining with immunizing peptide (HQGTNVPGNVYKNHPGEIV) was performed in some cases for DNase I-treated RNA was reverse transcribed using StrataScript first strand 15 min before staining. Foxp3 was detected according to the protocol pro- synthesis kits (Stratagene) and random hexamer primers. For each exper- vided by eBioscience. For detection of IL-2 production by EL4 cells, cells imental sample, a minimum of two biological replicates was performed.
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