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Induction of Therapeutic Tissue Tolerance Foxp3 Expression Is Downloaded from http://www.jimmunol.org/ by guest on September 30, 2021 is online at: average * The Journal of Immunology published online 17 September 2012 from submission to initial decision 4 weeks from acceptance to publication http://www.jimmunol.org/content/early/2012/09/17/jimmun ol.1200449 Foxp3 Expression Is Required for the Induction of Therapeutic Tissue Tolerance Frederico S. Regateiro, Ye Chen, Adrian R. Kendal, Robert Hilbrands, Elizabeth Adams, Stephen P. Cobbold, Jianbo Ma, Kristian G. Andersen, Alexander G. Betz, Mindy Zhang, Shruti Madhiwalla, Bruce Roberts, Herman Waldmann, Kathleen F. Nolan and Duncan Howie J Immunol Submit online. Every submission reviewed by practicing scientists ? is published twice each month by Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts http://jimmunol.org/subscription Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html http://www.jimmunol.org/content/suppl/2012/09/17/jimmunol.120044 9.DC1 Information about subscribing to The JI No Triage! Fast Publication! Rapid Reviews! 30 days* Why • • • Material Permissions Email Alerts Subscription Supplementary The Journal of Immunology The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2012 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. This information is current as of September 30, 2021. Published September 17, 2012, doi:10.4049/jimmunol.1200449 The Journal of Immunology Foxp3 Expression Is Required for the Induction of Therapeutic Tissue Tolerance Frederico S. Regateiro,*,1 Ye Chen,*,1 Adrian R. Kendal,* Robert Hilbrands,* Elizabeth Adams,* Stephen P. Cobbold,* Jianbo Ma,* Kristian G. Andersen,† Alexander G. Betz,‡ Mindy Zhang,x Shruti Madhiwalla,x Bruce Roberts,x Herman Waldmann,*,2 Kathleen F. Nolan,*,2 and Duncan Howie*,2 CD4+Foxp3+ regulatory T cells (Treg) are essential for immune homeostasis and maintenance of self-tolerance. They are produced in the thymus and also generated de novo in the periphery in a TGF-b–dependent manner. Foxp3+ Treg are also required to achieve tolerance to transplanted tissues when induced by coreceptor or costimulation blockade. Using TCR-transgenic mice to avoid issues of autoimmune pathology, we show that Foxp3 expression is both necessary and sufficient for tissue tolerance by Downloaded from coreceptor blockade. Moreover, the known need in tolerance induction for TGF-b signaling to T cells can wholly be explained by its role in induction of Foxp3, as such signaling proved dispensable for the suppressive process. We analyzed the relative contribution of TGF-b and Foxp3 to the transcriptome of TGF-b–induced Treg and showed that TGF-b elicited a large set of downregulated signature genes. The number of genes uniquely modulated due to the influence of Foxp3 alone was surprisingly limited. Retroviral-mediated conditional nuclear expression of Foxp3 proved sufficient to confer transplant-suppressive potency + b on CD4 T cells and was lost once nuclear Foxp3 expression was extinguished. These data support a dual role for TGF- and http://www.jimmunol.org/ Foxp3 in induced tolerance, in which TGF-b stimulates Foxp3 expression, for which sustained expression is then associated with acquisition of tolerance. The Journal of Immunology, 2012, 189: 000–000. mmune homeostasis and maintenance of self-tolerance pression. Short-term coreceptor blockade provided the first dem- depends upon constant vigilance by CD4+Foxp3+ regula- onstration that induction of tolerance could be achieved using low- I tory T cells (Treg). Commitment to the Treg lineage occurs impact intervention in a mature immune system (7). Studied in primarily in the thymus (1, 2), but also in the periphery in a TGF- a transplantation setting, this form of tolerance is totally depen- b–dependent manner (3–6). One of the major goals of modern dent on the ability of TGF-b to signal to T cells (6) and is also by guest on September 30, 2021 immunosuppression, be it in autoimmune disease or transplanta- associated with de novo induction of Ag specific Foxp3+ induced tion, is to harness tolerance mechanisms such as those used by Treg (iTreg) (4, 8). This raises the possibility that the absolute Treg to minimize the duration and extent of drug immunosup- need for TGF-b is simply to guarantee conversion of naive CD4+ T cells to stable Foxp3 expression. However, TGF-b signaling not only induces expression of *Sir William Dunn School of Pathology, Oxford University, Oxford OX1 3RE, Foxp3, but also many other effector molecules, including CD39, United Kingdom; †Faculty of Arts and Sciences Center for Systems Biology, Harvard CD73, CTLA4, CD103, neuropilin, perforin, and IL-10 (9–12). University, Cambridge, MA 02138; ‡Medical Research Council Laboratory of Mo- lecular Biology, Cambridge CB2 0QH, United Kingdom; and xGenzyme Corporation, There are also claims that TGF-b is needed for the effector arm of Framingham, MA 01701 suppression (13), and if so, this, too, could explain the need for 1F.S.R. and Y.C. are