1932

Abstract

Foxp3-expressing CD4+ regulatory T (Treg) cells play key roles in the prevention of autoimmunity and the maintenance of immune homeostasis and represent a major barrier to the induction of robust antitumor immune responses. Thus, a clear understanding of the mechanisms coordinating Treg cell differentiation is crucial for understanding numerous facets of health and disease and for developing approaches to modulate Treg cells for clinical benefit. Here, we discuss current knowledge of the signals that coordinate Treg cell development, the antigen-presenting cell types that direct Treg cell selection, and the nature of endogenous Treg cell ligands, focusing on evidence from studies in mice. We also highlight recent advances in this area and identify key unanswered questions.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-immunol-100219-020937
2020-04-26
2024-10-05
Loading full text...

Full text loading...

/deliver/fulltext/immunol/38/1/annurev-immunol-100219-020937.html?itemId=/content/journals/10.1146/annurev-immunol-100219-020937&mimeType=html&fmt=ahah

Literature Cited

  1. 1. 
    Arpaia N, Green JA, Moltedo B, Arvey A, Hemmers S et al. 2015. A distinct function of regulatory T cells in tissue protection. Cell 162:1078–89
    [Google Scholar]
  2. 2. 
    Burzyn D, Kuswanto W, Kolodin D, Shadrach JL, Cerletti M et al. 2013. A special population of regulatory T cells potentiates muscle repair. Cell 155:1282–95
    [Google Scholar]
  3. 3. 
    Feuerer M, Herrero L, Cipolletta D, Naaz A, Wong J et al. 2009. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat. Med. 15:930–39
    [Google Scholar]
  4. 4. 
    Ali N, Zirak B, Rodriguez RS, Pauli ML, Truong HA et al. 2017. Regulatory T cells in skin facilitate epithelial stem cell differentiation. Cell 169:1119–29.e11
    [Google Scholar]
  5. 5. 
    Savage PA, Malchow S, Leventhal DS 2013. Basic principles of tumor-associated regulatory T cell biology. Trends Immunol 34:33–40
    [Google Scholar]
  6. 6. 
    Tung KS, Smith S, Teuscher C, Cook C, Anderson RE 1987. Murine autoimmune oophoritis, epididymoorchitis, and gastritis induced by day 3 thymectomy: immunopathology. Am. J. Pathol. 126:293–302
    [Google Scholar]
  7. 7. 
    Nishizuka Y, Sakakura T. 1969. Thymus and reproduction: sex-linked dysgenesia of the gonad after neonatal thymectomy in mice. Science 166:753–55
    [Google Scholar]
  8. 8. 
    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. 155:1151–64
    [Google Scholar]
  9. 9. 
    Asano M, Toda M, Sakaguchi N, Sakaguchi S 1996. Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation. J. Exp. Med. 184:387–96
    [Google Scholar]
  10. 10. 
    Khattri R, Cox T, Yasayko SA, Ramsdell F 2003. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat. Immunol. 4:337–42
    [Google Scholar]
  11. 11. 
    Fontenot JD, Gavin MA, Rudensky AY 2003. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat. Immunol. 4:330–36
    [Google Scholar]
  12. 12. 
    Hori S, Nomura T, Sakaguchi S 2003. Control of regulatory T cell development by the transcription factor Foxp3. Science 299:1057–61
    [Google Scholar]
  13. 13. 
    Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ et al. 2001. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat. Genet. 27:20–21
    [Google Scholar]
  14. 14. 
    Wildin RS, Ramsdell F, Peake J, Faravelli F, Casanova JL et al. 2001. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat. Genet. 27:18–20
    [Google Scholar]
  15. 15. 
    Chatila TA, Blaeser F, Ho N, Lederman HM, Voulgaropoulos C et al. 2000. JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome. J. Clin. Investig. 106:R75–81
    [Google Scholar]
  16. 16. 
    Russell WL, Russell LB, Gower JS 1959. Exceptional inheritance of a sex-linked gene in the mouse explained on the basis that the X/O sex-chromosome constitution is female. PNAS 45:554–60
    [Google Scholar]
  17. 17. 
    Godfrey VL, Wilkinson JE, Russell LB 1991. X-linked lymphoreticular disease in the scurfy (sf) mutant mouse. Am. J. Pathol. 138:1379–87
    [Google Scholar]
  18. 18. 
    Brunkow ME, Jeffery EW, Hjerrild KA, Paeper B, Clark LB et al. 2001. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat. Genet. 27:68–73
    [Google Scholar]
  19. 19. 
    Blair PJ, Bultman SJ, Haas JC, Rouse BT, Wilkinson JE, Godfrey VL 1994. CD4+CD8 T cells are the effector cells in disease pathogenesis in the scurfy (sf) mouse. J. Immunol. 153:3764–74
    [Google Scholar]
  20. 20. 
    Tommasini A, Ferrari S, Moratto D, Badolato R, Boniotto M et al. 2002. X-chromosome inactivation analysis in a female carrier of FOXP3 mutation. Clin. Exp. Immunol. 130:127–30
    [Google Scholar]
  21. 21. 
    Schubert LA, Jeffery E, Zhang Y, Ramsdell F, Ziegler SF 2001. Scurfin (FOXP3) acts as a repressor of transcription and regulates T cell activation. J. Biol. Chem. 276:37672–79
    [Google Scholar]
  22. 22. 
    Lahl K, Loddenkemper C, Drouin C, Freyer J, Arnason J et al. 2007. Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease. J. Exp. Med. 204:57–63
    [Google Scholar]
  23. 23. 
    Kim JM, Rasmussen JP, Rudensky AY 2007. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat. Immunol. 8:191–97
    [Google Scholar]
  24. 24. 
    Itoh M, Takahashi T, Sakaguchi N, Kuniyasu Y, Shimizu J et al. 1999. Thymus and autoimmunity: production of CD25+CD4+ naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunologic self-tolerance. J. Immunol. 162:5317–26
    [Google Scholar]
  25. 25. 
    Fontenot JD, Dooley JL, Farr AG, Rudensky AY 2005. Developmental regulation of Foxp3 expression during ontogeny. J. Exp. Med. 202:901–6
    [Google Scholar]
  26. 26. 
    Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, Rudensky AY 2005. Regulatory T cell lineage specification by the forkhead transcription factor Foxp3. Immunity 22:329–41
    [Google Scholar]
  27. 27. 
    Yang S, Fujikado N, Kolodin D, Benoist C, Mathis D 2015. Immune tolerance: Regulatory T cells generated early in life play a distinct role in maintaining self-tolerance. Science 348:589–94
    [Google Scholar]
  28. 28. 
    Yu W, Nagaoka H, Jankovic M, Misulovin Z, Suh H et al. 1999. Continued RAG expression in late stages of B cell development and no apparent re-induction after immunization. Nature 400:682–87
    [Google Scholar]
  29. 29. 
    Thiault N, Darrigues J, Adoue V, Gros M, Binet B et al. 2015. Peripheral regulatory T lymphocytes recirculating to the thymus suppress the development of their precursors. Nat. Immunol. 16:628–34
    [Google Scholar]
  30. 30. 
    Yang E, Zou T, Leichner TM, Zhang SL, Kambayashi T 2014. Both retention and recirculation contribute to long-lived regulatory T-cell accumulation in the thymus. Eur. J. Immunol. 44:2712–20
    [Google Scholar]
  31. 31. 
    Lio CW, Hsieh CS. 2008. A two-step process for thymic regulatory T cell development. Immunity 28:100–11
    [Google Scholar]
  32. 32. 
    Bending D, Prieto Martin P, Paduraru A, Ducker C, Marzaganov E et al. 2018. A timer for analyzing temporally dynamic changes in transcription during differentiation in vivo. J. Cell Biol. 217:2931–50
    [Google Scholar]
  33. 33. 
    Liston A, Nutsch KM, Farr AG, Lund JM, Rasmussen JP et al. 2008. Differentiation of regulatory Foxp3+ T cells in the thymic cortex. PNAS 105:11903–8
    [Google Scholar]
  34. 34. 
    Ribot J, Enault G, Pilipenko S, Huchenq A, Calise M et al. 2007. Shaping of the autoreactive regulatory T cell repertoire by thymic cortical positive selection. J. Immunol. 179:6741–48
    [Google Scholar]
  35. 35. 
    Bensinger SJ, Bandeira A, Jordan MS, Caton AJ, Laufer TM 2001. Major histocompatibility complex class II-positive cortical epithelium mediates the selection of CD4+25+ immunoregulatory T cells. J. Exp. Med. 194:427–38
    [Google Scholar]
  36. 36. 
    Lee HM, Hsieh CS. 2009. Rare development of Foxp3+ thymocytes in the CD4+CD8+ subset. J. Immunol. 183:2261–66
    [Google Scholar]
  37. 37. 
    Malchow S, Leventhal DS, Lee V, Nishi S, Socci ND, Savage PA 2016. Aire enforces immune tolerance by directing autoreactive T cells into the regulatory T cell lineage. Immunity 44:1102–13
    [Google Scholar]
  38. 38. 
    Perry JSA, Lio CJ, Kau AL, Nutsch K, Yang Z et al. 2014. Distinct contributions of Aire and antigen-presenting-cell subsets to the generation of self-tolerance in the thymus. Immunity 41:414–26
    [Google Scholar]
  39. 39. 
    Khan IS, Mouchess ML, Zhu ML, Conley B, Fasano KJ et al. 2014. Enhancement of an anti-tumor immune response by transient blockade of central T cell tolerance. J. Exp. Med. 211:761–68
    [Google Scholar]
  40. 40. 
    Metzger TC, Khan IS, Gardner JM, Mouchess ML, Johannes KP et al. 2013. Lineage tracing and cell ablation identify a post-Aire-expressing thymic epithelial cell population. Cell Rep 5:166–79
    [Google Scholar]
  41. 41. 
    Hinterberger M, Aichinger M, Prazeres da Costa O, Voehringer D, Hoffmann R, Klein L 2010. Autonomous role of medullary thymic epithelial cells in central CD4+ T cell tolerance. Nat. Immunol. 11:512–19
    [Google Scholar]
  42. 42. 
    Inglesfield S, Cosway EJ, Jenkinson WE, Anderson G 2019. Rethinking thymic tolerance: lessons from mice. Trends Immunol 40:279–91
    [Google Scholar]
  43. 43. 
    Romo-Tena J, Gomez-Martin D, Alcocer-Varela J 2013. CTLA-4 and autoimmunity: new insights into the dual regulator of tolerance. Autoimmun. Rev. 12:1171–76
    [Google Scholar]
  44. 44. 
    Goudy K, Aydin D, Barzaghi F, Gambineri E, Vignoli M et al. 2013. Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity. Clin. Immunol. 146:248–61
    [Google Scholar]
  45. 45. 
    Cavanillas ML, Alcina A, Nunez C, de las Heras V, Fernandez-Arquero M et al. 2010. Polymorphisms in the IL2, IL2RA and IL2RB genes in multiple sclerosis risk. Eur. J. Hum. Genet. 18:794–99
    [Google Scholar]
  46. 46. 
    Alcina A, Fedetz M, Ndagire D, Fernandez O, Leyva L et al. 2009. IL2RA/CD25 gene polymorphisms: uneven association with multiple sclerosis (MS) and type 1 diabetes (T1D). PLOS ONE 4:e4137
    [Google Scholar]
  47. 47. 
    Matesanz F, Caro-Maldonado A, Fedetz M, Fernandez O, Milne RL et al. 2007. IL2RA/CD25 polymorphisms contribute to multiple sclerosis susceptibility. J. Neurol. 254:682–84
    [Google Scholar]
  48. 48. 
    Vella A, Cooper JD, Lowe CE, Walker N, Nutland S et al. 2005. Localization of a type 1 diabetes locus in the IL2RA/CD25 region by use of tag single-nucleotide polymorphisms. Am. J. Hum. Genet. 76:773–79
    [Google Scholar]
  49. 49. 
    Matesanz F, Fedetz M, Collado-Romero M, Fernandez O, Guerrero M et al. 2001. Allelic expression and interleukin-2 polymorphisms in multiple sclerosis. J. Neuroimmunol. 119:101–5
    [Google Scholar]
  50. 50. 
    Pacholczyk R, Kern J, Singh N, Iwashima M, Kraj P, Ignatowicz L 2007. Nonself-antigens are the cognate specificities of Foxp3+ regulatory T cells. Immunity 27:493–504
    [Google Scholar]
  51. 51. 
    Wong J, Obst R, Correia-Neves M, Losyev G, Mathis D, Benoist C 2007. Adaptation of TCR repertoires to self-peptides in regulatory and nonregulatory CD4+ T cells. J. Immunol. 178:7032–41
    [Google Scholar]
  52. 52. 
    Hsieh CS, Liang Y, Tyznik AJ, Self SG, Liggitt D, Rudensky AY 2004. Recognition of the peripheral self by naturally arising CD25+ CD4+ T cell receptors. Immunity 21:267–77
    [Google Scholar]
  53. 53. 
    Leung MW, Shen S, Lafaille JJ 2009. TCR-dependent differentiation of thymic Foxp3+ cells is limited to small clonal sizes. J. Exp. Med. 206:2121–30
    [Google Scholar]
  54. 54. 
    Bautista JL, Lio CW, Lathrop SK, Forbush K, Liang Y et al. 2009. Intraclonal competition limits the fate determination of regulatory T cells in the thymus. Nat. Immunol. 10:610–17
    [Google Scholar]
  55. 55. 
    Salomon B, Lenschow DJ, Rhee L, Ashourian N, Singh B et al. 2000. B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity 12:431–40
    [Google Scholar]
  56. 56. 
    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. 6:152–62
    [Google Scholar]
  57. 57. 
    Lio CW, Dodson LF, Deppong CM, Hsieh CS, Green JM 2010. CD28 facilitates the generation of Foxp3 cytokine responsive regulatory T cell precursors. J. Immunol. 184:6007–13
    [Google Scholar]
  58. 58. 
    Almeida AR, Legrand N, Papiernik M, Freitas AA 2002. Homeostasis of peripheral CD4+ T cells: IL-2R alpha and IL-2 shape a population of regulatory cells that controls CD4+ T cell numbers. J. Immunol. 169:4850–60
    [Google Scholar]
  59. 59. 
    Papiernik M, de Moraes ML, Pontoux C, Vasseur F, Penit C 1998. Regulatory CD4 T cells: expression of IL-2R alpha chain, resistance to clonal deletion and IL-2 dependency. Int. Immunol. 10:371–78
    [Google Scholar]
  60. 60. 
    Malek TR, Yu A, Vincek V, Scibelli P, Kong L 2002. CD4 regulatory T cells prevent lethal autoimmunity in IL-2Rβ-deficient mice: implications for the nonredundant function of IL-2. Immunity 17:167–78
    [Google Scholar]
  61. 61. 
    Bayer AL, Yu A, Adeegbe D, Malek TR 2005. Essential role for interleukin-2 for CD4+CD25+ T regulatory cell development during the neonatal period. J. Exp. Med. 201:769–77
    [Google Scholar]
  62. 62. 
    Setoguchi R, Hori S, Takahashi T, Sakaguchi S 2005. Homeostatic maintenance of natural Foxp3+ CD25+ CD4+ regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization. J. Exp. Med. 201:723–35
    [Google Scholar]
  63. 63. 
    Fan MY, Low JS, Tanimine N, Finn KK, Priyadharshini B et al. 2018. Differential roles of IL-2 signaling in developing versus mature Tregs. Cell Rep 25:1204–13.e4
    [Google Scholar]
  64. 64. 
    Burchill MA, Yang J, Vogtenhuber C, Blazar BR, Farrar MA 2007. IL-2 receptor β-dependent STAT5 activation is required for the development of Foxp3+ regulatory T cells. J. Immunol. 178:280–90
    [Google Scholar]
  65. 65. 
    Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY 2005. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat. Immunol. 6:1142–51
    [Google Scholar]
  66. 66. 
    D'Cruz LM, Klein L. 2005. Development and function of agonist-induced CD25+Foxp3+ regulatory T cells in the absence of interleukin 2 signaling. Nat. Immunol. 6:1152–59
    [Google Scholar]
  67. 67. 
    Vang KB, Yang J, Mahmud SA, Burchill MA, Vegoe AL, Farrar MA 2008. IL-2, -7, and -15, but not thymic stromal lymphopoeitin, redundantly govern CD4+Foxp3+ regulatory T cell development. J. Immunol. 181:3285–90
    [Google Scholar]
  68. 68. 
    Bayer AL, Lee JY, de la Barrera A, Surh CD, Malek TR 2008. A function for IL-7R for CD4+CD25+Foxp3+ T regulatory cells. J. Immunol. 181:225–34
    [Google Scholar]
  69. 69. 
    Burchill MA, Yang J, Vang KB, Moon JJ, Chu HH et al. 2008. Linked T cell receptor and cytokine signaling govern the development of the regulatory T cell repertoire. Immunity 28:112–21
    [Google Scholar]
  70. 70. 
    Yao Z, Kanno Y, Kerenyi M, Stephens G, Durant L et al. 2007. Nonredundant roles for Stat5a/b in directly regulating Foxp3. Blood 109:4368–75
    [Google Scholar]
  71. 71. 
    Vang KB, Yang J, Pagan AJ, Li LX, Wang J et al. 2010. Cutting edge: CD28 and c-Rel-dependent pathways initiate regulatory T cell development. J. Immunol. 184:4074–77
    [Google Scholar]
  72. 72. 
    Hinterberger M, Wirnsberger G, Klein L 2011. B7/CD28 in central tolerance: costimulation promotes maturation of regulatory T cell precursors and prevents their clonal deletion. Front. Immunol. 2:30
    [Google Scholar]
  73. 73. 
    Ouyang W, Beckett O, Ma Q, Li MO 2010. Transforming growth factor-β signaling curbs thymic negative selection promoting regulatory T cell development. Immunity 32:642–53
    [Google Scholar]
  74. 74. 
    Coquet JM, Ribot JC, Babala N, Middendorp S, van der Horst G et al. 2013. Epithelial and dendritic cells in the thymic medulla promote CD4+Foxp3+ regulatory T cell development via the CD27–CD70 pathway. J. Exp. Med. 210:715–28
    [Google Scholar]
  75. 75. 
    Mahmud SA, Manlove LS, Schmitz HM, Xing Y, Wang Y 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. 15:473–81
    [Google Scholar]
  76. 76. 
    Leventhal DS, Gilmore DC, Berger JM, Nishi S, Lee V et al. 2016. Dendritic cells coordinate the development and homeostasis of organ-specific regulatory T cells. Immunity 44:847–59
    [Google Scholar]
  77. 77. 
    Yang-Snyder JA, Rothenberg EV. 1998. Spontaneous expression of interleukin-2 in vivo in specific tissues of young mice. Dev. Immunol. 5:223–45
    [Google Scholar]
  78. 78. 
    Owen DL, Mahmud SA, Vang KB, Kelly RM, Blazar BR et al. 2018. Identification of cellular sources of IL-2 needed for regulatory T cell development and homeostasis. J. Immunol. 200:3926–33
    [Google Scholar]
  79. 79. 
