Organ-specific and memory Treg cells: Specificity, development, function, and maintenance

Frontiers in Immunology

Volumn 5, Issue JUL, 2014, Pages

  Gratz, Iris K ^a,b,c   Campbell, Daniel J ^d,e  

^a UNIVERSITY OF SALZBURG   (Austria)

^b UNIVERSITY OF CALIFORNIA   (United States)

^c PARACELSUS MEDICAL UNIVERSITY   (Austria)

^d BENAROYA RESEARCH INSTITUTE   (United States)

^e UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE   (United States)

Author keywords

Foxp3; Immune memory; Immune tolerance; Regulatory T cells; T cell homeostasis

Indexed keywords

EID: 84905645315     PISSN: None     EISSN: 16643224     Source Type: Journal    
DOI: 10.3389/fimmu.2014.00333     Document Type: Review

References (181)

1. Curotto de Lafaille MA, Lafaille JJ. Natural and adaptive Foxp3+ regulatory T cells: more of the same or a division of labor? Immunity (2009) 30:626-35. doi: 10.1016/j.immuni.2009.05.002
2. Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L, et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet (2001) 27:20-1. doi:10.1038/83713
3. Rai E, Wakeland EK. Genetic predisposition to autoimmunity - what have we learned? Semin Immunol (2011) 23:67-83. doi:10.1016/j.smim.2011.01.015
4. Veiga-Parga T, Sehrawat S, Rouse BT. Role of regulatory T cells during virus infection. Immunol Rev (2013) 255:182-96. doi:10.1111/imr.12085
5. Waldmann H, Hilbrands R, Howie D, Cobbold S. Harnessing FOXP3+ regulatory T cells for transplantation tolerance. J Clin Invest (2014) 124:1439-45. doi:10.1172/JCI67226
6. Nishikawa H, Sakaguchi S. Regulatory T cells in cancer immunotherapy. Curr Opin Immunol (2014) 27C:1-7. doi:10.1016/j.coi.2013.12.005
7. 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) 155:1151-64.
8. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science (2003) 299:1057-61. doi:10.1126/science.1079490
9. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol (2003) 4:330-6. doi:10.1038/ni904
10. Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, Rudensky AY. Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity (2005) 22:329-41. doi:10.1016/j.immuni.2005.01.016
11. Huehn J, Siegmund K, Lehmann JCU, Siewert C, Haubold U, Feuerer M, et al. Developmental stage, phenotype, and migration distinguish naive- and effector/memory-like CD4+ regulatory T cells. J Exp Med (2004) 199:303-13. doi:10.1084/jem.20031562
12. Sather BD, Treuting P, Perdue N, Miazgowicz M, Fontenot JD, Rudensky AY, et al. Altering the distribution of Foxp3(+) regulatory T cells results in tissue-specific inflammatory disease. J Exp Med (2007) 204:1335-47. doi:10.1084/jem.20070081
13. Suffia I, Reckling SK, Salay G, Belkaid Y. A role for CD103 in the retention of CD4+CD25+ Treg and control of Leishmania major infection. J Immunol (2005) 174:5444-55. doi:10.4049/jimmunol.174.9.5444
14. Chen Z, Herman AE, Matos M, Mathis D, Benoist C. Where CD4+CD25+ T reg cells impinge on autoimmune diabetes. J Exp Med (2005) 202:1387-97. doi:10.1084/jem.20051409
15. Nguyen LT, Jacobs J, Mathis D, Benoist C. Where FoxP3-dependent regulatory T cells impinge on the development of inflammatory arthritis. Arthritis Rheum (2007) 56:509-20. doi:10.1002/art.22272
16. Szanya V, Ermann J, Taylor C, Holness C, Fathman CG. The subpopulation of CD4+CD25+ splenocytes that delays adoptive transfer of diabetes expresses L-selectin and high levels of CCR7. J Immunol (2002) 169:2461-5. doi:10.4049/jimmunol.169.5.2461
17. Dudda JC, Perdue N, Bachtanian E, Campbell DJ. Foxp3+ regulatory T cells maintain immune homeostasis in the skin. J Exp Med (2008) 205:1559-65. doi:10.1084/jem.20072594
18. Denning TL, Kim G, Kronenberg M. Cutting edge: CD4+CD25+ regulatory T cells impaired for intestinal homing can prevent colitis. J Immunol (2005) 174:7487-91. doi:10.4049/jimmunol.174.12.7487
19. Willerford DM, Chen J, Ferry JA, Davidson L, Ma A, Alt FW. Interleukin-2 receptor alpha chain regulates the size and content of the peripheral lymphoid compartment. Immunity (1995) 3:521-30. doi:10.1016/1074-7613(95)90180-9
20. Sadlack B, Merz H, Schorle H, Schimpl A, Feller AC, Horak I. Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell (1993) 75:253-61. doi:10.1016/0092-8674(93)80067-O
21. Singh B, Read S, Asseman C, Malmström V, Mottet C, Stephens LA, et al. Control of intestinal inflammation by regulatory T cells. Immunol Rev (2001) 182:190-200. doi:10.1034/j.1600-065X.2001.1820115.x
22. Hirahara K, Liu L, Clark RA, Yamanaka K, Fuhlbrigge RC, Kupper TS. The majority of human peripheral blood CD4+CD25highFoxp3+ regulatory T cells bear functional skin-homing receptors. J Immunol (2006) 177:4488-94. doi:10.4049/jimmunol.177.7.4488
23. Iellem A, Colantonio L, D'Ambrosio D. Skin-versus gut-skewed homing receptor expression and intrinsic CCR4 expression on human peripheral blood CD4+CD25+ suppressor T cells. Eur J Immunol (2003) 33:1488-96. doi:10.1002/eji.200323658
24. Klonowski KD, Williams KJ, Marzo AL, Blair DA, Lingenheld EG, Lefrançois L. Dynamics of blood-borne CD8 memory T cell migration in vivo. Immunity (2004) 20:551-62. doi:10.1016/S1074-7613(04)00103-7
25. Smigiel KS, Richards E, Srivastava S, Thomas KR, Dudda JC, Klonowski KD, et al. CCR7 provides localized access to IL-2 and defines homeostatically distinct regulatory T cell subsets. J Exp Med (2014) 211:121-36. doi:10.1084/jem.20131142
26. Grindebacke H, Stenstad H, Quiding-Järbrink M, Waldenström J, Adlerberth I, Wold AE, et al. Dynamic development of homing receptor expression and memory cell differentiation of infant CD4+CD25high regulatory T cells. J Immunol (2009) 183:4360-70. doi:10.4049/jimmunol.0901091
27. Thornton AM, Korty PE, Tran DQ, Wohlfert EA, Murray PE, Belkaid Y, et al. Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells. J Immunol (2010) 184:3433-41. doi:10.4049/jimmunol.0904028
28. Weiss JM, Bilate AM, Gobert M, Ding Y, Curotto de Lafaille MA, Parkhurst CN, et al. Neuropilin 1 is expressed on thymus-derived natural regulatory T cells, but not mucosa-generated induced Foxp3+ T reg cells. J Exp Med (2012) 209(1723-1742):S1. doi:10.1084/jem.20120914
29. Yadav M, Louvet C, Davini D, Gardner JM, Martinez-Llordella M, Bailey-Bucktrout S, et al. Neuropilin-1 distinguishes natural and inducible regulatory T cells among regulatory T cell subsets in vivo. J Exp Med (2012) 209:1713-22. doi:10.1084/jem.20120822
30. Coombes JL, Siddiqui KRR, Arancibia-Cárcamo CV, Hall J, Sun C-M, Belkaid Y, et al. 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) 204:1757-64. doi:10.1084/jem.20070590
31. Sun C-M, Hall JA, Blank RB, Bouladoux N, Oukka M, Mora JR, et al. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J Exp Med (2007) 204:1775-85. doi:10.1084/jem.20070602
32. Jaensson E, Uronen-Hansson H, Pabst O, Eksteen B, Tian J, Coombes JL, et al. Small intestinal CD103+ dendritic cells display unique functional properties that are conserved between mice and humans. J Exp Med (2008) 205:2139-49. doi:10.1084/jem.20080414
33. Lathrop SK, Bloom SM, Rao SM, Nutsch K, Lio C-W, Santacruz N, et al. Peripheral education of the immune system by colonic commensal microbiota. Nature (2011) 478:250-4. doi:10.1038/nature10434
34. Hand TW, Dos Santos LM, Bouladoux N, Molloy MJ, Pagán AJ, Pepper M, et al. Acute gastrointestinal infection induces long-lived microbiota- specific T cell responses. Science (2012) 337:1553-6. doi:10.1126/science.1220961
35. Takeuchi H, Yokota A, Ohoka Y, Kagechika H, Kato C, Song S-Y, et al. Efficient induction of CCR9 on T cells requires coactivation of retinoic acid receptors and retinoid X receptors (RXRs): exaggerated T Cell homing to the intestine by RXR activation with organotins. J Immunol (2010) 185:5289-99. doi:10.4049/jimmunol.1000101
36. Sutmuller RPM, den Brok MHMGM, Kramer M, Bennink EJ, Toonen LWJ, Kullberg B-J, et al. Toll-like receptor 2 controls expansion and function of regulatory T cells. J Clin Invest (2006) 116:485-94. doi:10.1172/JCI25439
37. Hall JA, Bouladoux N, Sun CM, Wohlfert EA, Blank RB, Zhu Q, et al. Commensal DNA limits regulatory T cell conversion and is a natural adjuvant of intestinal immune responses. Immunity (2008) 29:637-49. doi:10.1016/j.immuni.2008.08.009
38. Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature (2006) 441:235-8. doi:10.1038/nature04753
39. Pasare C, Medzhitov R. Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science (2003) 299:1033-6. doi:10.1126/science.1078231
40. Arpaia N, Campbell C, Fan X, Dikiy S, van der Veeken J, deRoos P, et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature (2013) 504:451-5. doi:10.1038/nature12726
41. Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA, Bohlooly-Y M, et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science (2013) 341:569-73. doi:10.1126/science.1241165
42. Furusawa Y, Obata Y, Fukuda S, Endo TA, Nakato G, Takahashi D, et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature (2013) 504:446-50. doi:10.1038/nature12721
43. Maslowski KM, Vieira AT, Ng A, Kranich J, Sierro F, Yu D, et al. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature (2009) 461:1282-6. doi:10.1038/nature08530
44. Sanchez Rodriguez R, Pauli ML, Neuhaus IM, Yu SS, Arron ST, Harris HW, et al. Memory regulatory T cells reside in human skin. J Clin Invest (2014) 124:1027-36. doi:10.1172/JCI72932
45. Siegmund K, Feuerer M, Siewert C, Ghani S, Haubold U, Dankof A, et al. Migration matters: regulatory T-cell compartmentalization determines suppressive activity in vivo. Blood (2005) 106:3097-104. doi:10.1182/blood-2005-05-1864
46. Freyschmidt E-J, Mathias CB, Diaz N, MacArthur DH, Laouar A, Manjunath N, et al. Skin inflammation arising from cutaneous regulatory T cell deficiency leads to impaired viral immune responses. J Immunol (2010) 185:1295-302. doi:10.4049/jimmunol.0903144
47. Halabi-Tawil M, Ruemmele FM, Fraitag S, Rieux-Laucat F, Neven B, Brousse N, et al. Cutaneous manifestations of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Br J Dermatol (2009) 160:645-51. doi:10.1111/j.1365-2133.2008.08835.x
48. Godfrey VL, Wilkinson JE, Russell LB. X-linked lymphoreticular disease in the scurfy (sf) mutant mouse. Am J Pathol (1991) 138:1379-87.
49. Gratz IK, Truong H-A, Yang SH-Y, Maurano MM, Lee K, Abbas AK, et al. Cutting edge: memory regulatory T cells require IL-7 and not IL-2 for their maintenance in peripheral tissues. J Immunol (2013) 190(9):4483-7. doi:10.4049/jimmunol.1300212
50. Matsue H, Bergstresser PR, Takashima A. Keratinocyte-derived IL-7 serves as a growth factor for dendritic epidermal T cells in mice. J Immunol (1993) 151:6012-9.
51. Soontrapa K, Honda T, Sakata D, Yao C, Hirata T, Hori S, et al. Prostaglandin E2-prostaglandin E receptor subtype 4 (EP4) signaling mediates UV irradiation-induced systemic immunosuppression. Proc Natl Acad Sci U S A (2011) 108:6668-73. doi:10.1073/pnas.1018625108
52. Guilliams M, Crozat K, Henri S, Tamoutounour S, Grenot P, Devilard E, et al. Skin-draining lymph nodes contain dermis-derived CD103- dendritic cells that constitutively produce retinoic acid and induce Foxp3+ regulatory T cells. Blood (2010) 115:1958-68. doi:10.1182/blood-2009-09-245274
53. Lathrop SK, Santacruz NA, Pham D, Luo J, Hsieh C-S. Antigen-specific peripheral shaping of the natural regulatory T cell population. J Exp Med (2008) 205:3105-17. doi:10.1084/jem.20081359
54. Killebrew JR, Perdue N, Kwan A, Thornton AM, Shevach EM, Campbell DJ. A self-reactive TCR drives the development of Foxp3+ regulatory T cells that prevent autoimmune disease. J Immunol (2011) 187:861-9. doi:10.4049/jimmunol.1004009
55. Rosenblum MD, Gratz IK, Paw JS, Lee K, Marshak-Rothstein A, Abbas AK. Response to self antigen imprints regulatory memory in tissues. Nature (2011) 480:538-42. doi:10.1038/nature10664
56. Grice EA, Segre JA. The skin microbiome. Nat Rev Microbiol (2011) 9:244-53. doi:10.1038/nrmicro2537
57. Naik S, Bouladoux N, Wilhelm C, Molloy MJ, Salcedo R, Kastenmuller W, et al. Compartmentalized control of skin immunity by resident commensals. Science (2012) 337:1115-9. doi:10.1126/science.1225152
58. Schenten D, Nish SA, Yu S, Yan X, Lee HK, Brodsky I, et al. Signaling through the adaptor molecule MyD88 in CD4+ T cells is required to overcome suppression by regulatory T cells. Immunity (2014) 40:78-90. doi:10.1016/j.immuni.2013.10.023
59. Gratz IK, Rosenblum MD, Maurano MM, Paw JS, Truong H-A, Marshak-Rothstein A, et al. Cutting edge: self-antigen controls the balance between effector and regulatory T cells in peripheral tissues. J Immunol (2014) 192:1351-5. doi:10.4049/jimmunol.1301777
60. Mikhak Z, Fleming CM, Medoff BD, Thomas SY, Tager AM, Campanella GS, et al. STAT1 in peripheral tissue differentially regulates homing of antigen-specific Th1 and Th2 cells. J Immunol (2006) 176:4959-67. doi:10.4049/jimmunol.176.8.4959
61. Hirota K, Yoshitomi H, Hashimoto M, Maeda S, Teradaira S, Sugimoto N, et al. Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model. J Exp Med (2007) 204:2803-12. doi:10.1084/jem.20071397
62. Lord GM, Rao RM, Choe H, Sullivan BM, Lichtman AH, Luscinskas FW, et al. T-bet is required for optimal proinflammatory CD4+ T-cell trafficking. Blood (2005) 106:3432-9. doi:10.1182/blood-2005-04-1393
63. Koch MA, Tucker-Heard G, Perdue NR, Killebrew JR, Urdahl KB, Campbell DJ. The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nat Immunol (2009) 10:595-602. doi:10.1038/ni.1731
64. Chaudhry A, Rudra D, Treuting P, Samstein RM, Liang Y, Kas A, et al. CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner. Science (2009) 326:986-91. doi:10.1126/science.1172702
65. Zheng Y, Chaudhry A, Kas A, deRoos P, Kim JM, Chu T-T, et al. Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses. Nature (2009) 458:351-6. doi:10.1038/nature07674
66. Dominguez-Villar M, Baecher-Allan CM, Hafler DA. Identification of T helper type 1-like, Foxp3+ regulatory T cells in human autoimmune disease. Nat Med (2011) 17:673-5. doi:10.1038/nm.2389
67. McClymont SA, Putnam AL, Lee MR, Esensten JH, Liu W, Hulme MA, et al. Plasticity of human regulatory T cells in healthy subjects and patients with type 1 diabetes. J Immunol (2011) 186:3918-26. doi:10.4049/jimmunol.1003099
68. Duhen T, Duhen R, Lanzavecchia A, Sallusto F, Campbell DJ. Functionally distinct subsets of human FOXP3+ Treg cells that phenotypically mirror effector Th cells. Blood (2012) 119:4430-40. doi:10.1182/blood-2011-11-392324
69. Ayyoub M, Deknuydt F, Raimbaud I, Dousset C, Leveque L, Bioley G, et al. Human memory FOXP3+ Tregs secrete IL-17 ex vivo and constitutively express the TH17 lineage-specific transcription factor RORγt. Proc Natl Acad Sci U S A (2009) 106:8635-40. doi:10.1073/pnas.0900621106
70. Cretney E, Xin A, Shi W, Minnich M, Masson F, Miasari M, et al. The transcription factors Blimp-1 and IRF4 jointly control the differentiation and function of effector regulatory T cells. Nat Immunol (2011) 12:304-11. doi:10.1038/ni.2006
71. Makita S, Kanai T, Oshima S, Uraushihara K, Totsuka T, Sawada T, et al. CD4+CD25bright T cells in human intestinal lamina propria as regulatory cells. J Immunol (2004) 173:3119-30. doi:10.4049/jimmunol.173.5.3119
72. Feger U, Luther C, Poeschel S, Melms A, Tolosa E, Wiendl H. Increased frequency of CD4+ CD25+ regulatory T cells in the cerebrospinal fluid but not in the blood of multiple sclerosis patients. Clin Exp Immunol (2007) 147:412-8. doi:10.1111/j.1365-2249.2006.03271.x
73. Cao D, Malmström V, Baecher-Allan C, Hafler D, Klareskog L, Trollmo C. Isolation and functional characterization of regulatory CD25brightCD4+ T cells from the target organ of patients with rheumatoid arthritis. Eur J Immunol (2003) 33:215-23. doi:10.1002/immu.200390024
74. Korn T, Reddy J, Gao W, Bettelli E, Awasthi A, Petersen TR, et al. Myelin-specific regulatory T cells accumulate in the CNS but fail to control autoimmune inflammation. Nat Med (2007) 13:423-31. doi:10.1038/nm1564
75. Tang Q, Adams JY, Penaranda C, Melli K, Piaggio E, Sgouroudis E, et al. Central role of defective interleukin-2 production in the triggering of islet autoimmune destruction. Immunity (2008) 28:687-97. doi:10.1016/j.immuni.2008.03.016
76. Long SA, Buckner JH. CD4+FOXP3+ T regulatory cells in human autoimmunity: more than a numbers game. J Immunol (2011) 187:2061-6. doi:10.4049/jimmunol.1003224
77. Ohkura N, Hamaguchi M, Morikawa H, Sugimura K, Tanaka A, Ito Y, et al. T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development. Immunity (2012) 37:785-99. doi:10.1016/j.immuni.2012.09.010
78. Arvey A, van der Veeken J, Samstein RM, Feng Y, Stamatoyannopoulos JA, Rudensky AY. Inflammation-induced repression of chromatin bound by the transcription factor Foxp3 in regulatory T cells. Nat Immunol (2014) 15(6):580-7. doi:10.1038/ni.2868
79. Hippen KL, Riley JL, June CH, Blazar BR. Clinical perspectives for regulatory T cells in transplantation tolerance. Semin Immunol (2011) 23:462-8. doi:10.1016/j.smim.2011.07.008
80. Herold KC, Vignali DAA, Cooke A, Bluestone JA. Type 1 diabetes: translating mechanistic observations into effective clinical outcomes. Nat Rev Immunol (2013) 13:243-56. doi:10.1038/nri3422
81. Bensinger SJ, Bandeira A, Jordan MS, Caton AJ, Laufer TM. Major histocompatibility complex class II-positive cortical epithelium mediates the selection of CD4(+)25(+) immunoregulatory T cells. J Exp Med (2001) 194:427-38. doi:10.1084/jem.194.4.427
82. Fisson S, Darrasse-Jèze G, Litvinova E, Septier F, Klatzmann D, Liblau R, et al. Continuous activation of autoreactive CD4+ CD25+ regulatory T cells in the steady state. J Exp Med (2003) 198:737-46. doi:10.1084/jem.20030686
83. Hsieh C-S, Liang Y, Tyznik AJ, Self SG, Liggitt D, Rudensky AY. Recognition of the peripheral self by naturally arising CD25+ CD4+ T cell receptors. Immunity (2004) 21:267-77. doi:10.1016/j.immuni.2004.07.009
84. Walker LSK, Chodos A, Eggena M, Dooms H, Abbas AK. Antigen-dependent proliferation of CD4+ CD25+ regulatory T cells in vivo. J Exp Med (2003) 198:249-58. doi:10.1084/jem.20030315
85. Jordan MS, Boesteanu A, Reed AJ, Petrone AL, Holenbeck AE, Lerman MA, et al. Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide. Nat Immunol (2001) 2:301-6. doi:10.1038/86302
86. Klein L, Khazaie K, von Boehmer H. In vivo dynamics of antigen-specific regulatory T cells not predicted from behavior in vitro. Proc Natl Acad Sci U S A (2003) 100:8886-91. doi:10.1073/pnas.1533365100
87. Aschenbrenner K, D'Cruz LM, Vollmann EH, Hinterberger M, Emmerich J, Swee LK, et al. Selection of Foxp3+ regulatory T cells specific for self antigen expressed and presented by Aire+ medullary thymic epithelial cells. Nat Immunol (2007) 8:351-8. doi:10.1038/ni1444
88. Malchow S, Leventhal DS, Nishi S, Fischer BI, Shen L, Paner GP, et al. Aire-dependent thymic development of tumor-associated regulatory T cells. Science (2013) 339:1219-24. doi:10.1126/science.1233913
89. Daniely D, Kern J, Cebula A, Ignatowicz L. Diversity of TCRs on natural Foxp3+ T cells in mice lacking Aire expression. J Immunol (2010) 184:6865-73. doi:10.4049/jimmunol.0903609
90. Dongre AR, Kovats S, deRoos P, McCormack AL, Nakagawa T, Paharkova-Vatchkova V, et al. In vivo MHC class II presentation of cytosolic proteins revealed by rapid automated tandem mass spectrometry and functional analyses. Eur J Immunol (2001) 31:1485-94. doi:10.1002/1521-4141(200105)31:5<1485::AID-IMMU1485>3.0.CO;2-A
91. Bautista JL, Lio C-WJ, Lathrop SK, Forbush K, Liang Y, Luo J, et al. Intraclonal competition limits the fate determination of regulatory T cells in the thymus. Nat Immunol (2009) 10:610-7. doi:10.1038/ni.1739
92. Singh NJ, Bando JK, Schwartz RH. Subsets of nonclonal neighboring CD4+ T cells specifically regulate the frequency of individual antigen-reactive T cells. Immunity (2012) 37:735-46. doi:10.1016/j.immuni.2012.08.008
93. Belkaid Y, Tarbell K. Regulatory T cells in the control of host-microorganism interactions (*). Annu Rev Immunol (2009) 27:551-89. doi:10.1146/annurev.immunol.021908.132723
94. Shafiani S, Dinh C, Ertelt JM, Moguche AO, Siddiqui I, Smigiel KS, et al. Pathogen-specific Treg cells expand early during mycobacterium tuberculosis infection but are later eliminated in response to Interleukin-12. Immunity (2013) 38:1261-70. doi:10.1016/j.immuni.2013.06.003
95. Zhao J, Zhao J, Fett C, Trandem K, Fleming E, Perlman S. IFN-γ- and IL-10-expressing virus epitope-specific Foxp3(+) T reg cells in the central nervous system during encephalomyelitis. J Exp Med (2011) 208:1571-7. doi:10.1084/jem.20110236
96. Suffia IJ, Reckling SK, Piccirillo CA, Goldszmid RS, Belkaid Y. Infected site-restricted Foxp3+ natural regulatory T cells are specific for microbial antigens. J Exp Med (2006) 203:777-88. doi:10.1084/jem.20052056
97. 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. doi:10.1016/j.immuni.2007.07.019
98. Campbell DJ, Butcher EC. Rapid acquisition of tissue-specific homing phenotypes by CD4(+) T cells activated in cutaneous or mucosal lymphoid tissues. J Exp Med (2002) 195:135-41. doi:10.1084/jem.20011502
99. Reinhardt RL, Bullard DC, Weaver CT, Jenkins MK. Preferential accumulation of antigen-specific effector CD4 T cells at an antigen injection site involves CD62E-dependent migration but not local proliferation. J Exp Med (2003) 197:751-62. doi:10.1084/jem.20021690
100. Fu H, Kishore M, Gittens B, Wang G, Coe D, Komarowska I, et al. Self-recognition of the endothelium enables regulatory T-cell trafficking and defines the kinetics of immune regulation. Nat Commun (2014) 5:3436. doi:10.1038/ncomms4436
101. Chaudhry A, Rudensky AY. Control of inflammation by integration of environmental cues by regulatory T cells. J Clin Invest (2013) 123:939-44. doi:10.1172/JCI57175
102. Reiner SL. Development in motion: helper T cells at work. Cell (2007) 129:33-6. doi:10.1016/j.cell.2007.03.019
103. Koch MA, Thomas KR, Perdue NR, Smigiel KS, Srivastava S, Campbell DJ. T-bet(+) Treg cells undergo abortive Th1 cell differentiation due to impaired expression of IL-12 receptor β2. Immunity (2012) 37:501-10. doi:10.1016/j.immuni.2012.05.031
104. Hall AO, Beiting DP, Tato C, John B, Oldenhove G, Lombana CG, et al. The cytokines interleukin 27 and interferon-γ promote distinct Treg cell populations required to limit infection-induced pathology. Immunity (2012) 37:511-23. doi:10.1016/j.immuni.2012.06.014
105. Oldenhove G, Bouladoux N, Wohlfert EA, Hall JA, Chou D, Dos Santos L, et al. Decrease of Foxp3+ Treg cell number and acquisition of effector cell phenotype during lethal infection. Immunity (2009) 31:772-86. doi:10.1016/j.immuni.2009.10.001
106. Koenecke C, Lee C-W, Thamm K, Föhse L, Schafferus M, Mittrücker H-W, et al. IFN-γ production by allogeneic Foxp3+ regulatory T cells is essential for preventing experimental graft-versus-host disease. J Immunol (2012) 189:2890-6. doi:10.4049/jimmunol.1200413
107. Lim HW, Broxmeyer HE, Kim CH. Regulation of trafficking receptor expression in human forkhead box P3+ regulatory T cells. J Immunol (2006) 177:840-51. doi:10.4049/jimmunol.177.2.840
108. Kleinewietfeld M, Puentes F, Borsellino G, Battistini L, Rötzschke O, Falk K. CCR6 expression defines regulatory effector/memory-like cells within the CD25(+)CD4+ T-cell subset. Blood (2005) 105:2877-86. doi:10.1182/blood-2004-07-2505
109. Yamazaki T, Yang XO, Chung Y, Fukunaga A, Nurieva R, Pappu B, et al. CCR6 regulates the migration of inflammatory and regulatory T cells. J Immunol (2008) 181:8391-401. doi:10.4049/jimmunol.181.12.8391
110. Valmori D, Raffin C, Raimbaud I, Ayyoub M. Human RORγt+ TH17 cells preferentially differentiate from naive FOXP3+Treg in the presence of lineage-specific polarizing factors. Proc Natl Acad Sci U S A (2010) 107:19402-7. doi:10.1073/pnas.1008247107
111. Chaudhry A, Samstein RM, Treuting P, Liang Y, Pils MC, Heinrich J-M, et al. Interleukin-10 signaling in regulatory T cells is required for suppression of Th17 cell-mediated inflammation. Immunity (2011) 34:566-78. doi:10.1016/j.immuni.2011.03.018
112. Linterman MA, Pierson W, Lee SK, Kallies A, Kawamoto S, Rayner TF, et al. Foxp3+ follicular regulatory T cells control the germinal center response. Nat Med (2011) 17:975-82. doi:10.1038/nm.2425
113. Chung Y, Tanaka S, Chu F, Nurieva RI, Martinez GJ, Rawal S, et al. Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nat Med (2011) 17:983-8. doi:10.1038/nm.2426
114. Vaeth M, Müller G, Stauss D, Dietz L, Klein-Hessling S, Serfling E, et al. Follicular regulatory T cells control humoral autoimmunity via NFAT2- regulated CXCR5 expression. J Exp Med (2014) 211:545-61. doi:10.1084/jem.20130604
115. Mora JR, Bono MR, Manjunath N, Weninger W, Cavanagh LL, Rosemblatt M, et al. Selective imprinting of gut-homing T cells by Peyer's patch dendritic cells. Nature (2003) 424:88-93. doi:10.1038/nature01726
116. Iwata M, Hirakiyama A, Eshima Y, Kagechika H, Kato C, Song S-Y. Retinoic acid imprints gut-homing specificity on T cells. Immunity (2004) 21:527-38. doi:10.1016/j.immuni.2004.08.011
117. Sigmundsdottir H, Pan J, Debes GF, Alt C, Habtezion A, Soler D, et al. DCs metabolize sunlight-induced vitamin D3 to "program" T cell attraction to the epidermal chemokine CCL27. Nat Immunol (2007) 8:285-93. doi:10.1038/ni1433
118. Siewert C, Menning A, Dudda J, Siegmund K, Lauer U, Floess S, et al. Induction of organ-selective CD4+ regulatory T cell homing. Eur J Immunol (2007) 37:978-89. doi:10.1002/eji.200636575
119. Kim SV, Xiang WV, Kwak C, Yang Y, Lin XW, Ota M, et al. GPR15-mediated homing controls immune homeostasis in the large intestine mucosa. Science (2013) 340:1456-9. doi:10.1126/science.1237013
120. Vignali DA, Collison LW, Workman CJ. How regulatory T cells work. Nat Rev Immunol (2008) 8:523-32. doi:10.1038/nri2343
121. Wing JB, Sakaguchi S. Multiple Treg suppressive modules and their adaptability. Front Immunol (2012) 3:178. doi:10.3389/fimmu.2012.00178
122. Rubtsov YP, Rasmussen JP, Chi EY, Fontenot J, Castelli L, Ye X, et al. Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity (2008) 28:546-58. doi:10.1016/j.immuni.2008.02.017
123. Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z, et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science (2008) 322:271-5. doi:10.1126/science.1160062
124. Kim JM, Rasmussen JP, Rudensky AY. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat Immunol (2007) 8:191-7. doi:10.1038/ni1428
125. Darrasse-Jèze G, Deroubaix S, Mouquet H, Victora GD, Eisenreich T, Yao K, et al. Feedback control of regulatory T cell homeostasis by dendritic cells in vivo. J Exp Med (2009) 206:1853-62. doi:10.1084/jem.20090746
126. Qureshi OS, Zheng Y, Nakamura K, Attridge K, Manzotti C, Schmidt EM, et al. Trans-endocytosis of CD80 and CD86: a molecular basis for the cell extrinsic function of CTLA-4. Science (2011) 332(6029):600-3. doi:10.1126/science.1202947
127. Tang Q, Adams JY, Tooley AJ, Bi M, Fife BT, Serra P, et al. Visualizing regulatory T cell control of autoimmune responses in nonobese diabetic mice. Nat Immunol (2006) 7:83-92. doi:10.1038/ni1289
128. Tadokoro CE, Shakhar G, Shen S, Ding Y, Lino AC, Maraver A, et al. Regulatory T cells inhibit stable contacts between CD4+ T cells and dendritic cells in vivo. J Exp Med (2006) 203:505-11. doi:10.1084/jem.20050783
129. Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I, Trump S, et al. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature (2011) 478:197-203. doi:10.1038/nature10491
130. Mezrich JD, Fechner JH, Zhang X, Johnson BP, Burlingham WJ, Bradfield CA. An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J Immunol (2010) 185:3190-8. doi:10.4049/jimmunol.0903670
131. Deaglio S, Dwyer KM, Gao W, Friedman D, Usheva A, Erat A, et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med (2007) 204:1257-65. doi:10.1084/jem.20062512
132. Laurence A, Tato CM, Davidson TS, Kanno Y, Chen Z, Yao Z, et al. Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity (2007) 26:371-81. doi:10.1016/j.immuni.2007.02.009
133. Chen Y, Haines CJ, Gutcher I, Hochweller K, Blumenschein WM, McClanahan T, et al. Foxp3(+) regulatory T cells promote T helper 17 cell development in vivo through regulation of interleukin-2. Immunity (2011) 34:409-21. doi:10.1016/j.immuni.2011.02.011
134. Pandiyan P, Conti HR, Zheng L, Peterson AC, Mathern DR, Hernández-Santos N, et al. CD4(+)CD25(+)Foxp3(+) regulatory T cells promote Th17 cells in vitro and enhance host resistance in mouse Candida albicans Th17 cell infection model. Immunity (2011) 34:422-34. doi:10.1016/j.immuni.2011.03.002
135. León B, Bradley JE, Lund FE, Randall TD, Ballesteros-Tato A. FoxP3+ regulatory T cells promote influenza-specific Tfh responses by controlling IL-2 availability. Nat Commun (2014) 5:3495. doi:10.1038/ncomms4495
136. Powrie F, Leach MW, Mauze S, Caddle LB, Coffman RL. Phenotypically distinct subsets of CD4+ T cells induce or protect from chronic intestinal inflammation in C. B-17 scid mice. Int Immunol (1993) 5:1461-71. doi:10.1093/intimm/5.11.1461
137. Fehérvári Z, Sakaguchi S. Control of Foxp3+ CD25+CD4+ regulatory cell activation and function by dendritic cells. Int Immunol (2004) 16:1769-80. doi:10.1093/intimm/dxh178
138. Kubo T, Hatton RD, Oliver J, Liu X, Elson CO, Weaver CT. Regulatory T cell suppression and anergy are differentially regulated by proinflammatory cytokines produced by TLR-activated dendritic cells. J Immunol (2004) 173:7249-58. doi:10.4049/jimmunol.173.12.7249
139. Ballesteros-Tato A, León B, Lund FE, