Thymic and Peripheral Differentiation of Regulatory T Cells

Advances in Immunology

Volumn 112, Issue , 2011, Pages 25-71

  Lee, Hyang Mi ^a   Bautista, Jhoanne Lynne ^a   Hsieh, Chyi Song ^a  

^a WASHINGTON UNIVERSITY   (United States)

Author keywords

Development; Periphery; Regulatory T cells; Thymus; Tolerance

Indexed keywords

CD28 ANTIGEN; CD40 LIGAND; CYANOCOBALAMIN; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INTERLEUKIN 2; INTRINSIC FACTOR; PROTEIN KINASE B; PROTEIN KINASE ZAP 70; RETINOIC ACID; T LYMPHOCYTE RECEPTOR; TRANSCRIPTION FACTOR FOXP3; TRANSFORMING GROWTH FACTOR BETA;

ANTIGEN BINDING; ANTIGEN PRESENTING CELL; ANTIGEN SPECIFICITY; ARTICLE; BINDING AFFINITY; CELL LINEAGE; CELL SELECTION; CYTOKINE PRODUCTION; CYTOKINE RELEASE; EVOLUTIONARY ADAPTATION; HUMAN; IMMUNE RESPONSE; IMMUNOLOGICAL TOLERANCE; IMMUNOSTIMULATION; LYMPHOCYTE DIFFERENTIATION; LYMPHOCYTE SUBPOPULATION; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN INTERACTION; REGULATORY MECHANISM; REGULATORY T LYMPHOCYTE; SIGNAL TRANSDUCTION; TRANSCRIPTION REGULATION;

EID: 82155170631     PISSN: 00652776     EISSN: 15578445     Source Type: Book Series    
DOI: 10.1016/B978-0-12-387827-4.00002-4     Document Type: Chapter

References (207)

1. Anderson M.S., Venanzi E.S., Klein L., Chen Z., Berzins S.P., Turley S.J., von Boehmer H., Bronson R., Dierich A., Benoist C., Mathis D. Projection of an immunological self shadow within the thymus by the aire protein. Science 2002, 298:1395-1401.
2. Anderson M.S., Venanzi E.S., Chen Z., Berzins S.P., Benoist C., Mathis D. The cellular mechanism of Aire control of T cell tolerance. Immunity 2005, 23:227-239.
3. Apostolou I., von Boehmer H. In vivo instruction of suppressor commitment in naive T cells. J. Exp. Med. 2004, 199:1401-1408.
4. Apostolou I., Sarukhan A., Klein L., von Boehmer H. Origin of regulatory T cells with known specificity for antigen. Nat. Immunol. 2002, 3:756-763.
5. Appleby M.W., Ramsdell F. Scurfy, the Foxp3 locus, and the molecular basis of peripheral tolerance. Curr. Top. Microbiol. Immunol. 2008, 321:151-168.
6. Asano M., Toda M., Sakaguchi N., Sakaguchi S. Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation. J. Exp. Med. 1996, 184:387-396.
7. Aschenbrenner K., D'Cruz L.M., Vollmann E.H., Hinterberger M., Emmerich J., Swee L.K., Rolink A., Klein L. Selection of Foxp3+ regulatory T cells specific for self antigen expressed and presented by Aire+ medullary thymic epithelial cells. Nat. Immunol. 2007, 8:351-358.
8. Atarashi K., Tanoue T., Shima T., Imaoka A., Kuwahara T., Momose Y., Cheng G., Yamasaki S., Saito T., Ohba Y., Taniguchi T., Takeda K., et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 2011, 331:337-341.
9. Atibalentja D.F., Byersdorfer C.A., Unanue E.R. Thymus-blood protein interactions are highly effective in negative selection and regulatory T cell induction. J. Immunol. 2009, 183:7909-7918.
10. Azukizawa H., Dohler A., Kanazawa N., Nayak A., Lipp M., Malissen B., Autenrieth I., Katayama I., Riemann M., Weih F., Berberich-Siebelt F., Lutz M.B. Steady state migratory RelB+ langerin+ dermal dendritic cells mediate peripheral induction of antigen-specific CD4+ CD25+ Foxp3+ regulatory T cells. Eur. J. Immunol. 2011, 41:1420-1434.
11. Barnes M.J., Powrie F. Regulatory T cells reinforce intestinal homeostasis. Immunity 2009, 31:401-411.
12. Barnes M.J., Krebs P., Harris N., Eidenschenk C., Gonzalez-Quintial R., Arnold C.N., Crozat K., Sovath S., Moresco E.M., Theofilopoulos A.N., Beutler B., Hoebe K. Commitment to the regulatory T cell lineage requires CARMA1 in the thymus but not in the periphery. PLoS Biol. 2009, 7:e51.
13. Battaglia M., Stabilini A., Roncarolo M.G. Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells. Blood 2005, 105:4743-4748.
14. Bautista J.L., Lio C.W., Lathrop S.K., Forbush K., Liang Y., Luo J., Rudensky A.Y., Hsieh C.S. Intraclonal competition limits the fate determination of regulatory T cells in the thymus. Nat. Immunol. 2009, 10:610-617.
15. Bayer A.L., Lee J.Y., de la Barrera A., Surh C.D., Malek T.R. A function for IL-7R for CD4+CD25+Foxp3+ T regulatory cells. J. Immunol. 2008, 181:225-234.
16. Belkaid Y., Oldenhove G. Tuning microenvironments: Induction of regulatory T cells by dendritic cells. Immunity 2008, 29:362-371.
17. Belkaid Y., Tarbell K. Regulatory T cells in the control of host-microorganism interactions (*). Annu. Rev. Immunol. 2009, 27:551-589.
18. Bensinger S.J., Bandeira A., Jordan M.S., Caton A.J., Laufer T.M. Major histocompatibility complex class II-positive cortical epithelium mediates the selection of CD4(+)25(+) immunoregulatory T cells. J. Exp. Med. 2001, 194:427-438.
19. Benson M.J., Pino-Lagos K., Rosemblatt M., Noelle R.J. All-trans retinoic acid mediates enhanced T reg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation. J. Exp. Med. 2007, 204:1765-1774.
20. Bettelli E., Carrier Y., Gao W., Korn T., Strom T.B., Oukka M., Weiner H.L., Kuchroo V.K. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 2006, 441:235-238.
21. Bosco N., Agenes F., Rolink A.G., Ceredig R. Peripheral T cell lymphopenia and concomitant enrichment in naturally arising regulatory T cells: The case of the pre-Talpha gene-deleted mouse. J. Immunol. 2006, 177:5014-5023.