cofirst authors. TGF-b signaling to T cells. + 2H.W., K.F.N., and D.H. are cosenior authors. Despite a large literature on Foxp3 Treg in self-tolerance, it Received for publication February 3, 2012. Accepted for publication August 15, is not known whether Foxp3 expression is essential for domi- 2012. nant tolerance induced to foreign Ags or whether other genetic/ This work was supported by a program grant from the Medical Research Council and expression modalities (e.g., those potentially necessary for Th3, the European Framework 7 Betacell program. Tr1, and iTr35 cells) can operate in its absence. Using a combi- The microarray data presented in this article have been submitted to the National nation of genetically manipulated mouse strains unable to express Center for Biotechnology Information’s Gene Expression Omnibus (http://www.ncbi. Foxp3, retroviral constructs facilitating conditional nuclear lo- nlm.nih.gov/geo/) under accession number GSE39529. calization of Foxp3, and a dominant-negative TGF-bRII to ablate Address correspondence and reprint requests to Dr. Duncan Howie and Dr. Herman Waldmann, Sir William Dunn School of Pathology, Oxford University, South Parks TGF-b signaling in T cells, we have addressed the contributions of Road, Oxford OX1 3RE, U.K. E-mail addresses: [email protected] TGF-b and Foxp3 to the induction and function of iTreg. We show (D.H.) and [email protected] (H.W.) that Foxp3 expression is indispensible for tolerance induction to The online version of this article contains supplemental material. transplanted tissue, and its continued nuclear expression is nec- Abbreviations used in this article: B6, C57BL/6J; BMDC, bone marrow-derived essary for maintenance of tolerance. In contrast, once tolerance is dendritic cell; CBA, CBA/Ca; cTreg, conditional regulatory T cell; hCD2, human CD2; 4HT, 49hydroxytamoxifen; HY, Marilyn T cell untreated with TGF-b;HYAb, established, prevention of tissue damage does not depend on TGF- peptide of male Ag Dby (NAGFNSNRANSSRSS); HYT, Marilyn T cell treated with b signaling to naive T cells. This indicates that the major role of 2/2 TGF-b; iTreg, induced regulatory T cell; Marilyn, Marilyn.Rag1 ; nTreg, natural TGF-b in this form of acquired tolerance largely resides in the regulatory T cell; Treg, regulatory T cell. induction of Foxp3 expression in naive CD4+ T cells. Comparative Copyright Ó 2012 by The American Association of Immunologists, Inc. 0022-1767/12/$16.00 transcriptome analysis of in vitro-generated, TGF-b–experienced www.jimmunol.org/cgi/doi/10.4049/jimmunol.1200449 2 Foxp3 AND TGF-b IN ACQUIRED TOLERANCE 2 Foxp3+ and Foxp3 CD4+ T cells with TGF-b–experienced performed using a commercial kit (eBioscience) according to the manu- Foxp32/2 CD4+ T cells not only confirms TGF-b signaling in all facturer’s directions. the populations, but also demonstrates that, although crucial for MoFlo FACS sorting of cells maintenance of tolerance, the proportion of the transcriptome controlled specifically by Foxp3 in iTreg appears to be relatively Flow cytometry sorting was performed using a MoFlo sorter (DakoCyto- mation). limited. Production of conditional Foxp3 retroviral supernatant Materials and Methods All vectors used except pCL-ECO have previously been described (18). The Experimental animals conditional Foxp3 construct cFoxp3 was made by cloning sequence- encoding ERT2, a modified estrogen-binding domain, in-frame with the CBA/Ca (CBA), C57BL/6J (B6), CBA.Rag12/2, B6.Rag12/2, Marilyn. 2/2 2/2 C terminus of Foxp3. GFP coding sequence was cloned directly after the Rag1 (Marilyn) [derived from Marilyn.Rag2 (14)], Marilyn. fifth codon of Foxp3 to produce the fusion protein GFP-Foxp-ERT2. This Foxp3hCD2 (8), Marilyn.Foxp32/2 (9), CD4-dnTGFbRII (15), CD4- 2/2 2/2 was then cloned into a Moloney murine leukemia virus backbone, a cir- dnTGFbRII.Rag1 , and Marilyn.CD4-dnTGFbRII.Rag1 mice were cular plasmid that also contained a GPI-linked and internal ribosome entry bred and maintained under specific pathogen-free conditions at the Sir site-driven rat CD8a (rCD8) gene. The empty control vector contained William Dunn School of Pathology (University of Oxford, Oxford, U.K.). only the GFP and rCD8 segments, but no Foxp3. The packaging vector, . CD4-dnTGFbRII mice backcrossed to B6 for 10 generations were pCL-ECO, was purchased from Addgene (Cambridge, MA). The day be- crossed with B6.Rag12/2 mice for two generations to generate CD4- 2 2 fore transfection, a confluent plate of HEK 293eT cells were split at one in dnTGFbRII.Rag1 / animals, which were further crossed with Marilyn ∼ b three and plated in six-well plates at 40% confluency, with 2 ml/well. mice to introduce the Dby-H2A specific TCR-transgenic element. All Approximately 16 h later, the cells were transfected with 2 mg pCL-ECO experimental procedures received local ethics committee approval and Downloaded from packaging plasmid and 2 mg retroviral vector cFoxp3 using the CaCl2 were conducted in accordance with the Home Office Animals (Scientific method.
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