    Hemmers S, Schizas M, Azizi E, Dikiy S, Zhong Y et al. 2019. IL-2 production by self-reactive CD4 thymocytes scales regulatory T cell generation in the thymus. J. Exp. Med. 216:2466–78
    [Google Scholar]
  80. 80. 
    Weist BM, Kurd N, Boussier J, Chan SW, Robey EA 2015. Thymic regulatory T cell niche size is dictated by limiting IL-2 from antigen-bearing dendritic cells and feedback competition. Nat. Immunol. 16:635–41
    [Google Scholar]
  81. 81. 
    Owen DL, Mahmud SA, Sjaastad LE, Williams JB, Spanier JA et al. 2019. Thymic regulatory T cells arise via two distinct developmental programs. Nat. Immunol. 20:195–205
    [Google Scholar]
  82. 82. 
    Tai X, Erman B, Alag A, Mu J, Kimura M et al. 2013. Foxp3 transcription factor is proapoptotic and lethal to developing regulatory T cells unless counterbalanced by cytokine survival signals. Immunity 38:1116–28
    [Google Scholar]
  83. 83. 
    Moran AE, Holzapfel KL, Xing Y, Cunningham NR, Maltzman JS et al. 2011. T cell receptor signal strength in Treg and iNKT cell development demonstrated by a novel fluorescent reporter mouse. J. Exp. Med. 208:1279–89
    [Google Scholar]
  84. 84. 
    Hsieh CS, Lee HM, Lio CW 2012. Selection of regulatory T cells in the thymus. Nat. Rev. Immunol. 12:157–67
    [Google Scholar]
  85. 85. 
    Lee T, Sprouse ML, Banerjee P, Bettini M, Bettini ML 2017. Ectopic expression of self-antigen drives regulatory T cell development and not deletion of autoimmune T cells. J. Immunol. 199:2270–78
    [Google Scholar]
  86. 86. 
    Malhotra D, Linehan JL, Dileepan T, Lee YJ, Purtha WE et al. 2016. Tolerance is established in polyclonal CD4+ T cells by distinct mechanisms, according to self-peptide expression patterns. Nat. Immunol. 17:187–95
    [Google Scholar]
  87. 87. 
    Legoux FP, Lim JB, Cauley AW, Dikiy S, Ertelt J et al. 2015. CD4+ T cell tolerance to tissue-restricted self antigens is mediated by antigen-specific regulatory T cells rather than deletion. Immunity 43:896–908
    [Google Scholar]
  88. 88. 
    Lee HM, Bautista JL, Scott-Browne J, Mohan JF, Hsieh CS 2012. A broad range of self-reactivity drives thymic regulatory T cell selection to limit responses to self. Immunity 37:475–86
    [Google Scholar]
  89. 89. 
    Picca CC, Oh S, Panarey L, Aitken M, Basehoar A, Caton AJ 2009. Thymocyte deletion can bias Treg formation toward low-abundance self-peptide. Eur. J. Immunol. 39:3301–6
    [Google Scholar]
  90. 90. 
    Cabarrocas J, Cassan C, Magnusson F, Piaggio E, Mars L et al. 2006. Foxp3+ CD25+ regulatory T cells specific for a neo-self-antigen develop at the double-positive thymic stage. PNAS 103:8453–58
    [Google Scholar]
  91. 91. 
    van Santen HM, Benoist C, Mathis D 2004. Number of T reg cells that differentiate does not increase upon encounter of agonist ligand on thymic epithelial cells. J. Exp. Med. 200:1221–30
    [Google Scholar]
  92. 92. 
    Apostolou I, Sarukhan A, Klein L, von Boehmer H 2002. Origin of regulatory T cells with known specificity for antigen. Nat. Immunol. 3:756–63
    [Google Scholar]
  93. 93. 
    Jordan MS, Boesteanu A, Reed AJ, Petrone AL, Holenbeck AE et al. 2001. Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide. Nat. Immunol. 2:301–6
    [Google Scholar]
  94. 94. 
    Klein L, Robey EA, Hsieh CS 2019. Central CD4+ T cell tolerance: deletion versus regulatory T cell differentiation. Nat. Rev. Immunol. 19:7–18
    [Google Scholar]
  95. 95. 
    Li MO, Rudensky AY. 2016. T cell receptor signalling in the control of regulatory T cell differentiation and function. Nat. Rev. Immunol. 16:220–33
    [Google Scholar]
  96. 96. 
    Adamopoulou E, Tenzer S, Hillen N, Klug P, Rota IA et al. 2013. Exploring the MHC-peptide matrix of central tolerance in the human thymus. Nat. Commun. 4:2039
    [Google Scholar]
  97. 97. 
    Collado JA, Alvarez I, Ciudad MT, Espinosa G, Canals F et al. 2013. Composition of the HLA-DR-associated human thymus peptidome. Eur. J. Immunol. 43:2273–82
    [Google Scholar]
  98. 98. 
    Marrack P, Ignatowicz L, Kappler JW, Boymel J, Freed JH 1993. Comparison of peptides bound to spleen and thymus class II. J. Exp. Med. 178:2173–83
    [Google Scholar]
  99. 99. 
    Schmid D, Pypaert M, Munz C 2007. Antigen-loading compartments for major histocompatibility complex class II molecules continuously receive input from autophagosomes. Immunity 26:79–92
    [Google Scholar]
  100. 100. 
    Dengjel J, Schoor O, Fischer R, Reich M, Kraus M et al. 2005. Autophagy promotes MHC class II presentation of peptides from intracellular source proteins. PNAS 102:7922–27
    [Google Scholar]
  101. 101. 
    Nedjic J, Aichinger M, Emmerich J, Mizushima N, Klein L 2008. Autophagy in thymic epithelium shapes the T-cell repertoire and is essential for tolerance. Nature 455:396–400
    [Google Scholar]
  102. 102. 
    Atibalentja DF, Murphy KM, Unanue ER 2011. Functional redundancy between thymic CD8α+ and Sirpα+ conventional dendritic cells in presentation of blood-derived lysozyme by MHC class II proteins. J. Immunol. 186:1421–31
    [Google Scholar]
  103. 103. 
    Atibalentja DF, Byersdorfer CA, Unanue ER 2009. Thymus-blood protein interactions are highly effective in negative selection and regulatory T cell induction. J. Immunol. 183:7909–18
    [Google Scholar]
  104. 104. 
    Hanahan D. 1998. Peripheral-antigen-expressing cells in thymic medulla: factors in self-tolerance and autoimmunity. Curr. Opin. Immunol. 10:656–62
    [Google Scholar]
  105. 105. 
