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Prdm1 Regulates Thymic Epithelial Function to Prevent Autoimmunity Natalie A

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Prdm1 Regulates Thymic Epithelial Function to Prevent Autoimmunity Natalie A Prdm1 Regulates Thymic Epithelial Function To Prevent Autoimmunity Natalie A. Roberts, Brian D. Adams, Nicholas I. McCarthy, Reuben M. Tooze, Sonia M. Parnell, Graham Anderson, This information is current as Susan M. Kaech and Valerie Horsley of September 23, 2021. J Immunol 2017; 199:1250-1260; Prepublished online 12 July 2017; doi: 10.4049/jimmunol.1600941 http://www.jimmunol.org/content/199/4/1250 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2017/07/12/jimmunol.160094 Material 1.DCSupplemental http://www.jimmunol.org/ References This article cites 88 articles, 40 of which you can access for free at: http://www.jimmunol.org/content/199/4/1250.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 23, 2021 • 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 Author Choice Freely available online through The Journal of Immunology Author Choice option 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 © 2017 The Authors All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Prdm1 Regulates Thymic Epithelial Function To Prevent Autoimmunity Natalie A. Roberts,*,† Brian D. Adams,‡,x Nicholas I. McCarthy,{ Reuben M. Tooze,‖ Sonia M. Parnell,{ Graham Anderson,{ Susan M. Kaech,# and Valerie Horsley*,** Autoimmunity is largely prevented by medullary thymic epithelial cells (TECs) through their expression and presentation of tissue- specific Ags to developing thymocytes, resulting in deletion of self-reactive T cells and supporting regulatory T cell development. The transcription factor Prdm1 has been implicated in autoimmune diseases in humans through genome-wide association studies and in mice using cell type–specific deletion of Prdm1 in T and dendritic cells. In this article, we demonstrate that Prdm1 functions in TECs to prevent autoimmunity in mice. Prdm1 is expressed by a subset of mouse TECs, and conditional deletion of Prdm1 in either Keratin 14– or Foxn1-expressing cells in mice resulted in multisymptom autoimmune pathology. Notably, the development of Foxp3+ regulatory T cells occurs normally in the absence of Blimp1. Importantly, nude mice developed anti-nuclear Abs when Downloaded from transplanted with Prdm1 null TECs, but not wild-type TECs, indicating that Prdm1 functions in TECs to regulate autoantibody production. We show that Prdm1 acts independently of Aire, a crucial transcription factor implicated in medullary TEC function. Collectively, our data highlight a previously unrecognized role for Prdm1 in regulating thymic epithelial function. The Journal of Immunology, 2017, 199: 1250–1260. he thymus is essential for the prevention of autoimmunity transcription factor autoimmune regulator (Aire) is central to TSA http://www.jimmunol.org/ through the induction of T cell tolerance and the gener- expression (5). Aire can bind to the repressive MBD1-ATF7ip T ation of FoxP3+ regulatory T cells (Tregs). Thymocytes complex, which methylates CpG dinucleotides to target specific expressing a functional TCR are positively selected by interacting TSA genomic loci. Aire also recruits proteins that promote tran- with cortical thymic epithelial cells (TECs) (cTECs), after which scriptional elongation and pre-mRNA processing (6). However, they migrate and interact with tissue-specific Ags (TSAs) pre- additional molecular players that alter the epigenetic landscape to sented on medullary TECs (mTECs) and dendritic cells. Recog- enable the full function of Aire have yet to be fully elucidated. nition of TSAs results in negative selection, whereby autoreactive Furthermore, whereas Aire ensures that self-antigens are expressed T cells are eliminated (1–4). Although little is known about the within the thymus in mTECs (5, 7), several Aire-independent self- precise mechanisms that control TSA expression in TECs, the antigens are expressed within the thymus (8, 9), and each self- by guest on September 23, 2021 antigen is expressed by a low percentage of mTECs, (1) suggesting that multiple mechanisms exist to regulate mTEC function. *Department of Molecular, Cellular and Developmental Biology, Yale University, Prdm1 (Blimp1) is a transcription factor that controls gene New Haven, CT 06520; †The Francis Crick Institute, London NW1 1AT, United Kingdom; ‡The RNA Institute, University at Albany, State University of New York, expression and chromatin structure in several embryonic and adult Albany, NY 12222; xInvestigative Medicine Program, Yale University School of tissues. Prdm1 acts as a transcriptional repressor by binding to { Medicine, New Haven, CT 06520; School of Immunity and Infection, Medical DNA through its proline-rich zinc finger domain and recruiting Research Council Centre for Immune Regulation, University of Birmingham, Bir- mingham B15 2TT, United Kingdom; ‖Section of Experimental Haematology, Leeds transcriptional cofactors such as hGroucho, histone deacetylases Institute of Molecular Medicine, University of Leeds, Leeds LS2 9JT, United (HDACs), and histone methyltransferases (10–14). In differenti- # Kingdom; Department of Immunobiology, Yale University, New Haven, CT 06520; ating plasma cells, Prdm1 represses genes involved in B cell and **Department of Dermatology, Yale University, New Haven, CT 06520 maturation and proliferation (15, 16), mediating terminal differ- ORCIDs: 0000-0001-9113-6306 (N.A.R.); 0000-0001-8372-2970 (B.D.A.); 0000- 0003-2915-7119 (R.M.T.); 0000-0002-2917-4085 (G.A.). entiation (15, 17, 18). Prdm1 also controls gene expression pat- Received for publication June 3, 2016. Accepted for publication June 10, 2017. terns in many lymphocytes and myeloid cells, including dendritic cells (19), macrophages (20), T cells (21, 22), and NK cells (23). This work was supported by a Pew Scholar in Biomedical Research Award (to V.H.), a Medical Research Council Programme grant (to G.A.), Cancer Research UK Senior Beyond the immune system, Prdm1 has numerous roles in Clinical Fellowship C7845/A10066 (to R.M.T.), National Institutes of Health Grants regulating epithelial development. In the intestinal epithelium, R37AI066232 (to S.M.K.) and AR060295 (to V.H.), the Howard Hughes Med- ical Institute (to S.M.K.), and Connecticut Department of Public Health Grant Prdm1 controls multiple aspects of the neonatal-to-adult transition 12SCBYALE01 (to V.H.). (24, 25), namely terminal differentiation of the skin epidermis (26) Address correspondence and reprint requests to Dr. Valerie Horsley, Department of and sebocyte progenitor cell function (27). Molecular, Cellular and Developmental Biology, Yale University, 219 Prospect Given the similarities between skin and the thymic epithelium Street, Box 208103, New Haven, CT 06520. E-mail address: [email protected] (28–30) and the models used to describe the roles of skin in- The online version of this article contains supplemental material. flammation with age in Prdm1 conditional knockout (KO) (cKO) Abbreviations used in this article: Aire, autoimmune regulator; ANA, anti-nuclear mice (31, 32), we sought to determine whether Prdm1 influences Ab; cKO, conditional KO; cTEC, cortical TEC; E, embryonic day; HDAC, histone deacetylase; K14, keratin-14; KO, knockout; mGFP, membrane-localized GFP; thymic epithelial function. In this study, we identified and mapped MHCII, MHC class II; mTEC, medullary TEC; RT, room temperature; SLE, systemic the expression of Prdm1 to the thymus medulla. In addition, we b b lupus erythematosus; TCR , TCR -chain; TEC, thymic epithelial cell; Treg, regu- have shown that Prdm1 is expressed in TECs and that mice latory T cell; TSA, tissue-specific Ag; WT, wild-type. lacking Prdm1 in either keratin-14 (K14)- or FoxN1-expressing This article is distributed under the terms of the CC BY 4.0 Unported license. epithelial cells generate self-reactive Abs and develop several Copyright Ó 2017 The Authors autoimmune phenotypes. These phenotypes in mice lacking Prdm1 www.jimmunol.org/cgi/doi/10.4049/jimmunol.1600941 The Journal of Immunology 1251 in epithelium are not due to defects in the development of CD4, heat-mediated Ag retrieval was used, with standard streptavidin Avidin- CD8, or Foxp3+ Tregs. In fact, by performing thymus transplan- Biotin Complex immunocytochemistry and 3,39-diaminobenzidine as 3 tation experiments into nude mice, we demonstrated that Prdm1- the chromogen. We obtained 40 magnification using an Olympus BX50 microscope (Olympus, Tokyo, Japan), a Plan Apo 403/0.95 objective lens deficient mTECs are sufficient to induce autoimmunity. Together, (Tokyo, Japan), a Leica DFC-320 digital camera (Leica, Solms, Germany), our findings implicate Prdm1 in the regulation of autoimmunity in and associated Leica IM50 software. TECs and are consistent with the identification of polymorphisms Anti-nuclear Ab staining in Prdm1 associated with autoimmune diseases, such as systemic lupus erythematosus (SLE) (33, 34). A 1:40 dilution of the serum samples isolated from Prdm1fl/fl;K14Cre and Prdm1fl/+;K14Cre mice
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