22. Bouneaud C., Kourilsky P., Bousso P. Impact of negative selection on the T cell repertoire reactive to a self-peptide: A large fraction of T cell clones escapes clonal deletion. Immunity 2000, 13:829-840.
23. Burchill M.A., Yang J., Vang K.B., Moon J.J., Chu H.H., Lio C.W., Vegoe A.L., Hsieh C.S., Jenkins M.K., Farrar M.A. Linked T cell receptor and cytokine signaling govern the development of the regulatory T cell repertoire. Immunity 2008, 28:112-121.
24. Cai Q., Dierich A., Oulad-Abdelghani M., Chan S., Kastner P. Helios deficiency has minimal impact on T cell development and function. J. Immunol. 2009, 183:2303-2311.
25. Canelles M., Park M.L., Schwartz O.M., Fowlkes B.J. The influence of the thymic environment on the CD4-versus-CD8 T lineage decision. Nat. Immunol. 2003, 4:756-764.
26. Chan A.C., Iwashima M., Turck C.W., Weiss A. ZAP-70: A 70 kDa protein-tyrosine kinase that associates with the TCR zeta chain. Cell 1992, 71:649-662.
27. Chen W., Jin W., Hardegen N., Lei K.J., Li L., Marinos N., McGrady G., Wahl S.M. Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J. Exp. Med. 2003, 198:1875-1886.
28. Chen Q., Kim Y.C., Laurence A., Punkosdy G.A., Shevach E.M. IL-2 controls the stability of Foxp3 expression in TGF-beta-induced Foxp3+ T cells in vivo. J. Immunol. 2011, 186:6329-6337.
29. Coombes J.L., Siddiqui K.R., Arancibia-Carcamo C.V., Hall J., Sun C.M., Belkaid Y., Powrie F. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism. J. Exp. Med. 2007, 204:1757-1764.
30. Curotto de Lafaille M.A., Lino A.C., Kutchukhidze N., Lafaille J.J. CD25- T cells generate CD25+Foxp3+ regulatory T cells by peripheral expansion. J. Immunol. 2004, 173:7259-7268.
31. Daniels M.A., Teixeiro E., Gill J., Hausmann B., Roubaty D., Holmberg K., Werlen G., Hollander G.A., Gascoigne N.R., Palmer E. Thymic selection threshold defined by compartmentalization of Ras/MAPK signalling. Nature 2006, 444:724-729.
32. Daniely D., Kern J., Cebula A., Ignatowicz L. Diversity of TCRs on natural Foxp3+ T cells in mice lacking Aire expression. J. Immunol. 2010, 184:6865-6873.
33. Davidson T.S., DiPaolo R.J., Andersson J., Shevach E.M. Cutting edge: IL-2 is essential for TGF-beta-mediated induction of Foxp3+ T regulatory cells. J. Immunol. 2007, 178:4022-4026.
34. D'Cruz L.M., Klein L. Development and function of agonist-induced CD25+Foxp3+ regulatory T cells in the absence of interleukin 2 signaling. Nat. Immunol. 2005, 6:1152-1159.
35. Delgoffe G.M., Kole T.P., Zheng Y., Zarek P.E., Matthews K.L., Xiao B., Worley P.F., Kozma S.C., Powell J.D. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 2009, 30:832-844.
36. Denning T.L., Wang Y.C., Patel S.R., Williams I.R., Pulendran B. Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17-producing T cell responses. Nat. Immunol. 2007, 8:1086-1094.
37. Denning T.L., Norris B.A., Medina-Contreras O., Manicassamy S., Geem D., Madan R., Karp C.L., Pulendran B. Functional specializations of intestinal dendritic cell and macrophage subsets that control Th17 and regulatory T cell responses are dependent on the T cell/APC ratio, source of mouse strain, and regional localization. J. Immunol. 2011, 187:733-747.
38. d'Hennezel E., Ben-Shoshan M., Ochs H.D., Torgerson T.R., Russell L.J., Lejtenyi C., Noya F.J., Jabado N., Mazer B., Piccirillo C.A. FOXP3 forkhead domain mutation and regulatory T cells in the IPEX syndrome. N. Engl. J. Med. 2009, 361:1710-1713.
39. DiPaolo R.J., Shevach E.M. CD4+ T-cell development in a mouse expressing a transgenic TCR derived from a Treg. Eur. J. Immunol. 2009, 39:234-240.
40. Dooley J., Erickson M., Farr A.G. Alterations of the medullary epithelial compartment in the Aire-deficient thymus: Implications for programs of thymic epithelial differentiation. J. Immunol. 2008, 181:5225-5232.
41. Durant L., Watford W.T., Ramos H.L., Laurence A., Vahedi G., Wei L., Takahashi H., Sun H.W., Kanno Y., Powrie F., O'Shea J.J. Diverse targets of the transcription factor STAT3 contribute to T cell pathogenicity and homeostasis. Immunity 2010, 32:605-615.
42. Fang D., Liu Y.C. Proteolysis-independent regulation of PI3K by Cbl-b-mediated ubiquitination in T cells. Nat. Immunol. 2001, 2:870-875.
43. Fantini M.C., Becker C., Monteleone G., Pallone F., Galle P.R., Neurath M.F. Cutting edge: TGF-beta induces a regulatory phenotype in CD4+CD25- T cells through Foxp3 induction and down-regulation of Smad7. J. Immunol. 2004, 172:5149-5153.
44. Feuerer M., Jiang W., Holler P.D., Satpathy A., Campbell C., Bogue M., Mathis D., Benoist C. Enhanced thymic selection of FoxP3+ regulatory T cells in the NOD mouse model of autoimmune diabetes. Proc. Natl. Acad. Sci. USA 2007, 104:18181-18186.
45. Feuerer M., Hill J.A., Kretschmer K., von Boehmer H., Mathis D., Benoist C. Genomic definition of multiple ex vivo regulatory T cell subphenotypes. Proc. Natl. Acad. Sci. USA 2010, 107:5919-5924.
46. Floess S., Freyer J., Siewert C., Baron U., Olek S., Polansky J., Schlawe K., Chang H.D., Bopp T., Schmitt E., Klein-Hessling S., Serfling E., et al. Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol. 2007, 5:e38.
47. Fontenot J.D., Dooley J.L., Farr A.G., Rudensky A.Y. Developmental regulation of Foxp3 expression during ontogeny. J. Exp. Med. 2005, 202:901-906.
48. Fontenot J.D., Rasmussen J.P., Gavin M.A., Rudensky A.Y. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat. Immunol. 2005, 6:1142-1151.
49. Francisco L.M., Salinas V.H., Brown K.E., Vanguri V.K., Freeman G.J., Kuchroo V.K., Sharpe A.H. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J. Exp. Med. 2009, 206:3015-3029.
50. Furtado G.C., Curotto de Lafaille M.A., Kutchukhidze N., Lafaille J.J. Interleukin 2 signaling is required for CD4(+) regulatory T cell function. J. Exp. Med. 2002, 196:851-857.
51. Gandhi R., Kumar D., Burns E.J., Nadeau M., Dake B., Laroni A., Kozoriz D., Weiner H.L., Quintana F.J. Activation of the aryl hydrocarbon receptor induces human type 1 regulatory T cell-like and Foxp3(+) regulatory T cells. Nat. Immunol. 2010, 11:846-853.
52. Garza K.M., Agersborg S.S., Baker E., Tung K.S. Persistence of physiological self antigen is required for the regulation of self tolerance. J. Immunol. 2000, 164:3982-3989.
53. Getnet D., Grosso J.F., Goldberg M.V., Harris T.J., Yen H.R., Bruno T.C., Durham N.M., Hipkiss E.L., Pyle K.J., Wada S., Pan F., Pardoll D.M., et al. A role for the transcription factor Helios in human CD4(+)CD25(+) regulatory T cells. Mol. Immunol. 2010, 47:1595-1600.
54. Gillard G.O., Dooley J., Erickson M., Peltonen L., Farr A.G. Aire-dependent alterations in medullary thymic epithelium indicate a role for Aire in thymic epithelial differentiation. J. Immunol. 2007, 178:3007-3015.
55. Gorelik L., Constant S., Flavell R.A. Mechanism of transforming growth factor beta-induced inhibition of T helper type 1 differentiation. J. Exp. Med. 2002, 195:1499-1505.
56. Gottschalk R.A., Corse E., Allison J.P. TCR ligand density and affinity determine peripheral induction of Foxp3 in vivo. J. Exp. Med. 2010, 207:1701-1711.
57. Granucci F., Vizzardelli C., Pavelka N., Feau S., Persico M., Virzi E., Rescigno M., Moro G., Ricciardi-Castagnoli P. Inducible IL-2 production by dendritic cells revealed by global gene expression analysis. Nat. Immunol. 2001, 2:882-888.
58. Guo F., Iclozan C., Suh W.K., Anasetti C., Yu X.Z. CD28 controls differentiation of regulatory T cells from naive CD4 T cells. J. Immunol. 2008, 181:2285-2291.
59. Gupta S., Manicassamy S., Vasu C., Kumar A., Shang W., Sun Z. Differential requirement of PKC-theta in the development and function of natural regulatory T cells. Mol. Immunol. 2008, 46:213-224.
60. Hall J.A., Cannons J.L., Grainger J.R., Dos Santos L.M., Hand T.W., Naik S., Wohlfert E.A., Chou D.B., Oldenhove G., Robinson M., Grigg M.E., Kastenmayer R., et al. Essential role for retinoic acid in the promotion of CD4(+) T cell effector responses via retinoic acid receptor alpha. Immunity 2011, 34:435-447.
61. Harada Y., Harada Y., Elly C., Ying G., Paik J.H., DePinho R.A., Liu Y.C. Transcription factors Foxo3a and Foxo1 couple the E3 ligase Cbl-b to the induction of Foxp3 expression in induced regulatory T cells. J. Exp. Med. 2010, 207:1381-1391.
62. Haribhai D., Williams J.B., Jia S., Nickerson D., Schmitt E.G., Edwards B., Ziegelbauer J., Yassai M., Li S.H., Relland L.M., Wise P.M., Chen A., et al. A requisite role for induced regulatory T cells in tolerance based on expanding antigen receptor diversity. Immunity 2011, 35:109-122.
63. Hawiger D., Inaba K., Dorsett Y., Guo M., Mahnke K., Rivera M., Ravetch J.V., Steinman R.M., Nussenzweig M.C. Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo. J. Exp. Med. 2001, 194:769-779.
64. Haxhinasto S., Mathis D., Benoist C. The AKT-mTOR axis regulates de novo differentiation of CD4+Foxp3+ cells. J. Exp. Med. 2008, 205:565-574.
65. Hill J.A., Hall J.A., Sun C.M., Cai Q., Ghyselinck N., Chambon P., Belkaid Y., Mathis D., Benoist C. Retinoic acid enhances Foxp3 induction indirectly by relieving inhibition from CD4+CD44hi Cells. Immunity 2008, 29:758-770.
66. Hinterberger M., Aichinger M., da Costa O.P., Voehringer D., Hoffmann R., Klein L. Autonomous role of medullary thymic epithelial cells in central CD4(+) T cell tolerance. Nat. Immunol. 2010, 11:512-519.
67. Hinterberger M., Wirnsberger G., Klein L. B7/CD28 in central tolerance: Costimulation promotes maturation of regulatory T cell precursors and prevents their clonal deletion. Front.Immunol. 2011, 2:1-12.
68. Hori S. c-Rel: A pioneer in directing regulatory T-cell lineage commitment?. Eur. J. Immunol. 2010, 40:664-667.
69. Hsieh C.S., Liang Y., Tyznik A.J., Self S.G., Liggitt D., Rudensky A.Y. Recognition of the peripheral self by naturally arising CD25+ CD4+ T cell receptors. Immunity 2004, 21:267-277.
70. Hsieh C.S., Zheng Y., Liang Y., Fontenot J.D., Rudensky A.Y. An intersection between the self-reactive regulatory and nonregulatory T cell receptor repertoires. Nat. Immunol. 2006, 7:401-410.
71. Hsu L.Y., Tan Y.X., Xiao Z., Malissen M., Weiss A. A hypomorphic allele of ZAP-70 reveals a distinct thymic threshold for autoimmune disease versus autoimmune reactivity. J. Exp. Med. 2009, 206:2527-2541.
72. Huesmann M., Scott B., Kisielow P., von Boehmer H. Kinetics and efficacy of positive selection in the thymus of normal and T cell receptor transgenic mice. Cell 1991, 66:533-540.
73. Isomura I., Palmer S., Grumont R.J., Bunting K., Hoyne G., Wilkinson N., Banerjee A., Proietto A., Gugasyan R., Wu L., McNally A., Steptoe R.J., et al. c-Rel is required for the development of thymic Foxp3+ CD4 regulatory T cells. J. Exp. Med. 2009, 206:3001-3014.
74. Itoh M., Takahashi T., Sakaguchi N., Kuniyasu Y., Shimizu J., Otsuka F., Sakaguchi S. 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. 1999, 162:5317-5326.