    Derbinski J, Schulte A, Kyewski B, Klein L 2001. Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Nat. Immunol. 2:1032–39
    [Google Scholar]
  106. 106. 
    Finnish-German APECED Consortium 1997. An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Nat. Genet. 17:399–403
    [Google Scholar]
  107. 107. 
    Nagamine K, Peterson P, Scott HS, Kudoh J, Minoshima S et al. 1997. Positional cloning of the APECED gene. Nat. Genet. 17:393–98
    [Google Scholar]
  108. 108. 
    Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP et al. 2002. Projection of an immunological self shadow within the thymus by the aire protein. Science 298:1395–401
    [Google Scholar]
  109. 109. 
    Giraud M, Yoshida H, Abramson J, Rahl PB, Young RA et al. 2012. Aire unleashes stalled RNA polymerase to induce ectopic gene expression in thymic epithelial cells. PNAS 109:535–40
    [Google Scholar]
  110. 110. 
    Villasenor J, Besse W, Benoist C, Mathis D 2008. Ectopic expression of peripheral-tissue antigens in the thymic epithelium: probabilistic, monoallelic, misinitiated. PNAS 105:15854–59
    [Google Scholar]
  111. 111. 
    Derbinski J, Pinto S, Rosch S, Hexel K, Kyewski B 2008. Promiscuous gene expression patterns in single medullary thymic epithelial cells argue for a stochastic mechanism. PNAS 105:657–62
    [Google Scholar]
  112. 112. 
    Sansom SN, Shikama-Dorn N, Zhanybekova S, Nusspaumer G, Macaulay IC et al. 2014. Population and single-cell genomics reveal the Aire dependency, relief from Polycomb silencing, and distribution of self-antigen expression in thymic epithelia. Genome Res 24:1918–31
    [Google Scholar]
  113. 113. 
    Derbinski J, Gabler J, Brors B, Tierling S, Jonnakuty S et al. 2005. Promiscuous gene expression in thymic epithelial cells is regulated at multiple levels. J. Exp. Med. 202:33–45
    [Google Scholar]
  114. 114. 
    Takaba H, Morishita Y, Tomofuji Y, Danks L, Nitta T et al. 2015. Fezf2 orchestrates a thymic program of self-antigen expression for immune tolerance. Cell 163:975–87
    [Google Scholar]
  115. 115. 
    Koh AS, Miller EL, Buenrostro JD, Moskowitz DM, Wang J et al. 2018. Rapid chromatin repression by Aire provides precise control of immune tolerance. Nat. Immunol. 19:162–72
    [Google Scholar]
  116. 116. 
    Lin J, Yang L, Silva HM, Trzeciak A, Choi Y et al. 2016. Increased generation of Foxp3+ regulatory T cells by manipulating antigen presentation in the thymus. Nat. Commun. 7:10562
    [Google Scholar]
  117. 117. 
    Malchow S, Leventhal DS, Nishi S, Fischer BI, Shen L et al. 2013. Aire-dependent thymic development of tumor-associated regulatory T cells. Science 339:1219–24
    [Google Scholar]
  118. 118. 
    Leonard JD, Gilmore DC, Dileepan T, Nawrocka WI, Chao JL et al. 2017. Identification of natural regulatory T cell epitopes reveals convergence on a dominant autoantigen. Immunity 47:107–17.e8
    [Google Scholar]
  119. 119. 
    Setiady YY, Ohno K, Samy ET, Bagavant H, Qiao H et al. 2006. Physiologic self antigens rapidly capacitate autoimmune disease-specific polyclonal CD4+ CD25+ regulatory T cells. Blood 107:1056–62
    [Google Scholar]
  120. 120. 
    Hassler T, Urmann E, Teschner S, Federle C, Dileepan T et al. 2019. Inventories of naive and tolerant mouse CD4 T cell repertoires reveal a hierarchy of deleted and diverted T cell receptors. PNAS 116:18537–43
    [Google Scholar]
  121. 121. 
    Spence A, Purtha W, Tam J, Dong S, Kim Y et al. 2018. Revealing the specificity of regulatory T cells in murine autoimmune diabetes. PNAS 115:5265–70 Correction. 2018 PNAS 115:E5634
    [Google Scholar]
  122. 122. 
    Kieback E, Hilgenberg E, Stervbo U, Lampropoulou V, Shen P et al. 2016. Thymus-derived regulatory T cells are positively selected on natural self-antigen through cognate interactions of high functional avidity. Immunity 44:1114–26
    [Google Scholar]
  123. 123. 
    Stadinski BD, Blevins SJ, Spidale NA, Duke BR, Huseby PG et al. 2019. A temporal thymic selection switch and ligand binding kinetics constrain neonatal Foxp3+ Treg cell development. Nat. Immunol. 20:1046–58
    [Google Scholar]
  124. 124. 
    Breed ER, Watanabe M, Hogquist KA 2019. Measuring thymic clonal deletion at the population level. J. Immunol. 202:3226–33
    [Google Scholar]
  125. 125. 
    Guerri L, Peguillet I, Geraldo Y, Nabti S, Premel V, Lantz O 2013. Analysis of APC types involved in CD4 tolerance and regulatory T cell generation using reaggregated thymic organ cultures. J. Immunol. 190:2102–10
    [Google Scholar]
  126. 126. 
    Wirnsberger G, Mair F, Klein L 2009. Regulatory T cell differentiation of thymocytes does not require a dedicated antigen-presenting cell but is under T cell-intrinsic developmental control. PNAS 106:10278–83
    [Google Scholar]
  127. 127. 
    Perry JSA, Russler-Germain EV, Zhou YW, Purtha W, Cooper ML et al. 2018. Transfer of cell-surface antigens by scavenger receptor CD36 promotes thymic regulatory T cell receptor repertoire development and allo-tolerance. Immunity 48:923–36.e4
    [Google Scholar]
  128. 128. 
    Koble C, Kyewski B. 2009. The thymic medulla: a unique microenvironment for intercellular self-antigen transfer. J. Exp. Med. 206:1505–13
    [Google Scholar]
  129. 129. 
    Millet V, Naquet P, Guinamard RR 2008. Intercellular MHC transfer between thymic epithelial and dendritic cells. Eur. J. Immunol. 38:1257–63
    [Google Scholar]
  130. 130. 
    Proietto AI, van Dommelen S, Zhou P, Rizzitelli A, D'Amico A et al. 2008. Dendritic cells in the thymus contribute to T-regulatory cell induction. PNAS 105:19869–74
    [Google Scholar]
  131. 131. 
    Hadeiba H, Lahl K, Edalati A, Oderup C, Habtezion A et al. 2012. Plasmacytoid dendritic cells transport peripheral antigens to the thymus to promote central tolerance. Immunity 36:438–50
    [Google Scholar]
  132. 132. 
    Yamano T, Nedjic J, Hinterberger M, Steinert M, Koser S et al. 2015. Thymic B cells are licensed to present self antigens for central T cell tolerance induction. Immunity 42:1048–61
    [Google Scholar]
  133. 133. 
    Anderson MS, Venanzi ES, Chen Z, Berzins SP, Benoist C, Mathis D 2005. The cellular mechanism of Aire control of T cell tolerance. Immunity 23:227–39
    [Google Scholar]
  134. 134. 
    Gabler J, Arnold J, Kyewski B 2007. Promiscuous gene expression and the developmental dynamics of medullary thymic epithelial cells. Eur. J. Immunol. 37:3363–72
    [Google Scholar]
  135. 135. 
    Lei Y, Ripen AM, Ishimaru N, Ohigashi I, Nagasawa T et al. 2011. Aire-dependent production of XCL1 mediates medullary accumulation of thymic dendritic cells and contributes to regulatory T cell development. J. Exp. Med. 208:383–94
    [Google Scholar]
  136. 136. 
    Hu Z, Li Y, Van Nieuwenhuijze A, Selden HJ, Jarrett AM et al. 2017. CCR7 modulates the generation of thymic regulatory T cells by altering the composition of the thymic dendritic cell compartment. Cell Rep 21:168–80
    [Google Scholar]
  137. 137. 
    Aichinger M, Wu C, Nedjic J, Klein L 2013. Macroautophagy substrates are loaded onto MHC class II of medullary thymic epithelial cells for central tolerance. J. Exp. Med. 210:287–300
    [Google Scholar]
  138. 138. 
    Hildner K, Edelson BT, Purtha WE, Diamond M, Matsushita H et al. 2008. Batf3 deficiency reveals a critical role for CD8α+ dendritic cells in cytotoxic T cell immunity. Science 322:1097–100
    [Google Scholar]
  139. 139. 
    Dudziak D, Kamphorst AO, Heidkamp GF, Buchholz VR, Trumpfheller C et al. 2007. Differential antigen processing by dendritic cell subsets in vivo. Science 315:107–11
    [Google Scholar]
  140. 140. 
    Panduro M, Benoist C, Mathis D 2016. Tissue Tregs. Annu. Rev. Immunol. 34:609–33
    [Google Scholar]
  141. 141. 
    Gratz IK, Campbell DJ. 2014. Organ-specific and memory Treg cells: specificity, development, function, and maintenance. Front. Immunol. 5:333
    [Google Scholar]
  142. 142. 
    Campbell C, Rudensky A. 2020. Roles of regulatory T cells in tissue pathophysiology and metabolism. Cell Metab 31:18–25
    [Google Scholar]
  143. 143. 
    Koch MA, Tucker-Heard G, Perdue NR, Killebrew JR, Urdahl KB et al. 2009. The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nat. Immunol. 10:595–602
    [Google Scholar]
  144. 144. 
    Levine AG, Mendoza A, Hemmers S, Moltedo B, Niec RE et al. 2017. Stability and function of regulatory T cells expressing the transcription factor T-bet. Nature 546:421–25 Corrigendum. 2017 Nature 550 142
    [Google Scholar]
  145. 145. 
    Li C, Dispirito JR, Zemmour D, Spallanzani RG, Kuswanto W et al. 2018. TCR transgenic mice reveal stepwise, multi-site acquisition of the distinctive fat-Treg phenotype. Cell 174:285–99.e212
    [Google Scholar]
  146. 146. 
    Zhou X, Bailey-Bucktrout SL, Jeker LT, Penaranda C, Martinez-Llordella M et al. 2009. Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat. Immunol. 10:1000–7
    [Google Scholar]
  147. 147. 
    Duarte JH, Zelenay S, Bergman ML, Martins AC, Demengeot J 2009. Natural Treg cells spontaneously differentiate into pathogenic helper cells in lymphopenic conditions. Eur. J. Immunol. 39:948–55
    [Google Scholar]
  148. 148. 
    Komatsu N, Mariotti-Ferrandiz ME, Wang Y, Malissen B, Waldmann H, Hori S 2009. Heterogeneity of natural Foxp3+ T cells: a committed regulatory T-cell lineage and an uncommitted minor population retaining plasticity. PNAS 106:1903–8
    [Google Scholar]
  149. 149. 
    Rubtsov YP, Niec RE, Josefowicz S, Li L, Darce J et al. 2010. Stability of the regulatory T cell lineage in vivo. Science 329:1667–71
    [Google Scholar]
  150. 150. 
    Miyao T, Floess S, Setoguchi R, Luche H, Fehling HJ et al. 2012. Plasticity of Foxp3+ T cells reflects promiscuous Foxp3 expression in conventional T cells but not reprogramming of regulatory T cells. Immunity 36:262–75
    [Google Scholar]
  151. 151. 
    Kitagawa Y, Sakaguchi S. 2017. Molecular control of regulatory T cell development and function. Curr. Opin. Immunol. 49:64–70
    [Google Scholar]
  152. 152. 
    Huehn J, Beyer M. 2015. Epigenetic and transcriptional control of Foxp3+ regulatory T cells. Semin. Immunol. 27:10–18
    [Google Scholar]
  153. 153. 
    Ohkura N, Hamaguchi M, Morikawa H, Sugimura K, Tanaka A et al. 2012. T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development. Immunity 37:785–99
    [Google Scholar]
  154. 154. 
    Floess S, Freyer J, Siewert C, Baron U, Olek S et al. 2007. Epigenetic control of the foxp3 locus in regulatory T cells. PLOS Biol 5:e38
    [Google Scholar]
  155. 155. 
    Zheng Y, Josefowicz S, Chaudhry A, Peng XP, Forbush K, Rudensky AY 2010. Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature 463:808–12
    [Google Scholar]
  156. 156. 
    Toker A, Engelbert D, Garg G, Polansky JK, Floess S et al. 2013. Active demethylation of the Foxp3 locus leads to the generation of stable regulatory T cells within the thymus. J. Immunol. 190:3180–88
    [Google Scholar]
  157. 157. 
    Polansky JK, Kretschmer K, Freyer J, Floess S, Garbe A et al. 2008. DNA methylation controls Foxp3 gene expression. Eur. J. Immunol. 38:1654–63
    [Google Scholar]
  158. 158. 
    Polansky JK, Schreiber L, Thelemann C, Ludwig L, Kruger M et al. 2010. Methylation matters: Binding of Ets-1 to the demethylated Foxp3 gene contributes to the stabilization of Foxp3 expression in regulatory T cells. J. Mol. Med. 88:1029–40
    [Google Scholar]
  159. 159. 
    Wolf KJ, Emerson RO, Pingel J, Buller RM, DiPaolo RJ 2016. Conventional and regulatory CD4+ T cells that share identical TCRs are derived from common clones. PLOS ONE 11:e0153705
    [Google Scholar]
  160. 160. 
    Wojciech L, Ignatowicz A, Seweryn M, Rempala G, Pabla SS et al. 2014. The same self-peptide selects conventional and regulatory CD4+ T cells with identical antigen receptors. Nat. Commun. 5:5061
    [Google Scholar]
  161. 161. 
    Hsieh CS, Zheng Y, Liang Y, Fontenot JD, Rudensky AY 2006. An intersection between the self-reactive regulatory and nonregulatory T cell receptor repertoires. Nat. Immunol. 7:401–10
    [Google Scholar]
  162. 162. 
    Ooi JD, Petersen J, Tan YH, Huynh M, Willett ZJ et al. 2017. Dominant protection from HLA-linked autoimmunity by antigen-specific regulatory T cells. Nature 545:243–47
    [Google Scholar]
  163. 163. 
    Su LF, Del Alcazar D, Stelekati E, Wherry EJ, Davis MM 2016. Antigen exposure shapes the ratio between antigen-specific Tregs and conventional T cells in human peripheral blood. PNAS 113:E6192–98
    [Google Scholar]
  164. 164. 
    Bacher P, Heinrich F, Stervbo U, Nienen M, Vahldieck M et al. 2016. Regulatory T cell specificity directs tolerance versus allergy against aeroantigens in humans. Cell 167:1067–78.e16
    [Google Scholar]
  165. 165. 
    Shafiani S, Dinh C, Ertelt JM, Moguche AO, Siddiqui I et al. 2013. Pathogen-specific Treg cells expand early during Mycobacterium tuberculosis infection but are later eliminated in response to interleukin-12. Immunity 38:1261–70
    [Google Scholar]
  166. 166. 
    Moon JJ, Dash P, Oguin TH 3rd, McClaren JL, Chu HH et al. 2011. Quantitative impact of thymic selection on Foxp3+ and Foxp3 subsets of self-peptide/MHC class II-specific CD4+ T cells. PNAS 108:14602–7
    [Google Scholar]
  167. 167. 
    Curotto de Lafaille MA, Lino AC, Kutchukhidze N, Lafaille JJ 2004. CD25 T cells generate CD25+Foxp3+ regulatory T cells by peripheral expansion. J. Immunol. 173:7259–68
    [Google Scholar]
  168. 168. 
    Xu M, Pokrovskii M, Ding Y, Yi R, Au C et al. 2018. c-MAF-dependent regulatory T cells mediate immunological tolerance to a gut pathobiont. Nature 554:373–77
    [Google Scholar]
  169. 169. 
    Gottschalk RA, Corse E, Allison JP 2010. TCR ligand density and affinity determine peripheral induction of Foxp3 in vivo. J. Exp. Med. 207:1701–11
    [Google Scholar]
  170. 170. 
    Sun CM, Hall JA, Blank RB, Bouladoux N, Oukka M et al. 2007. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J. Exp. Med. 204:1775–85
    [Google Scholar]
  171. 171. 
    Kretschmer K, Apostolou I, Hawiger D, Khazaie K, Nussenzweig MC, von Boehmer H 2005. Inducing and expanding regulatory T cell populations by foreign antigen. Nat. Immunol. 6:1219–27
    [Google Scholar]
  172. 172. 
    Apostolou I, von Boehmer H 2004. In vivo instruction of suppressor commitment in naive T cells. J. Exp. Med. 199:1401–8
    [Google Scholar]
  173. 173. 
    Thornton AM, Korty PE, Tran DQ, Wohlfert EA, Murray PE et al. 2010. Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells. J. Immunol. 184:3433–41
    [Google Scholar]
  174. 174. 
    Yadav M, Louvet C, Davini D, Gardner JM, Martinez-Llordella M et al. 2012. Neuropilin-1 distinguishes natural and inducible regulatory T cells among regulatory T cell subsets in vivo. J. Exp. Med. 209:1713–22
    [Google Scholar]
  175. 175. 
    Weiss JM, Bilate AM, Gobert M, Ding Y, Curotto de Lafaille MA et al. 2012. Neuropilin 1 is expressed on thymus-derived natural regulatory T cells, but not mucosa-generated induced Foxp3+ T reg cells. J. Exp. Med. 209:1723–42
    [Google Scholar]
  176. 176. 
    Szurek E, Cebula A, Wojciech L, Pietrzak M, Rempala G et al. 2015. Differences in expression level of Helios and neuropilin-1 do not distinguish thymus-derived from extrathymically-induced CD4+Foxp3+ regulatory T cells. PLOS ONE 10:e0141161
    [Google Scholar]
  177. 177. 
    Petzold C, Steinbronn N, Gereke M, Strasser RH, Sparwasser T et al. 2014. Fluorochrome-based definition of naturally occurring Foxp3+ regulatory T cells of intra- and extrathymic origin. Eur. J. Immunol. 44:3632–45
    [Google Scholar]
  178. 178. 
    Schliesser U, Chopra M, Beilhack A, Appelt C, Vogel S et al. 2013. Generation of highly effective and stable murine alloreactive Treg cells by combined anti-CD4 mAb, TGF-β, and RA treatment. Eur. J. Immunol. 43:3291–305
    [Google Scholar]
  179. 179. 
    Gottschalk RA, Corse E, Allison JP 2012. Expression of Helios in peripherally induced Foxp3+ regulatory T cells. J. Immunol. 188:976–80
    [Google Scholar]
  180. 180. 
    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:e24226
    [Google Scholar]
  181. 181. 
    Schlenner SM, Weigmann B, Ruan Q, Chen Y, von Boehmer H 2012. Smad3 binding to the foxp3 enhancer is dispensable for the development of regulatory T cells with the exception of the gut. J. Exp. Med. 209:1529–35
    [Google Scholar]
  182. 182. 
    Josefowicz SZ, Niec RE, Kim HY, Treuting P, Chinen T et al. 2012. Extrathymically generated regulatory T cells control mucosal TH2 inflammation. Nature 482:395–99
    [Google Scholar]
  183. 183. 
    Samstein RM, Josefowicz SZ, Arvey A, Treuting PM, Rudensky AY 2012. Extrathymic generation of regulatory T cells in placental mammals mitigates maternal-fetal conflict. Cell 150:29–38
    [Google Scholar]
  184. 184. 
    Holohan DR, Van Gool F, Bluestone JA 2019. Thymically-derived Foxp3+ regulatory T cells are the primary regulators of type 1 diabetes in the non-obese diabetic mouse model. PLOS ONE 14:e0217728
    [Google Scholar]
  185. 185. 
    Lathrop SK, Bloom SM, Rao SM, Nutsch K, Lio CW et al. 2011. Peripheral education of the immune system by colonic commensal microbiota. Nature 478:250–54
    [Google Scholar]
  186. 186. 
    Wegorzewska MM, Glowacki RWP, Hsieh SA, Donermeyer DL, Hickey CA et al. 2019. Diet modulates colonic T cell responses by regulating the expression of a Bacteroides thetaiotaomicron antigen. Sci. Immunol. 4:eaau9079
    [Google Scholar]
  187. 187. 
    Chai JN, Peng Y, Rengarajan S, Solomon BD, Ai TL et al. 2017. Helicobacter species are potent drivers of colonic T cell responses in homeostasis and inflammation. Sci. Immunol. 2:eaal5068
    [Google Scholar]
  188. 188. 
    Nutsch K, Chai JN, Ai TL, Russler-Germain E, Feehley T et al. 2016. Rapid and efficient generation of regulatory T cells to commensal antigens in the periphery. Cell Rep 17:206–20
    [Google Scholar]
  189. 189. 
    Solomon BD, Hsieh CS. 2016. Antigen-specific development of mucosal Foxp3+RORγt+ T cells from regulatory T cell precursors. J. Immunol. 197:3512–19
    [Google Scholar]
  190. 190. 
    Sefik E, Geva-Zatorsky N, Oh S, Konnikova L, Zemmour D et al. 2015. Individual intestinal symbionts induce a distinct population of RORγ+ regulatory T cells. Science 349:993–97
    [Google Scholar]
  191. 191. 
    Ohnmacht C, Park JH, Cording S, Wing JB, Atarashi K et al. 2015. The microbiota regulates type 2 immunity through RORγt+ T cells. Science 349:989–93
    [Google Scholar]
  192. 192. 
    Cebula A, Seweryn M, Rempala GA, Pabla SS, McIndoe RA et al. 2013. Thymus-derived regulatory T cells contribute to tolerance to commensal microbiota. Nature 497:258–62
    [Google Scholar]
  193. 193. 
    Schallenberg S, Tsai PY, Riewaldt J, Kretschmer K 2010. Identification of an immediate Foxp3 precursor to Foxp3+ regulatory T cells in peripheral lymphoid organs of nonmanipulated mice. J. Exp. Med. 207:1393–407
    [Google Scholar]
  194. 194. 
    Paiva RS, Lino AC, Bergman ML, Caramalho I, Sousa AE et al. 2013. Recent thymic emigrants are the preferential precursors of regulatory T cells differentiated in the periphery. PNAS 110:6494–99
    [Google Scholar]
  195. 195. 
    Kalekar LA, Schmiel SE, Nandiwada SL, Lam WY, Barsness LO et al. 2016. CD4+ T cell anergy prevents autoimmunity and generates regulatory T cell precursors. Nat. Immunol. 17:304–14
    [Google Scholar]
  196. 196. 
    Li J, Park J, Foss D, Goldschneider I 2009. Thymus-homing peripheral dendritic cells constitute two of the three major subsets of dendritic cells in the steady-state thymus. J. Exp. Med. 206:607–22
    [Google Scholar]
  197. 197. 
    Au-Yeung BB, Zikherman J, Mueller JL, Ashouri JF, Matloubian M et al. 2014. A sharp T-cell antigen receptor signaling threshold for T-cell proliferation. PNAS 111:E3679–88
    [Google Scholar]
  198. 198. 
    Aschenbrenner K, D'Cruz LM, Vollmann EH, Hinterberger M, Emmerich J et al. 2007. Selection of Foxp3+ regulatory T cells specific for self antigen expressed and presented by Aire+ medullary thymic epithelial cells. Nat. Immunol. 8:351–58
    [Google Scholar]
  199. 199. 
    Lathrop SK, Santacruz NA, Pham D, Luo J, Hsieh CS 2008. Antigen-specific peripheral shaping of the natural regulatory T cell population. J. Exp. Med. 205:3105–17
    [Google Scholar]
  200. 200. 
    Wheeler KM, Samy ET, Tung KS 2009. Cutting edge: normal regional lymph node enrichment of antigen-specific regulatory T cells with autoimmune disease-suppressive capacity. J. Immunol. 183:7635–38
    [Google Scholar]
  201. 201. 
    Samy ET, Wheeler KM, Roper RJ, Teuscher C, Tung KS 2008. Cutting edge: Autoimmune disease in day 3 thymectomized mice is actively controlled by endogenous disease-specific regulatory T cells. J. Immunol. 180:4366–70
    [Google Scholar]
  202. 202. 
    Samy ET, Parker LA, Sharp CP, Tung KS 2005. Continuous control of autoimmune disease by antigen-dependent polyclonal CD4+CD25+ regulatory T cells in the regional lymph node. J. Exp. Med. 202:771–81
    [Google Scholar]
  203. 203. 
    Smigiel KS, Richards E, Srivastava S, Thomas KR, Dudda JC et al. 2014. CCR7 provides localized access to IL-2 and defines homeostatically distinct regulatory T cell subsets. J. Exp. Med. 211:121–36
    [Google Scholar]
  204. 204. 
    Levine AG, Arvey A, Jin W, Rudensky AY 2014. Continuous requirement for the TCR in regulatory T cell function. Nat. Immunol. 15:1070–78
    [Google Scholar]
  205. 205. 
    Vahl JC, Drees C, Heger K, Heink S, Fischer JC et al. 2014. Continuous T cell receptor signals maintain a functional regulatory T cell pool. Immunity 41:722–36
    [Google Scholar]
  206. 206. 
    Sullivan JM, Hollbacher B, Campbell DJ 2019. Cutting edge: Dynamic expression of Id3 defines the stepwise differentiation of tissue-resident regulatory T cells. J. Immunol. 202:31–36
    [Google Scholar]
/content/journals/10.1146/annurev-immunol-100219-020937
Loading
/content/journals/10.1146/annurev-immunol-100219-020937
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error