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Development of Thymic Regulatory T Lymphocytes

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Thymus Transcriptome and Cell Biology

Abstract

A healthy immune system should maintain a balance between the ability to respond to infectious agents and tumor cells at the same time that sustains self-tolerance. For this purpose, the immune system must be capable of restraining foreign antigens, stopping the immune response after the resolution of a problem and blocking autoreactivity of immune cells that have escaped negative selection. For the maintenance of homeostasis and peripheral tolerance, a group of T lymphocytes named regulatory T (Treg) cells is produced from the CD4+ T cells in the thymus or in the periphery, where they have the ability to control the immune response. This chapter reviews the development of Treg cells within the thymus, detailing their markers and involved factors, including Foxp3 and other recently discovered transcription factors, as well as some noncoding RNAs. We ultimately discuss disorders associated with Treg cell deficiency and the modulation of thymic Treg cells to treat diseases.

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References

  • Abbas AK, Benoist C, Bluestone JA, Campbell DJ, Ghosh S, Hori S et al (2013) Regulatory T cells: recommendations to simplify the nomenclature. Nat Immunol 14(4):307–308. https://doi.org/10.1038/ni.2554

    Article  CAS  PubMed  Google Scholar 

  • Adriani M, Aoki J, Horai R, Thornton AM, Konno A, Kirby M et al (2007) Impaired in vitro regulatory T cell function associated with Wiskott-Aldrich syndrome. Clin Immunol 124(1):41–48

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Adriani M, Jones KA, Uchiyama T, Kirby MR, Silvin C, Anderson SM et al (2011) Defective inhibition of B-cell proliferation by Wiskott-Aldrich syndrome protein-deficient regulatory T cells. Blood 117(24):6608–6611

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Aiuti A, Biasco L, Scaramuzza S, Ferrua F, Cicalese MP, Baricordi C et al (2013) Lentivirus-based gene therapy of hematopoietic stem cells in Wiskott-Aldrich Syndrome. Science 341(6148):1233151

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Akimova T, Beier UH, Wang L, Levine MH, Hancock WW (2011) Helios expression is a marker of T cell activation and proliferation. PLoS One 6(8):e24226

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Aschenbrenner K, D’Cruz LM, Vollmann EH, Hinterberger M, Emmerich J, Swee LK et al (2007) Selection of Foxp3+ regulatory T cells specific for self antigen expressed and presented by Aire+ medullary thymic epithelial cells. Nat Immunol 8(4):351–358

    Article  CAS  PubMed  Google Scholar 

  • Bacchetta R, Passerini L, Gambineri E, Dai M, Allan SE, Lawitschka A et al (2006) Defective regulatory and effector T cell functions in patients with FOXP3 mutations. J Clin Invest 116(6):1713–1722

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bacchetta R, Barzaghi F, Roncarolo MG (2018) From IPEX syndrome to FOXP3 mutation: a lesson on immune dysregulation. Ann N Y Acad Sci 1417(1):5–22

    Article  CAS  PubMed  Google Scholar 

  • Barzaghi F, Amaya Hernandez LC, Neven B, Ricci S, Kucuk ZY, Bleesing JJ et al (2018) Long-term follow-up of IPEX syndrome patients after different therapeutic strategies: an international multicenter retrospective study. J Allergy Clin Immunol 141(3):1036–1049.e5

    Article  PubMed  Google Scholar 

  • Belkaid Y, Piccirillo CA, Mendez S (2002) CD4+ CD25+ regulatory T cells control Leishmania major persistence and immunity. Nature 420(September):633–637

    Google Scholar 

  • Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L et al (2001) The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 27(1):20–21

    Article  CAS  PubMed  Google Scholar 

  • Bluestone JA, Buckner JH, Fitch M, Gitelman SE, Gupta S, Hellerstein MK et al (2015) Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci Transl Med 7(315):315ra189. http://stm.sciencemag.org/cgi/doi/10.1126/scitranslmed.aad4134