75. Jiang W., Anderson M.S., Bronson R., Mathis D., Benoist C. Modifier loci condition autoimmunity provoked by Aire deficiency. J. Exp. Med. 2005, 202:805-815.
76. Jordan M.S., Boesteanu A., Reed A.J., Petrone A.L., Holenbeck A.E., Lerman M.A., Naji A., Caton A.J. Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide. Nat. Immunol. 2001, 2:301-306.
77. Josefowicz S.Z., Rudensky A. Control of regulatory T cell lineage commitment and maintenance. Immunity 2009, 30:616-625.
78. Josefowicz S.Z., Wilson C.B., Rudensky A.Y. Cutting edge: TCR stimulation is sufficient for induction of Foxp3 expression in the absence of DNA methyltransferase 1. J. Immunol. 2009, 182:6648-6652.
79. Kawahata K., Misaki Y., Yamauchi M., Tsunekawa S., Setoguchi K., Miyazaki J., Yamamoto K. Generation of CD4(+)CD25(+) regulatory T cells from autoreactive T cells simultaneously with their negative selection in the thymus and from nonautoreactive T cells by endogenous TCR expression. J. Immunol. 2002, 168:4399-4405.
80. Kerdiles Y.M., Stone E.L., Beisner D.R., McGargill M.A., Ch'en I.L., Stockmann C., Katayama C.D., Hedrick S.M. Foxo transcription factors control regulatory T cell development and function. Immunity 2010, 33:890-904.
81. Killebrew J.R., Perdue N., Kwan A., Thornton A.M., Shevach E.M., Campbell D.J. A self-reactive TCR drives the development of Foxp3+ regulatory T cells that prevent autoimmune disease. J. Immunol. 2011, 187:861-869.
82. Kim H.P., Leonard W.J. CREB/ATF-dependent T cell receptor-induced FoxP3 gene expression: A role for DNA methylation. J. Exp. Med. 2007, 204:1543-1551.
83. Kim J.M., Rudensky A. The role of the transcription factor Foxp3 in the development of regulatory T cells. Immunol. Rev. 2006, 212:86-98.
84. Kim J.M., Rasmussen J.P., Rudensky A.Y. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat. Immunol. 2007, 8:191-197.
85. Knoechel B., Lohr J., Kahn E., Bluestone J.A., Abbas A.K. Sequential development of interleukin 2-dependent effector and regulatory T cells in response to endogenous systemic antigen. J. Exp. Med. 2005, 202:1375-1386.
86. Koonpaew S., Shen S., Flowers L., Zhang W. LAT-mediated signaling in CD4+CD25+ regulatory T cell development. J. Exp. Med. 2006, 203:119-129.
87. Korn T., Bettelli E., Gao W., Awasthi A., Jager A., Strom T.B., Oukka M., Kuchroo V.K. IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature 2007, 448:484-487.
88. Kramer S., Schimpl A., Hunig T. Immunopathology of interleukin (IL) 2-deficient mice: Thymus dependence and suppression by thymus-dependent cells with an intact IL-2 gene. J. Exp. Med. 1995, 182:1769-1776.
89. Kretschmer K., Apostolou I., Hawiger D., Khazaie K., Nussenzweig M.C., von Boehmer H. Inducing and expanding regulatory T cell populations by foreign antigen. Nat. Immunol. 2005, 6:1219-1227.
90. Kronin V., Wu L., Gong S., Nussenzweig M.C., Shortman K. DEC-205 as a marker of dendritic cells with regulatory effects on CD8 T cell responses. Int. Immunol. 2000, 12:731-735.
91. Kuroda N., Mitani T., Takeda N., Ishimaru N., Arakaki R., Hayashi Y., Bando Y., Izumi K., Takahashi T., Nomura T., Sakaguchi S., Ueno T., et al. Development of autoimmunity against transcriptionally unrepressed target antigen in the thymus of Aire-deficient mice. J. Immunol. 2005, 174:1862-1870.
92. Lahl K., Loddenkemper C., Drouin C., Freyer J., Arnason J., Eberl G., Hamann A., Wagner H., Huehn J., Sparwasser T. Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease. J. Exp. Med. 2007, 204:57-63.
93. Lal G., Zhang N., van der Touw W., Ding Y., Ju W., Bottinger E.P., Reid S.P., Levy D.E., Bromberg J.S. Epigenetic regulation of Foxp3 expression in regulatory T cells by DNA methylation. J. Immunol. 2009, 182:259-273.
94. Lathrop S.K., Santacruz N.A., Pham D., Luo J., Hsieh C.S. Antigen-specific peripheral shaping of the natural regulatory T cell population. J. Exp. Med. 2008, 205:3105-3117.
95. Lathrop S.K., Bloom S.M., Rao S.M., Nutsch K., Lio C.-W., Santacruz N., Peterson D.A., Stappenbeck T.S., Hsieh C.S. Peripheral education of the immune system by colonic commensal microbiota. Nature 2011, doi:10.1038/nature10434.
96. Lee H.M., Hsieh C.S. Rare development of Foxp3+ thymocytes in the CD4+CD8+ subset. J. Immunol. 2009, 183:2261-2266.
97. Lei Y., Ripen A.M., Ishimaru N., Ohigashi I., Nagasawa T., Jeker L.T., Bosl M.R., Hollander G.A., Hayashi Y., Malefyt Rde W., Nitta T., Takahama Y. Aire-dependent production of XCL1 mediates medullary accumulation of thymic dendritic cells and contributes to regulatory T cell development. J. Exp. Med. 2011, 208:383-394.
98. Leung M.W., Shen S., Lafaille J.J. TCR-dependent differentiation of thymic Foxp3+ cells is limited to small clonal sizes. J. Exp. Med. 2009, 206:2121-2130.
99. Li M.O., Sanjabi S., Flavell R.A. Transforming growth factor-beta controls development, homeostasis, and tolerance of T cells by regulatory T cell-dependent and -independent mechanisms. Immunity 2006, 25:455-471.
100. Liang S., Alard P., Zhao Y., Parnell S., Clark S.L., Kosiewicz M.M. Conversion of CD4+ CD25- cells into CD4+ CD25+ regulatory T cells in vivo requires B7 costimulation, but not the thymus. J. Exp. Med. 2005, 201:127-137.
101. Lio C.W., Hsieh C.S. A two-step process for thymic regulatory T cell development. Immunity 2008, 28:100-111.
102. Lio C.W., Dodson L.F., Deppong C.M., Hsieh C.S., Green J.M. CD28 facilitates the generation of Foxp3(-) cytokine responsive regulatory T cell precursors. J. Immunol. 2010, 184:6007-6013.
