A distal Foxp3 enhancer enables interleukin-2 dependent thymic Treg cell lineage commitment for robust immune tolerance

Anderson, 2002, Projection of an immunological self shadow within the thymus by the aire protein, Science, 298, 1395, 10.1126/science.1075958 Aschenbrenner, 2007, Selection of Foxp3+ regulatory T cells specific for self antigen expressed and presented by Aire+ medullary thymic epithelial cells, Nat. Immunol., 8, 351, 10.1038/ni1444 Bagadia, 2019, An Nfil3-Zeb2-Id2 pathway imposes Irf8 enhancer switching during cDC1 development, Nat. Immunol., 20, 1174, 10.1038/s41590-019-0449-3 Bending, 2018, A timer for analyzing temporally dynamic changes in transcription during differentiation in vivo, J. Cell Biol., 217, 2931, 10.1083/jcb.201711048 Björses, 1998, Gene defect behind APECED: a new clue to autoimmunity, Hum. Mol. Genet., 7, 1547, 10.1093/hmg/7.10.1547 Blaschke, 2013, Vitamin C induces Tet-dependent DNA demethylation and a blastocyst-like state in ES cells, Nature, 500, 222, 10.1038/nature12362 Bolger, 2014, Trimmomatic: a flexible trimmer for Illumina sequence data, Bioinformatics, 30, 2114, 10.1093/bioinformatics/btu170 Buenrostro, 2013, Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position, Nat. Methods, 10, 1213, 10.1038/nmeth.2688 Buenrostro, 2015, ATAC-seq: A Method for Assaying Chromatin Accessibility Genome-Wide, Curr Protoc Mol Biol, 109, 10.1002/0471142727.mb2129s109 Burchill, 2003, Distinct effects of STAT5 activation on CD4+ and CD8+ T cell homeostasis: development of CD4+CD25+ regulatory T cells versus CD8+ memory T cells, J. Immunol., 171, 5853, 10.4049/jimmunol.171.11.5853 Burchill, 2007, IL-2 receptor beta-dependent STAT5 activation is required for the development of Foxp3+ regulatory T cells, J. Immunol., 178, 280, 10.4049/jimmunol.178.1.280 Burchill, 2008, Linked T cell receptor and cytokine signaling govern the development of the regulatory T cell repertoire, Immunity, 28, 112, 10.1016/j.immuni.2007.11.022 Campbell, 2018, Extrathymically Generated Regulatory T Cells Establish a Niche for Intestinal Border-Dwelling Bacteria and Affect Physiologic Metabolite Balance, Immunity, 48, 1245, 10.1016/j.immuni.2018.04.013 Chaudhry, 2009, CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner, Science, 326, 986, 10.1126/science.1172702 Chen, 2005, How defects in central tolerance impinge on a deficiency in regulatory T cells, Proc. Natl. Acad. Sci. USA, 102, 14735, 10.1073/pnas.0507014102 Chinen, 2016, An essential role for the IL-2 receptor in Treg cell function, Nat. Immunol., 17, 1322, 10.1038/ni.3540 Darce, 2012, An N-terminal mutation of the Foxp3 transcription factor alleviates arthritis but exacerbates diabetes, Immunity, 36, 731, 10.1016/j.immuni.2012.04.007 Dash, 2015, Single-Cell Analysis of T-Cell Receptor αβ Repertoire, Methods Mol. Biol., 1343, 181, 10.1007/978-1-4939-2963-4_15 Dobin, 2013, STAR: ultrafast universal RNA-seq aligner, Bioinformatics, 29, 15, 10.1093/bioinformatics/bts635 Ellmeier, 1998, Multiple developmental stage-specific enhancers regulate CD8 expression in developing thymocytes and in thymus-independent T cells, Immunity, 9, 485, 10.1016/S1074-7613(00)80632-9 Fan, 2018, Differential Roles of IL-2 Signaling in Developing versus Mature Tregs, Cell Rep., 25, 1204, 10.1016/j.celrep.2018.10.002 Feng, 2014, Control of the inheritance of regulatory T cell identity by a cis element in the Foxp3 locus, Cell, 158, 749, 10.1016/j.cell.2014.07.031 Feng, 2015, A mechanism for expansion of regulatory T-cell repertoire and its role in self-tolerance, Nature, 528, 132, 10.1038/nature16141 Fontenot, 2003, Foxp3 programs the development and function of CD4+CD25+ regulatory T cells, Nat. Immunol., 4, 330, 10.1038/ni904 Fontenot, 2005, A function for interleukin 2 in Foxp3-expressing regulatory T cells, Nat. Immunol., 6, 1142, 10.1038/ni1263 Fontenot, 2005, Regulatory T cell lineage specification by the forkhead transcription factor foxp3, Immunity, 22, 329, 10.1016/j.immuni.2005.01.016 Fontenot, 2005, Developmental regulation of Foxp3 expression during ontogeny, J. Exp. Med., 202, 901, 10.1084/jem.20050784 Furtado, 2002, Interleukin 2 signaling is required for CD4(+) regulatory T cell function, J. Exp. Med., 196, 851, 10.1084/jem.20020190 Gaspar, 2020 Gaud, 2018, Regulatory mechanisms in T cell receptor signalling, Nat. Rev. Immunol., 18, 485, 10.1038/s41577-018-0020-8 Gavin, 2007, Foxp3-dependent programme of regulatory T-cell differentiation, Nature, 445, 771, 10.1038/nature05543 Grant, 2011, FIMO: scanning for occurrences of a given motif, Bioinformatics, 27, 1017, 10.1093/bioinformatics/btr064 Guerau-de-Arellano, 2009, Neonatal tolerance revisited: a perinatal window for Aire control of autoimmunity, J. Exp. Med., 206, 1245, 10.1084/jem.20090300 Heinz, 2010, Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities, Mol. Cell, 38, 576, 10.1016/j.molcel.2010.05.004 Hemmers, 2019, IL-2 production by self-reactive CD4 thymocytes scales regulatory T cell generation in the thymus, J. Exp. Med., 216, 2466, 10.1084/jem.20190993 Hernández-Munain, 1999, A developmental switch from TCR delta enhancer to TCR alpha enhancer function during thymocyte maturation, Immunity, 10, 723, 10.1016/S1074-7613(00)80071-0 Herppich, 2019, Dynamic Imprinting of the Treg Cell-Specific Epigenetic Signature in Developing Thymic Regulatory T Cells, Front. Immunol., 10, 2382, 10.3389/fimmu.2019.02382 Hori, 2003, Control of regulatory T cell development by the transcription factor Foxp3, Science, 299, 1057, 10.1126/science.1079490 Josefowicz, 2012, Regulatory T cells: mechanisms of differentiation and function, Annu. Rev. Immunol., 30, 531, 10.1146/annurev.immunol.25.022106.141623 Josefowicz, 2012, Extrathymically generated regulatory T cells control mucosal TH2 inflammation, Nature, 482, 395, 10.1038/nature10772 Kang, 1992, Induction of the POU domain transcription factor Oct-2 during T-cell activation by cognate antigen, Mol. Cell. Biol., 12, 3149 Kawakami, 2021, Distinct Foxp3 enhancer elements coordinate development, maintenance and function of regulatory T cells, Immunity, 54, 10.1016/j.immuni.2021.04.005 Kent, 2002, The human genome browser at UCSC, Genome Res., 12, 996, 10.1101/gr.229102 Kent, 2010, BigWig and BigBed: enabling browsing of large distributed datasets, Bioinformatics, 26, 2204, 10.1093/bioinformatics/btq351 Khattri, 2003, An essential role for Scurfin in CD4+CD25+ T regulatory cells, Nat. Immunol., 4, 337, 10.1038/ni909 Kim, 2007, Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice, Nat. Immunol., 8, 191, 10.1038/ni1428 Kitagawa, 2017, Guidance of regulatory T cell development by Satb1-dependent super-enhancer establishment, Nat. Immunol., 18, 173, 10.1038/ni.3646 Kurachi, 2019, Hidden Caveat of Inducible Cre Recombinase, Immunity, 51, 591, 10.1016/j.immuni.2019.09.010 Lawrence, 2013, Software for computing and annotating genomic ranges, PLoS Comput. Biol., 9, e1003118, 10.1371/journal.pcbi.1003118 Levine, 2017, Suppression of lethal autoimmunity by regulatory T cells with a single TCR specificity, J. Exp. Med., 214, 609, 10.1084/jem.20161318 Li, 2009, The Sequence Alignment/Map format and SAMtools, Bioinformatics, 25, 2078, 10.1093/bioinformatics/btp352 Li, 2014, Function of a Foxp3 cis-element in protecting regulatory T cell identity, Cell, 158, 734, 10.1016/j.cell.2014.07.030 Lin, 2007, Regulatory T cell development in the absence of functional Foxp3, Nat. Immunol., 8, 359, 10.1038/ni1445 Lio, 2008, A two-step process for thymic regulatory T cell development, Immunity, 28, 100, 10.1016/j.immuni.2007.11.021 Liu, 2015, Immune homeostasis enforced by co-localized effector and regulatory T cells, Nature, 528, 225, 10.1038/nature16169 Love, 2014, Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2, Genome Biol., 15, 550, 10.1186/s13059-014-0550-8 Malchow, 2013, Aire-dependent thymic development of tumor-associated regulatory T cells, Science, 339, 1219, 10.1126/science.1233913 Malek, 2002, CD4 regulatory T cells prevent lethal autoimmunity in IL-2Rbeta-deficient mice. Implications for the nonredundant function of IL-2, Immunity, 17, 167, 10.1016/S1074-7613(02)00367-9 Mombaerts, 1992, Mutations in T-cell antigen receptor genes alpha and beta block thymocyte development at different stages, Nature, 360, 225, 10.1038/360225a0 Moore, 2018, ZFP36 RNA-binding proteins restrain T cell activation and anti-viral immunity, eLife, 7, 10.7554/eLife.33057 Nikolouli, 2017, Alloantigen-Induced Regulatory T Cells Generated in Presence of Vitamin C Display Enhanced Stability of Foxp3 Expression and Promote Skin Allograft Acceptance, Front. Immunol., 8, 748, 10.3389/fimmu.2017.00748 Owen, 2018, Identification of Cellular Sources of IL-2 Needed for Regulatory T Cell Development and Homeostasis, J. Immunol., 200, 3926, 10.4049/jimmunol.1800097 Owen, 2019, Thymic regulatory T cells arise via two distinct developmental programs, Nat. Immunol., 20, 195, 10.1038/s41590-018-0289-6 Pacholczyk, 2002, Peptide specificity of thymic selection of CD4+CD25+ T cells, J. Immunol., 168, 613, 10.4049/jimmunol.168.2.613 Panduro, 2016, Tissue Tregs, Annu. Rev. Immunol., 34, 609, 10.1146/annurev-immunol-032712-095948 Perry, 2014, Distinct contributions of Aire and antigen-presenting-cell subsets to the generation of self-tolerance in the thymus, Immunity, 41, 414, 10.1016/j.immuni.2014.08.007 Placek, 2017, MLL4 prepares the enhancer landscape for Foxp3 induction via chromatin looping, Nat. Immunol., 18, 1035, 10.1038/ni.3812 Pollard, 2010, Detection of nonneutral substitution rates on mammalian phylogenies, Genome Res., 20, 110, 10.1101/gr.097857.109 Popmihajlov, 2012, Conditional IL-2 Gene Deletion: Consequences for T Cell Proliferation, Front. Immunol., 3, 102, 10.3389/fimmu.2012.00102 Proekt, 2017, Insights into immune tolerance from AIRE deficiency, Curr. Opin. Immunol., 49, 71, 10.1016/j.coi.2017.10.003 Quinlan, 2010, BEDTools: a flexible suite of utilities for comparing genomic features, Bioinformatics, 26, 841, 10.1093/bioinformatics/btq033 2020 Romagnoli, 2002, Preferential recognition of self antigens despite normal thymic deletion of CD4(+)CD25(+) regulatory T cells, J. Immunol., 168, 1644, 10.4049/jimmunol.168.4.1644 Rubtsov, 2010, Stability of the regulatory T cell lineage in vivo, Science, 329, 1667, 10.1126/science.1191996 Ruzankina, 2007, Deletion of the developmentally essential gene ATR in adult mice leads to age-related phenotypes and stem cell loss, Cell Stem Cell, 1, 113, 10.1016/j.stem.2007.03.002 Sakaguchi, 1995, Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases, J. Immunol., 155, 1151, 10.4049/jimmunol.155.3.1151 Sakaguchi, 2020, Regulatory T Cells and Human Disease, Annu. Rev. Immunol., 38, 541, 10.1146/annurev-immunol-042718-041717 Sasidharan Nair, 2016, Vitamin C Facilitates Demethylation of the Foxp3 Enhancer in a Tet-Dependent Manner, J. Immunol., 196, 2119, 10.4049/jimmunol.1502352 Scherer, 1993, Superantigens: bacterial and viral proteins that manipulate the immune system, Annu. Rev. Cell Biol., 9, 101, 10.1146/annurev.cb.09.110193.000533 Schuster, 2017, c-REL and IκBNS Govern Common and Independent Steps of Regulatory T Cell Development from Novel CD122-Expressing Pre-Precursors, J. Immunol., 199, 920, 10.4049/jimmunol.1600877 Sharan, 2009, Recombineering: a homologous recombination-based method of genetic engineering, Nat. Protoc., 4, 206, 10.1038/nprot.2008.227 Shen, 1985, Cloning of Ly-5 cDNA, Proc. Natl. Acad. Sci. USA, 82, 7360, 10.1073/pnas.82.21.7360 Shugay, 2014, Towards error-free profiling of immune repertoires, Nat. Methods, 11, 653, 10.1038/nmeth.2960 Shugay, 2015, VDJtools: Unifying Post-analysis of T Cell Receptor Repertoires, PLoS Comput. Biol., 11, e1004503, 10.1371/journal.pcbi.1004503 Siepel, 2005, Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes, Genome Res., 15, 1034, 10.1101/gr.3715005 Toomer, 2019, Essential and non-overlapping IL-2Rα-dependent processes for thymic development and peripheral homeostasis of regulatory T cells, Nat. Commun., 10, 1037, 10.1038/s41467-019-08960-1 Waterston, 2002, Initial sequencing and comparative analysis of the mouse genome, Nature, 420, 520, 10.1038/nature01262 Weirauch, 2014, Determination and inference of eukaryotic transcription factor sequence specificity, Cell, 158, 1431, 10.1016/j.cell.2014.08.009 Wickham, 2009 Williams, 2007, Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3, Nat. Immunol., 8, 277, 10.1038/ni1437 Xi, 2009, BSMAP: whole genome bisulfite sequence MAPping program, BMC Bioinformatics, 10, 232, 10.1186/1471-2105-10-232 Yang, 2015, Immune tolerance. Regulatory T cells generated early in life play a distinct role in maintaining self-tolerance, Science, 348, 589, 10.1126/science.aaa7017 Yao, 2007, Nonredundant roles for Stat5a/b in directly regulating Foxp3, Blood, 109, 4368, 10.1182/blood-2006-11-055756 Yin, 2013, Ascorbic acid enhances Tet-mediated 5-methylcytosine oxidation and promotes DNA demethylation in mammals, J. Am. Chem. Soc., 135, 10396, 10.1021/ja4028346 Yue, 2016, Control of Foxp3 stability through modulation of TET activity, J. Exp. Med., 213, 377, 10.1084/jem.20151438 Zemmour, 2017, Flicr, a long noncoding RNA, modulates Foxp3 expression and autoimmunity, Proc. Natl. Acad. Sci. USA, 114, E3472, 10.1073/pnas.1700946114 Zheng, 2010, Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate, Nature, 463, 808, 10.1038/nature08750 Zorn, 2006, IL-2 regulates FOXP3 expression in human CD4+CD25+ regulatory T cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo, Blood, 108, 1571, 10.1182/blood-2006-02-004747