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Brunstein CG, Miller JS, Cao Q, Mckenna DH, Hippen KL, Curtsinger J et al (2013) Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics. Blood 117(3):1061–1070

    Article  CAS  Google Scholar 

  • Buchbinder D, Nugent DJ, Fillipovich AH (2014) Wiskott-Aldrich syndrome: diagnosis, current management, and emerging treatments. Appl Clin Genet 7:55–66. http://www.ncbi.nlm.nih.gov/pubmed/24817816

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Buhlmann JE, Elkin SK, Sharpe AH (2003) A role for the B7-1/B7-2:CD28/CTLA-4 pathway during negative selection. J Immunol 170(11):5421–5428

    Article  CAS  PubMed  Google Scholar 

  • Burchill MA, Yang J, Vogtenhuber C, Blazar BR, Farrar MA (2007) IL-2 receptor beta-dependent STAT5 activation is required for the development of Foxp3+ regulatory T cells. J Immunol 178(1):280–290. http://www.ncbi.nlm.nih.gov/pubmed/17182565. http://www.jimmunol.org/content/178/1/280.full.pdf

    Article  CAS  PubMed  Google Scholar 

  • Burchill MA, Yang J, Vang KB, Moon JJ, Chu HH, Lio C-WJ et al (2008) Linked T cell receptor and cytokine signaling govern the development of the regulatory T cell repertoire. Immunity 28(1):112–121. http://www.sciencedirect.com/science/article/pii/S1074761307005870

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carpenter AC, Wohlfert E, Chopp LB, Vacchio MS, Nie J, Zhao Y et al (2017) Control of regulatory T cell differentiation by the transcription factors Thpok and LRF. J Immunol 199(5):1716–1728

    Article  CAS  PubMed  Google Scholar 

  • Chandran S, Tang Q, Sarwal M, Laszik ZG, Putnam AL, Lee K et al (2017) Polyclonal regulatory T cell therapy for control of inflammation in kidney transplants. Am J Transplant 17(11):2945–2954

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chatila TA, Blaeser F, Ho N, Lederman HM, Voulgaropoulos C, Helms C et al (2000) JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome. J Clin Invest 106(12):75–81

    Article  Google Scholar 

  • Ciofani M, Zúñiga-Pflücker JC (2007) The thymus as an inductive site for T lymphopoiesis. Annu Rev Cell Dev Biol 23:463–493. http://www.ncbi.nlm.nih.gov/pubmed/17506693

    Article  CAS  PubMed  Google Scholar 

  • Cobb BS, Hertweck A, Smith J, O’Connor E, Graf D, Cook T et al (2006) A role for Dicer in immune regulation. J Exp Med 203(11):2519–2527

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dijke IE, Hoeppli RE, Ellis T, Pearcey J, Huang Q, McMurchy AN et al (2016) Discarded human thymus is a novel source of stable and long-lived therapeutic regulatory T cells. Am J Transplant 16(1):58–71

    Article  CAS  PubMed  Google Scholar 

  • Dudley EC, Petrie HT, Shah LM, Owen MJ, Hayday AC (1994) T cell receptor beta chain gene rearrangement and selection during thymocyte development in adult mice. Immunity 1(2):83–93

    Article  CAS  PubMed  Google Scholar 

  • Dupuis-Girod S, Medioni J, Haddad E, Quartier P, Cavazzana-Calvo M, Le Deist F et al (2003) Autoimmunity in Wiskott-Aldrich syndrome: risk factors, clinical features, and outcome in a single-center cohort of 55 patients. Pediatrics 111(5 Pt 1):e622–e627

    Article  PubMed  Google Scholar 

  • Fontenot JD, Gavin MA, Rudensky AY (2003) Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 4(4):330–336

    Article  CAS  PubMed  Google Scholar 

  • Furtado GC, Curotto de Lafaille MA, Kutchukhidze N, Lafaille JJ (2002) Interleukin 2 signaling is required for CD4(+) regulatory T cell function. J Exp Med 196(6):851–857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gershon RK, Kondo K (1970) Cell interactions in the induction of tolerance: the role of thymic lymphocytes. Immunology 18(5):723–737

    CAS  PubMed  PubMed Central  Google Scholar 

  • Getnet D, Grosso J, Goldberg M, Harris T, Yen H, Bruno T et al (2010) A role for the transcription factor Helios in human CD4+CD25+ regulatory T cells. Mol Immunol 47(7–18):1595–1600

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gliwiński M, Iwaszkiewicz-Grześ D, Trzonkowski P (2017) Cell-based therapies with T regulatory cells. BioDrugs 31(4):335–347

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Godfrey VL, Wilkinson JE, Russell LB (1991) X-linked lymphoreticular disease in the scurfy (sf) mutant mouse. Am J Pathol 138(6):1379–1387. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1886400&tool=pmcentrez&rendertype=abstract

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hacein-Bey Abina S, Gaspar HB, Blondeau J, Caccavelli L, Charrier S, Buckland K et al (2015) Outcome following gene therapy in patients with severe Wiskott-Aldrich syndrome. HHS Public Access 33(4):395–401

    Google Scholar 

  • Hadaschik EN, Wei X, Leiss H, Heckmann B, Niederreiter B, Steiner G et al (2015) Regulatory T cell-deficient scurfy mice develop systemic autoimmune features resembling lupus-like disease. Arthritis Res Ther 17(1):1–12

    Article  CAS  Google Scholar 

  • Haljasorg U, Dooley J, Laan M, Kisand K, Bichele R, Liston A et al (2017) Irf4 expression in thymic epithelium is critical for thymic regulatory T cell homeostasis. J Immunol 198(5):1952–1960

    Article  CAS  PubMed  Google Scholar 

  • Hall BYBM, Pearce NW, Gurley KAYE, Dorschi SE (1990) Specific unresponsiveness in rats with prolonged cardiac allograft survival after treatment with cyclosporine. J Exp Med 171:141–157

    Article  CAS  PubMed  Google Scholar 

  • Hinterberger M, Aichinger M, da Costa OP, Voehringer D, Hoffmann R, Klein L (2010) Autonomous role of medullary thymic epithelial cells in central CD4(+) T cell tolerance. Nat Immunol 11(6):512–519. https://doi.org/10.1038/ni.1874

    Article  CAS  PubMed  Google Scholar 

  • Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299(5609):1057–1061

    Article  CAS  PubMed  Google Scholar 

  • Humblet-baron S, Sather B, Anover S, Becker-herman S, Kasprowicz DJ, Khim S et al (2007) Wiskott-Aldrich syndrome protein is required for regulatory T cell homeostasis. J Clin Invest 117(2):407–418

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Iizuka-Koga M, Nakatsukasa H, Ito M, Akanuma T, Lu Q, Yoshimura A (2017) Induction and maintenance of regulatory T cells by transcription factors and epigenetic modifications. J Autoimmun 83:113–121

    Article  CAS  PubMed  Google Scholar 

  • Josefowicz SZ, Lu L-F, Rudensky AY (2012) Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol 30(1):531–564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kanamaru F, Youngnak P, Hashiguchi M, Nishioka T, Takahashi T, Sakaguchi S et al (2004) Costimulation via glucocorticoid-induced TNF receptor in both conventional and CD25+ regulatory CD4+ T cells. J Immunol 172(12):7306–7314. http://www.jimmunol.org/cgi/doi/10.4049/jimmunol.172.12.7306

    Article  CAS  PubMed  Google Scholar 

  • Khattri R, Cox T, Yasayko S-A, Ramsdell F (2003) An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol 4(4):337–342

    Article  CAS  PubMed  Google Scholar 

  • Kitagawa Y, Ohkura N, Sakaguchi S (2015) Epigenetic control of thymic Treg-cell development. Eur J Immunol 45(1):11–16. http://doi.wiley.com/10.1002/eji.201444577