103. Liston A., Lesage S., Wilson J., Peltonen L., Goodnow C.C. Aire regulates negative selection of organ-specific T cells. Nat. Immunol. 2003, 4:350-354.
104. Liston A., Lesage S., Gray D.H., O'Reilly L.A., Strasser A., Fahrer A.M., Boyd R.L., Wilson J., Baxter A.G., Gallo E.M., Crabtree G.R., Peng K., et al. Generalized resistance to thymic deletion in the NOD mouse; a polygenic trait characterized by defective induction of Bim. Immunity 2004, 21:817-830.
105. Liston A., Nutsch K.M., Farr A.G., Lund J.M., Rasmussen J.P., Koni P.A., Rudensky A.Y. Differentiation of regulatory Foxp3+ T cells in the thymic cortex. Proc. Natl. Acad. Sci. USA 2008, 105:11903-11908.
106. Liu Y., Zhang P., Li J., Kulkarni A.B., Perruche S., Chen W. A critical function for TGF-beta signaling in the development of natural CD4+CD25+Foxp3+ regulatory T cells. Nat. Immunol. 2008, 9:632-640.
107. Lohr J., Knoechel B., Jiang S., Sharpe A.H., Abbas A.K. The inhibitory function of B7 costimulators in T cell responses to foreign and self-antigens. Nat. Immunol. 2003, 4:664-669.
108. Long M., Park S.G., Strickland I., Hayden M.S., Ghosh S. Nuclear factor-kappaB modulates regulatory T cell development by directly regulating expression of Foxp3 transcription factor. Immunity 2009, 31:921-931.
109. Maloy K.J., Powrie F. Regulatory T cells in the control of immune pathology. Nat. Immunol. 2001, 2:816-822.
110. Mangan P.R., Harrington L.E., O'Quinn D.B., Helms W.S., Bullard D.C., Elson C.O., Hatton R.D., Wahl S.M., Schoeb T.R., Weaver C.T. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 2006, 441:231-234.
111. Mantel P.Y., Kuipers H., Boyman O., Rhyner C., Ouaked N., Ruckert B., Karagiannidis C., Lambrecht B.N., Hendriks R.W., Crameri R., Akdis C.A., Blaser K., et al. GATA3-driven Th2 responses inhibit TGF-beta1-induced FOXP3 expression and the formation of regulatory T cells. PLoS Biol. 2007, 5:e329.
112. Marie J.C., Letterio J.J., Gavin M., Rudensky A.Y. TGF-beta1 maintains suppressor function and Foxp3 expression in CD4+CD25+ regulatory T cells. J. Exp. Med. 2005, 201:1061-1067.
113. Marie J.C., Liggitt D., Rudensky A.Y. Cellular mechanisms of fatal early-onset autoimmunity in mice with the T cell-specific targeting of transforming growth factor-beta receptor. Immunity 2006, 25:441-454.
114. Maruyama T., Li J., Vaque J.P., Konkel J.E., Wang W., Zhang B., Zhang P., Zamarron B.F., Yu D., Wu Y., Zhuang Y., Gutkind J.S., et al. Control of the differentiation of regulatory T cells and T(H)17 cells by the DNA-binding inhibitor Id3. Nat. Immunol. 2011, 12:86-95.
115. McCaughtry T.M., Hogquist K.A. Central tolerance: What have we learned from mice?. Semin. Immunopathol. 2008, 30:399-409.
116. McCaughtry T.M., Wilken M.S., Hogquist K.A. Thymic emigration revisited. J. Exp. Med. 2007, 204:2513-2520.
117. Medoff B.D., Sandall B.P., Landry A., Nagahama K., Mizoguchi A., Luster A.D., Xavier R.J. Differential requirement for CARMA1 in agonist-selected T-cell development. Eur. J. Immunol. 2009, 39:78-84.
118. Molinero L.L., Yang J., Gajewski T., Abraham C., Farrar M.A., Alegre M.L. CARMA1 controls an early checkpoint in the thymic development of FoxP3+ regulatory T cells. J. Immunol. 2009, 182:6736-6743.
119. Moon J.J., Chu H.H., Pepper M., McSorley S.J., Jameson S.C., Kedl R.M., Jenkins M.K. Naive CD4(+) T cell frequency varies for different epitopes and predicts repertoire diversity and response magnitude. Immunity 2007, 27:203-213.
120. Moran A.E., Holzapfel K.L., Xing Y., Cunningham N.R., Maltzman J.S., Punt J., Hogquist K.A. T cell receptor signal strength in Treg and iNKT cell development demonstrated by a novel fluorescent reporter mouse. J. Exp. Med. 2011, 208:1279-1289.
121. Mouly E., Chemin K., Nguyen H.V., Chopin M., Mesnard L., Leite-de-Moraes M., Burlen-defranoux O., Bandeira A., Bories J.C. The Ets-1 transcription factor controls the development and function of natural regulatory T cells. J. Exp. Med. 2010, 207:2113-2125.
122. Mucida D., Kutchukhidze N., Erazo A., Russo M., Lafaille J.J., Curotto de Lafaille M.A. Oral tolerance in the absence of naturally occurring Tregs. J. Clin. Invest. 2005, 115:1923-1933.
123. Naeher D., Daniels M.A., Hausmann B., Guillaume P., Luescher I., Palmer E. A constant affinity threshold for T cell tolerance. J. Exp. Med. 2007, 204:2553-2559.
124. Nakagawa T., Roth W., Wong P., Nelson A., Farr A., Deussing J., Villadangos J.A., Ploegh H., Peters C., Rudensky A.Y. Cathepsin L: Critical role in Ii degradation and CD4 T cell selection in the thymus. Science 1998, 280:450-453.
125. Nguyen L.P., Bradfield C.A. The search for endogenous activators of the aryl hydrocarbon receptor. Chem. Res. Toxicol. 2008, 21:102-116.
126. Nishio J., Feuerer M., Wong J., Mathis D., Benoist C. Anti-CD3 therapy permits regulatory T cells to surmount T cell receptor-specified peripheral niche constraints. J. Exp. Med. 2010, 207:1879-1889.
127. Nishizuka Y., Sakakura T. Thymus and reproduction: Sex-linked dysgenesia of the gonad after neonatal thymectomy in mice. Science 1969, 166:753-755.
128. Ochando J.C., Homma C., Yang Y., Hidalgo A., Garin A., Tacke F., Angeli V., Li Y., Boros P., Ding Y., Jessberger R., Trinchieri G., et al. Alloantigen-presenting plasmacytoid dendritic cells mediate tolerance to vascularized grafts. Nat. Immunol. 2006, 7:652-662.
129. Olivares-Villagomez D., Wang Y., Lafaille J.J. Regulatory CD4(+) T cells expressing endogenous T cell receptor chains protect myelin basic protein-specific transgenic mice from spontaneous autoimmune encephalomyelitis. J. Exp. Med. 1998, 188:1883-1894.
130. Olivares-Villagomez D., Wensky A.K., Wang Y., Lafaille J.J. Repertoire requirements of CD4+ T cells that prevent spontaneous autoimmune encephalomyelitis. J. Immunol. 2000, 164:5499-5507.
131. O'Malley J.T., Sehra S., Thieu V.T., Yu Q., Chang H.C., Stritesky G.L., Nguyen E.T., Mathur A.N., Levy D.E., Kaplan M.H. Signal transducer and activator of transcription 4 limits the development of adaptive regulatory T cells. Immunology 2009, 127:587-595.
132. Oppenheim J.J. IL-2: More than a T cell growth factor. J. Immunol. 2007, 179:1413-1414.
133. Ouyang W., Beckett O., Ma Q., Li M.O. Transforming growth factor-beta signaling curbs thymic negative selection promoting regulatory T cell development. Immunity 2010, 32:642-653.
134. Ouyang W., Beckett O., Ma Q., Paik J.H., DePinho R.A., Li M.O. Foxo proteins cooperatively control the differentiation of Foxp3+ regulatory T cells. Nat. Immunol. 2010, 11:618-627.
135. Pacholczyk R., Ignatowicz H., Kraj P., Ignatowicz L. Origin and T cell receptor diversity of Foxp3+CD4+CD25+ T cells. Immunity 2006, 25:249-259.
136. Pacholczyk R., Kern J., Singh N., Iwashima M., Kraj P., Ignatowicz L. Nonself-antigens are the cognate specificities of Foxp3+ regulatory T cells. Immunity 2007, 27:493-504.
137. Palmer E., Naeher D. Affinity threshold for thymic selection through a T-cell receptor-co-receptor zipper. Nat. Rev. Immunol. 2009, 9:207-213.
138. Papiernik M., de Moraes M.L., Pontoux C., Vasseur F., Penit C. Regulatory CD4 T cells: Expression of IL-2R alpha chain, resistance to clonal deletion and IL-2 dependency. Int. Immunol. 1998, 10:371-378.
139. Pennington D.J., Silva-Santos B., Silberzahn T., Escorcio-Correia M., Woodward M.J., Roberts S.J., Smith A.L., Dyson P.J., Hayday A.C. Early events in the thymus affect the balance of effector and regulatory T cells. Nature 2006, 444:1073-1077.
140. Picca C.C., Oh S., Panarey L., Aitken M., Basehoar A., Caton A.J. Thymocyte deletion can bias Treg formation toward low-abundance self-peptide. Eur. J. Immunol. 2009, 39:3301-3306.
141. Polansky J.K., Schreiber L., Thelemann C., Ludwig L., Kruger M., Baumgrass R., Cording S., Floess S., Hamann A., Huehn J. 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. 2010, 88:1029-1040.
142. Proietto A.I., van Dommelen S., Zhou P., Rizzitelli A., D'Amico A., Steptoe R.J., Naik S.H., Lahoud M.H., Liu Y., Zheng P., Shortman K., Wu L. Dendritic cells in the thymus contribute to T-regulatory cell induction. Proc. Natl. Acad. Sci. USA 2008, 105:19869-19874.
143. Quintana F.J., Basso A.S., Iglesias A.H., Korn T., Farez M.F., Bettelli E., Caccamo M., Oukka M., Weiner H.L. Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor. Nature 2008, 453:65-71.
144. Quintana F.J., Murugaiyan G., Farez M.F., Mitsdoerffer M., Tukpah A.M., Burns E.J., Weiner H.L. An endogenous aryl hydrocarbon receptor ligand acts on dendritic cells and T cells to suppress experimental autoimmune encephalomyelitis. Proc. Natl. Acad. Sci. USA 2010, 107:20768-20773.
145. Rao S., Gerondakis S., Woltring D., Shannon M.F. c-Rel is required for chromatin remodeling across the IL-2 gene promoter. J. Immunol. 2003, 170:3724-3731.
146. Relland L.M., Mishra M.K., Haribhai D., Edwards B., Ziegelbauer J., Williams C.B. Affinity-based selection of regulatory T cells occurs independent of agonist-mediated induction of Foxp3 expression. J. Immunol. 2009, 182:1341-1350.
147. Ribot J., Enault G., Pilipenko S., Huchenq A., Calise M., Hudrisier D., Romagnoli P., van Meerwijk J.P. Shaping of the autoreactive regulatory T cell repertoire by thymic cortical positive selection. J. Immunol. 2007, 179:6741-6748.
148. Roman E., Shino H., Qin F.X., Liu Y.J. Cutting edge: Hematopoietic-derived APCs select regulatory T cells in thymus. J. Immunol. 2010, 185:3819-3823.
149. Ruan Q., Kameswaran V., Tone Y., Li L., Liou H.C., Greene M.I., Tone M., Chen Y.H. Development of Foxp3(+) regulatory t cells is driven by the c-Rel enhanceosome. Immunity 2009, 31:932-940.
150. Rubtsov Y.P., Rudensky A.Y. TGFbeta signalling in control of T-cell-mediated self-reactivity. Nat. Rev. Immunol. 2007, 7:443-453.
151. Rudra D., Egawa T., Chong M.M., Treuting P., Littman D.R., Rudensky A.Y. Runx-CBFbeta complexes control expression of the transcription factor Foxp3 in regulatory T cells. Nat. Immunol. 2009, 10:1170-1177.
152. Sakaguchi S., Sakaguchi N., Asano M., Itoh M., Toda M. 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. 1995, 155:1151-1164.
153. Salomon B., Lenschow D.J., Rhee L., Ashourian N., Singh B., Sharpe A., Bluestone J.A. B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity 2000, 12:431-440.
154. Saoudi A., Seddon B., Heath V., Fowell D., Mason D. The physiological role of regulatory T cells in the prevention of autoimmunity: The function of the thymus in the generation of the regulatory T cell subset. Immunol. Rev. 1996, 149:195-216.
155. Sasaki T., Irie-Sasaki J., Jones R.G., Oliveira-dos-Santos A.J., Stanford W.L., Bolon B., Wakeham A., Itie A., Bouchard D., Kozieradzki I., Joza N., Mak T.W., et al. Function of PI3Kgamma in thymocyte development, T cell activation, and neutrophil migration. Science 2000, 287:1040-1046.
156. Sauer S., Bruno L., Hertweck A., Finlay D., Leleu M., Spivakov M., Knight Z.A., Cobb B.S., Cantrell D., O'Connor E., Shokat K.M., Fisher A.G., et al. T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR. Proc. Natl. Acad. Sci. USA 2008, 105:7797-7802.
157. Schallenberg S., Tsai P.Y., Riewaldt J., Kretschmer K. Identification of an immediate Foxp3(-) precursor to Foxp3(+) regulatory T cells in peripheral lymphoid organs of nonmanipulated mice. J. Exp. Med. 2010, 207:1393-1407.
158. Schmidt-Supprian M., Courtois G., Tian J., Coyle A.J., Israel A., Rajewsky K., Pasparakis M. Mature T cells depend on signaling through the IKK complex. Immunity 2003, 19:377-389.
159. Schmidt-Supprian M., Tian J., Grant E.P., Pasparakis M., Maehr R., Ovaa H., Ploegh H.L., Coyle A.J., Rajewsky K. Differential dependence of CD4+CD25+ regulatory and natural killer-like T cells on signals leading to NF-kappaB activation. Proc. Natl. Acad. Sci. USA 2004, 101:4566-4571.
160. Schorle H., Holtschke T., Hunig T., Schimpl A., Horak I. Development and function of T cells in mice rendered interleukin-2 deficient by gene targeting. Nature 1991, 352:621-624.
161. Seddon B., Mason D. Peripheral autoantigen induces regulatory T cells that prevent autoimmunity. J. Exp. Med. 1999, 189:877-882.
162. Semple K., Nguyen A., Yu Y., Wang H., Anasetti C., Yu X.Z. Strong CD28 costimulation suppresses induction of regulatory T cells from naive precursors through Lck signaling. Blood 2011, 117:3096-3103.
163. Siggs O.M., Makaroff L.E., Liston A. The why and how of thymocyte negative selection. Curr. Opin. Immunol. 2006, 18:175-183.
164. Siggs O.M., Miosge L.A., Yates A.L., Kucharska E.M., Sheahan D., Brdicka T., Weiss A., Liston A., Goodnow C.C. Opposing functions of the T cell receptor kinase ZAP-70 in immunity and tolerance differentially titrate in response to nucleotide substitutions. Immunity 2007, 27:912-926.
165. Spence P.J., Green E.A. Foxp3+ regulatory T cells promiscuously accept thymic signals critical for their development. Proc. Natl. Acad. Sci. USA 2008, 105:973-978.
166. Starr T.K., Jameson S.C., Hogquist K.A. Positive and negative selection of T cells. Annu. Rev. Immunol. 2003, 21:139-176.
167. Sun C.M., Hall J.A., Blank R.B., Bouladoux N., Oukka M., Mora J.R., Belkaid Y. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J. Exp. Med. 2007, 204:1775-1785.
168. Suzuki H., Kundig T.M., Furlonger C., Wakeham A., Timms E., Matsuyama T., Schmits R., Simard J.J., Ohashi P.S., Griesser H., et al. Deregulated T cell activation and autoimmunity in mice lacking interleukin-2 receptor beta. Science 1995, 268:1472-1476.
169. Suzuki H., Zhou Y.W., Kato M., Mak T.W., Nakashima I. Normal regulatory alpha/beta T cells effectively eliminate abnormally activated T cells lacking the interleukin 2 receptor beta in vivo. J. Exp. Med. 1999, 190:1561-1572.
170. Taguchi O., Kontani K., Ikeda H., Kezuka T., Takeuchi M., Takahashi T., Takahashi T. Tissue-specific suppressor T cells involved in self-tolerance are activated extrathymically by self-antigens. Immunology 1994, 82:365-369.
171. Tai X., Cowan M., Feigenbaum L., Singer A. CD28 costimulation of developing thymocytes induces Foxp3 expression and regulatory T cell differentiation independently of interleukin 2. Nat. Immunol. 2005, 6:152-162.
172. Takaki H., Ichiyama K., Koga K., Chinen T., Takaesu G., Sugiyama Y., Kato S., Yoshimura A., Kobayashi T. STAT6 Inhibits TGF-beta1-mediated Foxp3 induction through direct binding to the Foxp3 promoter, which is reverted by retinoic acid receptor. J. Biol. Chem. 2008, 283:14955-14962.
173. Thornton A.M., Korty P.E., Tran D.Q., Wohlfert E.A., Murray P.E., Belkaid Y., Shevach E.M. Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells. J. Immunol. 2010, 184:3433-3441.
174. Tone Y., Furuuchi K., Kojima Y., Tykocinski M.L., Greene M.I., Tone M. Smad3 and NFAT cooperate to induce Foxp3 expression through its enhancer. Nat. Immunol. 2008, 9:194-202.
175. van Santen H.M., Benoist C., Mathis D. Number of T reg cells that differentiate does not increase upon encounter of agonist ligand on thymic epithelial cells. J. Exp. Med. 2004, 200:1221-1230.
176. Vang K.B., Yang J., Mahmud S.A., Burchill M.A., Vegoe A.L., Farrar M.A. IL-2, -7, and -15, but not thymic stromal lymphopoeitin, redundantly govern CD4+Foxp3+ regulatory T cell development. J. Immunol. 2008, 181:3285-3290.
177. Vang K.B., Yang J., Pagan A.J., Li L.X., Wang J., Green J.M., Beg A.A., Farrar M.A. Cutting edge: CD28 and c-Rel-dependent pathways initiate regulatory T cell development. J. Immunol. 2010, 184:4074-4077.
178. Veldhoen M., Hocking R.J., Atkins C.J., Locksley R.M., Stockinger B. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 2006, 24:179-189.
179. Veldhoen M., Hirota K., Westendorf A.M., Buer J., Dumoutier L., Renauld J.C., Stockinger B. The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 2008, 453:106-109.
180. Venuprasad K., Huang H., Harada Y., Elly C., Subramaniam M., Spelsberg T., Su J., Liu Y.C. The E3 ubiquitin ligase Itch regulates expression of transcription factor Foxp3 and airway inflammation by enhancing the function of transcription factor TIEG1. Nat. Immunol. 2008, 9:245-253.
181. Verginis P., McLaughlin K.A., Wucherpfennig K.W., von Boehmer H., Apostolou I. Induction of antigen-specific regulatory T cells in wild-type mice: Visualization and targets of suppression. Proc. Natl. Acad. Sci. USA 2008, 105:3479-3484.
182. Verhagen J., Gabrysova L., Minaee S., Sabatos C.A., Anderson G., Sharpe A.H., Wraith D.C. Enhanced selection of FoxP3+ T-regulatory cells protects CTLA-4-deficient mice from CNS autoimmune disease. Proc. Natl. Acad. Sci. USA 2009, 106:3306-3311.
