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Function Foxp3 and Its Effect on Regulatory T Cell Regulation Of Regulation of MHC Class I Expression by Foxp3 and Its Effect on Regulatory T Cell Function This information is current as Jie Mu, Xuguang Tai, Shankar S. Iyer, Jocelyn D. of September 26, 2021. Weissman, Alfred Singer and Dinah S. Singer J Immunol 2014; 192:2892-2903; Prepublished online 12 February 2014; doi: 10.4049/jimmunol.1302847 http://www.jimmunol.org/content/192/6/2892 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2014/02/12/jimmunol.130284 Material 7.DCSupplemental http://www.jimmunol.org/ References This article cites 38 articles, 11 of which you can access for free at: http://www.jimmunol.org/content/192/6/2892.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 26, 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 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 All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Regulation of MHC Class I Expression by Foxp3 and Its Effect on Regulatory T Cell Function Jie Mu,1 Xuguang Tai,1 Shankar S. Iyer,2 Jocelyn D. Weissman, Alfred Singer, and Dinah S. Singer Expression of MHC class I molecules, which provide immune surveillance against intracellular pathogens, is higher on lymphoid cells than on any other cell types. In T cells, this is a result of activation of class I transcription by the T cell enhanceosome consisting of Runx1, CBFb, and LEF1. We now report that MHC class I transcription in T cells also is enhanced by Foxp3, resulting in higher levels of class I in CD4+CD25+ T regulatory cells than in conventional CD4+CD252 T cells. Interestingly, the effect of Foxp3 regulation of MHC class I transcription is cell type specific: Foxp3 increases MHC class I expression in T cells but represses it in epithelial tumor cells. In both cell types, Foxp3 targets the upstream IFN response element and downstream core promoter of the class I gene. Importantly, expression of MHC class I contributes to the function of CD4+CD25+ T regulatory cells by enhancing Downloaded from immune suppression, both in in vitro and in vivo. These findings identify MHC class I genes as direct targets of Foxp3 whose expression augments regulatory T cell function. The Journal of Immunology, 2014, 192: 2892–2903. ajor histocompatibility class I molecules function to which integrates upstream signals targeting distinct transcription provide immune surveillance against intracellular patho- starts in response to tissue-specific or dynamic signals (5, 6). M gens. In the mature immune system, presentation offoreign A variety of DNA-binding transcription factors have been http://www.jimmunol.org/ peptides by class I molecules regulates both innate and adaptive identified that interact either directly or indirectly with tissue- immunity by inhibiting nonspecific NK responses and triggering specific and hormone-specific regulatory elements. For example, specific CTL responses, respectively. During development, MHCclass a B lymphocyte–specific enhanceosome consisting of the coac- I expression on nonhematopoietic thymic epithelial cells is essential tivator CIITA and DNA-bound transcription factors RFX, CREB/ for the maturation and survival of CD8+ T cells. Although originally ATF, and NF-Y leads to high cell surface class I and II expression thought to be passive receptors of intracellularly derived peptides, in B cells (8–11). In T cells, the constitutive high level expression emerging evidence reveals that maintenance of homeostatic levels of class I is not due to CIITA but is established by a T cell en- of MHC class I is critical for a functional immune response (1–4). hanceosome consisting of RUNX1, CBFb, and LEF1 (12). Whether MHC class I molecules are ubiquitously expressed in somatic additional factors in the different T cell subsets superimpose on by guest on September 26, 2021 cells, although at different levels in different cell types, and their the T cell enhanceosome to differentially regulate MHC class I expression is dynamically regulated by hormones and cytokines. expression has not been examined previously. Lymphoid cells express the highest levels of class I, whereas In the present study, we have examined the regulation of MHC neurons express two orders of magnitude less. MHC class I ex- class I expression in T cell subsets. We report that class I levels in pression is controlled transcriptionally by the interaction of tissue- CD4+CD25+ T regulatory cells are consistently higher than in specific transcription factors with cognate DNA sequence elements either conventional CD4+ T effector cells or CD8+ T cells as a result on the extended class I promoter. The DNA sequence elements that of Foxp3-mediated transcriptional