    Article  CAS  PubMed  Google Scholar 

  • Kitagawa Y, Ohkura N, Kidani Y, Vandenbon A, Hirota K, Kawakami R et al (2017) Guidance of regulatory T cell development by Satb1-dependent super-enhancer establishment. Nat Immunol 18(2):173–183

    Article  CAS  PubMed  Google Scholar 

  • Kumar P, Marinelarena A, Raghunathan D, Ragothaman VK, Saini S, Bhattacharya P et al (2018) Critical role of OX40 signaling in the TCR-independent phase of human and murine thymic Treg generation. Cell Mol Immunol. https://doi.org/10.1038/cmi.2018.8

    Article  Google Scholar 

  • Lee W, Lee GR (2018) Transcriptional regulation and development of regulatory T cells. Exp Mol Med 50(3):e456

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Leventhal J, Abecassis M, Miller J, Gallon L, Ravindra K, Tollerud DJ et al (2012) Chimerism and tolerance without GVHD or engraftment syndrome in HLA-mismatched combined kidney and hematopoietic stem cell transplantation. Sci Transl Med 4(124):124ra28

    Article  PubMed  PubMed Central  Google Scholar 

  • Leventhal DS, Gilmore DC, Berger JM, Nishi S, Lee V, Kline DE et al (2016) Dendritic cells coordinate the development and homeostasis of organ-specific regulatory T cells. Immunity 44(4):847–859

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li QJ, Chau J, Ebert PJR, Sylvester G, Min H, Liu G et al (2007) miR-181a is an intrinsic modulator of T cell sensitivity and selection. Cell 129(1):147–161

    Article  CAS  PubMed  Google Scholar 

  • Lin W, Haribhai D, Relland LM, Truong N, Carlson MR, Williams CB et al (2007) Regulatory T cell development in the absence of functional Foxp3. Nat Immunol 8(4):359–368

    Article  CAS  PubMed  Google Scholar 

  • Liu Y, Zhang P, Li J, Kulkarni AB, Perruche S, Chen W (2008) A critical function for TGF-beta signaling in the development of natural CD4+CD25+Foxp3+ regulatory T cells. Nat Immunol 9(6):632–640

    Article  CAS  PubMed  Google Scholar 

  • Lu LF, Thai TH, Calado DP, Chaudhry A, Kubo M, Tanaka K et al (2009) Foxp3-dependent microRNA155 confers competitive fitness to regulatory T cells by targeting SOCS1 protein. Immunity 30(1):80–91

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lu F-T, Yang W, Wang Y-H, Ma H-D, Tang W, Yang J-B et al (2015) Thymic B cells promote thymus-derived regulatory T cell development and proliferation. J Autoimmun 61:62–72. http://linkinghub.elsevier.com/retrieve/pii/S0896841115000797

    Article  CAS  PubMed  Google Scholar 

  • Luu M, Jenike E, Vachharajani N, Visekruna A (2017) Transcription factor c-Rel is indispensable for generation of thymic but not of peripheral Foxp3+ regulatory T cells. Oncotarget 8(32):52678–52689

    Article  PubMed  PubMed Central  Google Scholar 

  • Mahmud SA, Manlove LS, Schmitz HM, Xing Y, Wang Y, Owen DL et al (2014) Costimulation via the tumor-necrosis factor receptor superfamily couples TCR signal strength to the thymic differentiation of regulatory T cells. Nat Immunol 15(5):473–481. http://www.ncbi.nlm.nih.gov/pubmed/24633226

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maillard MH, Cotta-de-Almeida V, Takeshima F, Nguyen DD, Michetti P, Nagler C et al (2007) The Wiskott-Aldrich syndrome protein is required for the function of CD4(+)CD25(+)Foxp3(+) regulatory T cells. J Exp Med 204(2):381–391. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2118715&tool=pmcentrez&rendertype=abstract

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Marangoni F, Trifari S, Scaramuzza S, Panaroni C, Martino S, Notarangelo LD et al (2007) WASP regulates suppressor activity of human and murine CD4(+)CD25(+)FOXP3(+) natural regulatory T cells. J Exp Med 204(2):369–380

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Marson A, Kretschmer K, Frampton GM, Jacobsen ES, Polansky JK, MacIsaac KD et al (2007) Foxp3 occupancy and regulation of key target genes during T-cell stimulation. Nature 445(7130):931–935

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Massaad MJ, Ramesh N, Geha RS (2013) Wiskott-Aldrich syndrome: a comprehensive review. Ann N Y Acad Sci 1285(1):26–43

    Article  CAS  PubMed  Google Scholar 

  • Mathew JM, H-Voss J, LeFever A, Konieczna I, Stratton C, He J et al (2018) A phase I clinical trial with ex vivo expanded recipient regulatory T cells in living donor kidney transplants. Sci Rep 8(1):1–12

    Article  CAS  Google Scholar 

  • Miyara M, Yoshioka Y, Kitoh A, Shima T, Wing K, Niwa A et al (2009) Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 30(6):899–911. https://doi.org/10.1016/j.immuni.2009.03.019

    Article  CAS  PubMed  Google Scholar 

  • Morris GP, Allen PM (2012) How the TCR balances sensitivity and specificity for the recognition of self and pathogens. Nat Immunol 13(2):121–128

    Article  CAS  PubMed  Google Scholar 

  • Morris EC, Fox T, Chakraverty R, Tendeiro R, Snell K, Rivat C et al (2017) Gene therapy for Wiskott-Aldrich syndrome in a severely affected adult. Blood 130(11):1327–1335

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nishizuka Y, Sakakura T (1969) Thymus and reproduction: sex-linked dysgenesia of the Gonad after neonatal thymectomy in mice. Science 166:753–755

    Article  CAS  PubMed  Google Scholar 

  • Notarangelo L, Miao C, Ochs H (2008) Wiskott-Aldrich syndrome - UpToDate. Curr Opin Hematol 15:30–36. https://www.uptodate.com/contents/wiskott-aldrich-syndrome

    Article  CAS  PubMed  Google Scholar 

  • Ochs HD, Ziegler SF, Torgerson TR (2005) FOXP3 acts as a rheostat of the immune response. Immunol Rev 203:156–164

    Article  CAS  PubMed  Google Scholar 

  • Ochs HD, Gambineri E, Torgerson TR (2007) IPEX, FOXP3 and regulatory T-cells: a model for autoimmunity. Immunol Res 38(1–3):112–121

    Article  CAS  PubMed  Google Scholar 

  • Oh J, Wang W, Thomas R, Su DM (2017) Capacity of tTreg generation is not impaired in the atrophied thymus. PLoS Biol 15(11):1–22

    Article  CAS  Google Scholar 

  • Ohkura N, Kitagawa Y, Sakaguchi S (2013) Development and maintenance of regulatory T cells. Immunity 38(3):414–423. http://www.ncbi.nlm.nih.gov/pubmed/23521883

    Article  CAS  PubMed  Google Scholar 

  • Ouyang W, Beckett O, Ma Q, Li MO (2010) Transforming growth factor-beta signaling curbs thymic negative selection promoting regulatory T cell development. Immunity 32(5):642–653. https://doi.org/10.1016/j.immuni.2010.04.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Passos GA, Mendes-da-Cruz DA, Oliveira EH (2015) The thymic orchestration involving Aire, miRNAs, and cell–cell interactions during the induction of central tolerance. Front Immunol 6(July):1–7. http://journal.frontiersin.org/Article/10.3389/fimmu.2015.00352/abstract

    CAS  Google Scholar 

  • Perry JSA, Lio CJ, Kau AL, Nutsch K, Yang Z, Gordon JI et al (2014) Distinct contributions of Aire and antigen-presenting-cell subsets to the generation of self-tolerance in the thymus. Immunity 41(3):414–426. https://doi.org/10.1016/j.immuni.2014.08.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Perry JSA, Russler-Germain EV, Zhou YW, Purtha W, Cooper ML, Choi J et al (2018) CD36 mediates cell-surface antigens to promote thymic development of the regulatory T cell receptor repertoire and allo-tolerance. Immunity 48(5):923–936.e4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Petrie HT, Zúñiga-Pflücker JC (2007) Zoned out: functional mapping of stromal signaling microenvironments in the thymus. Annu Rev Immunol 25:649–679. http://www.ncbi.nlm.nih.gov/pubmed/17291187

    Article  CAS  PubMed  Google Scholar 

  • Petrie HT, Livak F, Schatz DG, Strasser A, Crispe IN, Shortman K (1993) Multiple rearrangements in T cell receptor alpha chain genes maximize the production of useful thymocytes. J Exp Med 178(2):615–622

    Article  CAS  PubMed  Google Scholar 

  • Proietto AI, van Dommelen S, Zhou P, Rizzitelli A, D’Amico A, Steptoe RJ et al (2008) Dendritic cells in the thymus contribute to T-regulatory cell induction. Proc Natl Acad Sci U S A 105(50):19869–19874

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Redecke V, Chaturvedi V, Kuriakose J, Häcker H (2016) SHARPIN controls the development of regulatory T cells. Immunology 148(2):216–226

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Richards DM, Delacher M, Goldfarb Y, Kägebein D, Hofer A-C, Abramson J et al (2015) Treg cell differentiation: from thymus to peripheral tissue. Prog Mol Biol Transl Sci 136:175–205. http://linkinghub.elsevier.com/retrieve/pii/S1877117315001465

    Article  CAS  PubMed  Google Scholar 

  • Roncarolo MG, Battaglia M (2007) Regulatory T-cell immunotherapy for tolerance to self antigens and alloantigens in humans. Nat Rev Immunol 7(8):585–598

    Article  CAS  PubMed  Google Scholar 

  • Ross SH, Cantrell DA (2018) Signaling and function of interleukin-2 in T lymphocytes. Annu Rev Immunol 36:411–433

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sakaguchi S (2005) Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol 6(4):345–352

    Article  CAS  PubMed  Google Scholar 

  • Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M (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(3):1151–1164

    CAS  PubMed  Google Scholar 

  • Salomon B, Lenschow DJ, Rhee L, Ashourian N, Singh B, Sharpe A et al (2000) B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity 12(4):431–440

    Article  CAS  PubMed  Google Scholar 

  • Savino W, Dardenne M (2010) Nutritional imbalances and infections affect the thymus: consequences on T-cell-mediated immune responses. Proc Nutr Soc 69(4):636–643. http://www.ncbi.nlm.nih.gov/pubmed/20860857

    Article  CAS  PubMed  Google Scholar 

  • Shimizu J, Yamazaki S, Takahashi T, Ishida Y, Sakaguchi S (2002) Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance. Nat Immunol 3(2):135–142

    Article  CAS  PubMed  Google Scholar 

  • Singer A, Adoro S, Park J (2009) Lineage fate and intense debate: myths, models and mechanisms of CD4/CD8 lineage choice. Nat Rev Immunol 8(10):788–801

    Article  CAS  Google Scholar 

  • Snapper SB, Rosen FS, Mizoguchi E, Cohen P, Khan W, Liu CH et al (1998) Wiskott-Aldrich syndrome protein-deficient mice reveal a role for WASP in T but not B cell activation. Immunity 9:81–91

    Article  CAS  PubMed  Google Scholar 

  • Snow JW, Abraham N, Ma MC, Herndier BG, Pastuszak AW, Goldsmith MA (2003) Loss of tolerance and autoimmunity affecting multiple organs in STAT5A/5B-deficient mice. J Immunol 171(10):5042–5050