183. Walsh P.T., Buckler J.L., Zhang J., Gelman A.E., Dalton N.M., Taylor D.K., Bensinger S.J., Hancock W.W., Turka L.A. PTEN inhibits IL-2 receptor-mediated expansion of CD4+ CD25+ Tregs. J. Clin. Invest. 2006, 116:2521-2531.
184. Wan Y.Y., Chi H., Xie M., Schneider M.D., Flavell R.A. The kinase TAK1 integrates antigen and cytokine receptor signaling for T cell development, survival and function. Nat. Immunol. 2006, 7:851-858.
185. Weaver C.T., Hatton R.D. Interplay between the TH17 and TReg cell lineages: A (co-)evolutionary perspective. Nat. Rev. Immunol. 2009, 9:883-889.
186. Webster K.E., Walters S., Kohler R.E., Mrkvan T., Boyman O., Surh C.D., Grey S.T., Sprent J. In vivo expansion of T reg cells with IL-2-mAb complexes: Induction of resistance to EAE and long-term acceptance of islet allografts without immunosuppression. J. Exp. Med. 2009, 206:751-760.
187. Wei J., Duramad O., Perng O.A., Reiner S.L., Liu Y.J., Qin F.X. Antagonistic nature of T helper 1/2 developmental programs in opposing peripheral induction of Foxp3+ regulatory T cells. Proc. Natl. Acad. Sci. USA 2007, 104:18169-18174.
188. Wilson C.B., Makar K.W., Shnyreva M., Fitzpatrick D.R. DNA methylation and the expanding epigenetics of T cell lineage commitment. Semin. Immunol. 2005, 17:105-119.
189. Wing K., Sakaguchi S. Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nat. Immunol. 2010, 11:7-13.
190. Wirnsberger G., Mair F., Klein L. Regulatory T cell differentiation of thymocytes does not require a dedicated antigen-presenting cell but is under T cell-intrinsic developmental control. Proc. Natl. Acad. Sci. USA 2009, 106:10278-10283.
191. Wohlfert E.A., Gorelik L., Mittler R., Flavell R.A., Clark R.B. Cutting edge: Deficiency in the E3 ubiquitin ligase Cbl-b results in a multifunctional defect in T cell TGF-beta sensitivity in vitro and in vivo. J. Immunol. 2006, 176:1316-1320.
192. Wong J., Mathis D., Benoist C. TCR-based lineage tracing: No evidence for conversion of conventional into regulatory T cells in response to a natural self-antigen in pancreatic islets. J. Exp. Med. 2007, 204:2039-2045.
193. Wong J., Obst R., Correia-Neves M., Losyev G., Mathis D., Benoist C. Adaptation of TCR repertoires to self-peptides in regulatory and nonregulatory CD4+ T cells. J. Immunol. 2007, 178:7032-7041.
194. Xiao S., Jin H., Korn T., Liu S.M., Oukka M., Lim B., Kuchroo V.K. Retinoic acid increases Foxp3+ regulatory T cells and inhibits development of Th17 cells by enhancing TGF-beta-driven Smad3 signaling and inhibiting IL-6 and IL-23 receptor expression. J. Immunol. 2008, 181:2277-2284.
195. Xu L., Kitani A., Stuelten C., McGrady G., Fuss I., Strober W. Positive and negative transcriptional regulation of the Foxp3 gene is mediated by access and binding of the Smad3 protein to enhancer I. Immunity 2010, 33:313-325.
196. Yamaguchi T., Sakaguchi S. Regulatory T cells in immune surveillance and treatment of cancer. Semin. Cancer Biol. 2006, 16:115-123.
197. Yamazaki S., Bonito A.J., Spisek R., Dhodapkar M., Inaba K., Steinman R.M. Dendritic cells are specialized accessory cells along with TGF- for the differentiation of Foxp3+ CD4+ regulatory T cells from peripheral Foxp3 precursors. Blood 2007, 110:4293-4302.
198. Yang X.P., Ghoreschi K., Steward-Tharp S.M., Rodriguez-Canales J., Zhu J., Grainger J.R., Hirahara K., Sun H.W., Wei L., Vahedi G., Kanno Y., O'Shea J.J., et al. Opposing regulation of the locus encoding IL-17 through direct, reciprocal actions of STAT3 and STAT5. Nat. Immunol. 2011, 12:247-254.
199. Yano M., Kuroda N., Han H., Meguro-Horike M., Nishikawa Y., Kiyonari H., Maemura K., Yanagawa Y., Obata K., Takahashi S., Ikawa T., Satoh R., et al. Aire controls the differentiation program of thymic epithelial cells in the medulla for the establishment of self-tolerance. J. Exp. Med. 2008, 205:2827-2838.
200. Yao Z., Kanno Y., Kerenyi M., Stephens G., Durant L., Watford W.T., Laurence A., Robinson G.W., Shevach E.M., Moriggl R., Hennighausen L., Wu C., et al. Nonredundant roles for Stat5a/b in directly regulating Foxp3. Blood 2007, 109:4368-4375.
201. Zehn D., Bevan M.J. T cells with low avidity for a tissue-restricted antigen routinely evade central and peripheral tolerance and cause autoimmunity. Immunity 2006, 25:261-270.
202. Zheng S.G., Wang J.H., Stohl W., Kim K.S., Gray J.D., Horwitz D.A. TGF-beta requires CTLA-4 early after T cell activation to induce FoxP3 and generate adaptive CD4+CD25+ regulatory cells. J. Immunol. 2006, 176:3321-3329.
203. Zheng Y., Josefowicz S., Chaudhry A., Peng X.P., Forbush K., Rudensky A.Y. Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature 2010, 463:808-812.
204. Zhou L., Lopes J.E., Chong M.M., Ivanov I.I., Min R., Victora G.D., Shen Y., Du J., Rubtsov Y.P., Rudensky A.Y., Ziegler S.F., Littman D.R. TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature 2008, 453:236-240.
205. Zhou X., Bailey-Bucktrout S.L., Jeker L.T., Penaranda C., Martinez-Llordella M., Ashby M., Nakayama M., Rosenthal W., Bluestone J.A. Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat. Immunol. 2009, 10:1000-1007.
206. Ziegler S.F. FOXP3: Of mice and men. Annu. Rev. Immunol. 2006, 24:209-226.
207. Zorn E., Nelson E.A., Mohseni M., Porcheray F., Kim H., Litsa D., Bellucci R., Raderschall E., Canning C., Soiffer R.J., Frank D.A., Ritz J. 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 2006, 108:1571-1579.