activation. Importantly, these mediate class I regulation have been mapped to distinct domains elevated levels of class I contribute to efficient regulatory T cell that mediate tissue-specific and hormone-specific signals (3, 5–7). (Treg) suppressive function. Surprisingly, Foxp3 affects MHC Transcription initiates at multiple sites within the core promoter, class I transcription differently in different cell types as it represses class I transcription in epithelial tumor cells. Thus, these studies show that Foxp3 is an active, context-dependent regulator of MHC Experimental Immunology Branch, Center for Cancer Research, National Cancer class I expression and function. Institute, National Institutes of Health, Bethesda, MD 20892 1J.M. and X.T. contributed equally to this work. Materials and Methods 2Current address: Molecular Biology Institute, University of California, Los Angeles, Animals Los Angeles, CA. 2/2 2/2 2/2 b2-microglobulin (b2m) and b2m RAG2 mice were bred in the Received for publication October 22, 2013. Accepted for publication January 16, National Cancer Institute Center for Cancer Research animal colony. PD1 2014. transgenic mice and Foxp3 transgenic mice (A10 and T3) have been de- This work was supported by the Intramural Research Program of the National In- scribed previously (13, 14). The PD1 dropout transgenic mouse was gen- stitutes of Health, National Cancer Institute, Center for Cancer Research. erated in the National Cancer Institute core facility by microinjection of 2 Address correspondence and reprint requests to Dr. Dinah S. Singer, Experimental a genomic clone of PD1 from which 50 to +3 bp of promoter sequences Immunology Branch, National Cancer Institute, National Institutes of Health, Build- were deleted. B6 (CD45.2) mice were purchased from The Jackson Labo- ing 10, Room 4B-36, Bethesda, MD 20892. E-mail address: [email protected] ratory (Bar Harbor, ME), and B6 (CD45.1) mice were obtained from the The online version of this article contains supplemental material. Frederick Cancer Research Center (Frederick, MD). All mice were cared for in accordance with National Institutes of Health guidelines. Abbreviations used in this article: DP, double-positive; FKH, forkhead; IBD, inflam- matory bowel disease; IRE, IFN response element; LN, lymph node; LNT, lymph Reagents for flow cytometry and protein immunoblotting node T; b2m, b2-microglobulin; MFI, mean fluorescence intensity; SP, single-posi- tive; TCE, T cell enhanceosome; Tconv, conventional T cell; Treg, regulatory T cell; mAbs with the following specificities were used in this study: CD4 (RM4.5 WT, wild-type. and GK1.5), CD25 (PC61 and 7D4), H-2Kb (AF6-88.5), H-2Db (28-14-8), www.jimmunol.org/cgi/doi/10.4049/jimmunol.1302847 The Journal of Immunology 2893 H-2Kd (SF1-1.1), H-2Dd (34-2-12), CD45.1 (A20), CD45.2 (104), CD45RB irradiated T cell–depleted B6 spleen cells (2000R) as accessory cells (16A), and CD152 (CTLA-4; UC10-4F10-11) were obtained from BD (APCs) and stimulated with anti-CD3 mAb (1 mg/ml) and/or rIL-2 (200 Biosciences (San Diego, CA); PD1 and HLA class I (PT85A with specificity U/ml) for 72 h. For in vitro suppression assays, CD4+CD252 responder for both porcine and human MHC class I, but not mouse MHC class I) T cells (3–5 3 104/well) were cultured with an equal number of CD4+ were obtained from VMRD (Pullman, WA); and Foxp3 (FJK-16s) was CD25+ T cells, APCs, and anti-CD3 mAb (1 mg/ml) for 72 h. Where in- obtained from eBioscience (San Diego, CA). Stained cells were analyzed dicated, cultures were pulsed with [3H]thymidine 8 h prior to harvest. on a BD LSR flow cytometer (Becton Dickinson). Where indicated, fluo- Alternatively, CFSE-labeled CD4+CD252 responder T cells were cocul- rescence was quantified and expressed as mean fluorescence intensity (MFI). turedwithCD4+CD25+ and APCs (which expressed a different CD45 Abs with the following specificities were used for protein immuno- allele from the Tconvs) and stimulated with anti-CD3 (1 mg/ml) for 72 h. blotting: FLAG from Sigma-Aldrich (St. Louis, MO), and heat shock At the end of culture, CFSE fluorescence of the responder T cells was protein 60 from Santa Cruz Biotechnology (Santa Cruz, CA). Total cell determined. lysates from transfected HeLa or Jurkat cells were resolved by SDS-PAGE followed by blotting. T cell reconstitution and in vivo induction of inflammatory bowl disease Cells lines and cultivation b2m2/2RAG22/2 mice were injected i.v. with 4 3 105 purified CD4+ HeLa epithelial cells were grown in DMEM supplemented with 10% FBS, CD45RBhi T cells either alone or in combination with 4 3 105 CD4+ 2mML-glutamine, 20 mM HEPES (pH 7.2), and gentamicin sulfate (10 ng/ CD25+ T cells from the indicated sources.
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