    Article  CAS  PubMed  Google Scholar 

  • So T, Seung-Woo L, Croft M (2008) Immune regulation and control of regulatory T cells by OX40 and 41BB. Cytokine Growth Factor Rev 19:253–262

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Soper DM, Kasprowicz DJ, Ziegler SF (2007) IL-2R?? links IL-2R signaling with Foxp3 expression. Eur J Immunol 37(7):1817–1826

    Article  CAS  PubMed  Google Scholar 

  • Sugimoto N, Oida T, Hirota K, Nakamura K, Nomura T, Uchiyama T et al (2006) Foxp3-dependent and -independent molecules specific for CD25+CD4+ natural regulatory T cells revealed by DNA microarray analysis. Int Immunol 18(8):1197–1209

    Article  CAS  PubMed  Google Scholar 

  • Sullivan KE, Mullen CA, Blaese RM, Winkelstein JA (1994) A multiinstitutional survey of the Wiskott-Aldrich syndrome. J Pediatr 125(6 Pt 1):876–885

    Article  CAS  PubMed  Google Scholar 

  • Surh CD, Sprent J (1994) T-cell apoptosis detected in situ during positive and negative selection in the thymus. Nature 372(6501):100–103

    Article  CAS  PubMed  Google Scholar 

  • Symons M, Derry JMJ, Karlak B, Jiang S, Lemahieu V, McCormick F et al (1996) Wiskott-Aldrich syndrome protein, a novel effector for the GTPase CDC42Hs, is implicated in actin polymerization. Cell 84(5):723–734

    Article  CAS  PubMed  Google Scholar 

  • Tai X, Cowan M, Feigenbaum L, Singer A (2005) CD28 costimulation of developing thymocytes induces Foxp3 expression and regulatory T cell differentiation independently of interleukin 2. Nat Immunol 6(2):152–162

    Article  CAS  PubMed  Google Scholar 

  • Takahashi T, Tagami T, Yamazaki S, Uede T, Shimizu J, Sakaguchi N et al (2000) Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med 192(2):303–310

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Teh CE, Lalaoui N, Jain R, Policheni AN, Heinlein M, Alvarez-Diaz S et al (2016) Linear ubiquitin chain assembly complex coordinates late thymic T-cell differentiation and regulatory T-cell homeostasis. Nat Commun 7:13353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thornton AM, Shevach EM (1998) CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J Exp Med 188(2):287–296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thornton AM, Donovan EE, Piccirillo CA, Shevach EM (2004) Cutting edge: IL-2 is critically required for the in vitro activation of CD4+CD25+ T cell suppressor function. J Immunol 172(11):6519–6523

    Article  CAS  PubMed  Google Scholar 

  • Thornton AM, Korty PE, Tran DQ, Wohlfert EA, Murray PE, Belkaid Y et al (2010) Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally Induced Foxp3+ T regulatory cells. J Immunol 184(7):3433–3441. http://www.jimmunol.org/cgi/doi/10.4049/jimmunol.0904028

    Article  CAS  PubMed  Google Scholar 

  • Todo S, Yamashita K, Goto R, Zaitsu M, Nagatsu A, Oura T et al (2016) A pilot study of operational tolerance with a regulatory T-cell-based cell therapy in living donor liver transplantation. Hepatology 64(2):632–643

    Article  CAS  PubMed  Google Scholar 

  • Trzonkowski P, Bieniaszewska M, Juścińska J, Dobyszuk A, Krzystyniak A, Marek N et al (2009) First-in-man clinical results of the treatment of patients with graft versus host disease with human ex vivo expanded CD4+CD25+CD127- T regulatory cells. Clin Immunol 133(1):22–26

    Article  CAS  PubMed  Google Scholar 

  • Van Der Vliet HJJ, Nieuwenhuis EE (2007) IPEX as a result of mutations in FOXP3. Clin Dev Immunol 2007:3–7

    Google Scholar 

  • Verhagen J, Wraith D (2010) Comment on “Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells”. J Immunol 184:3433–3441

    Article  Google Scholar 

  • Westerberg L, Larsson M, Hardy SJ, Fernández C, Thrasher AJ, Ferna C (2005) Wiskott-Aldrich syndrome protein deficiency leads to reduced B-cell adhesion, migration, and homing, and a delayed humoral immune response. Immunobiology 105(3):1144–1152

    CAS  Google Scholar 

  • Wildin RS, Ramsdell F, Peake J, Faravelli F, Casanova JL, Buist N et al (2001) X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet 27(1):18–20

    Article  CAS  PubMed  Google Scholar 

  • Wildin RS, Smyk-Pearson S, Filipovich AH (2002) Clinical and molecular features of the immunodysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome. J Med Genet 39(8):537–545. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1735203&tool=pmcentrez&rendertype=abstract

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xing Y, Hogquist KA (2012) T-Cell tolerance: central and peripheral. Cold Spring Harb Perspect Biol 4:1–15

    Article  CAS  Google Scholar 

  • Xu L, Kitani A, Stuelten C, McGrady G, Fuss I, Strober W (2010) Positive and negative transcriptional regulation of the Foxp3 gene is mediated by access and binding of the Smad3 protein to enhancer I. Immunity 33(3):313–325. https://doi.org/10.1016/j.immuni.2010.09.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zemmour D, Pratama A, Loughhead SM, Mathis D, Benoist C (2017) Flicr, a long noncoding RNA, modulates Foxp3 expression and autoimmunity. Proc Natl Acad Sci U S A 114(17):E3472–E3480

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang Q, Cui F, Fang L, Hong J, Zheng B, Zhang JZ (2013) TNF-alpha impairs differentiation and function of TGF-beta-induced Treg cells in autoimmune diseases through Akt and Smad3 signaling pathway. J Mol Cell Biol 5:85–98. http://www.ncbi.nlm.nih.gov/pubmed/23243069

    Article  CAS  PubMed  Google Scholar 

  • Zheng SG, Wang JH, Stohl W, Kim KS, Gray JD, Horwitz DA (2006) TGF-beta requires CTLA-4 early after T cell activation to induce FoxP3 and generate adaptive CD4+CD25+ regulatory cells. J Immunol 176(6):3321–3329

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was financially supported by the Oswaldo Cruz Institute/Fiocruz, the Brazilian National Institute of Science and Technology on Neuroimmunomodulation/INCT-NIM, MERCOSUL Fund for Structural Convergence/FOCEM, the Brazilian Research Council/CNPq, Estacio de Sá University (Productivity in Research Program) and the Rio de Janeiro State Research Council (FAPERJ).

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Authors and Affiliations

  1. Laboratory on Thymus Research, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil

    Larissa Vasconcelos-Fontes, Rafaella Ferreira-Reis, João Ramalho Ortigão-Farias, Arnon Dias Jurberg & Vinicius Cotta-de-Almeida

  2. Estácio de Sá University (UNESA), Rio de Janeiro, RJ, Brazil

    Vinicius Cotta-de-Almeida

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  1. Larissa Vasconcelos-Fontes
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  2. Rafaella Ferreira-Reis
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  3. João Ramalho Ortigão-Farias
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  4. Arnon Dias Jurberg
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  5. Vinicius Cotta-de-Almeida
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Correspondence to Larissa Vasconcelos-Fontes or Vinicius Cotta-de-Almeida .

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Editors and Affiliations

  1. Laboratory of Genetics and Molecular Biology, Department of Basic and Oral Biology, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil

    Geraldo A. Passos

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Vasconcelos-Fontes, L., Ferreira-Reis, R., Ortigão-Farias, J.R., Jurberg, A.D., Cotta-de-Almeida, V. (2019). Development of Thymic Regulatory T Lymphocytes. In: Passos, G. (eds) Thymus Transcriptome and Cell Biology. Springer, Cham. https://doi.org/10.1007/978-3-030-12040-5_12

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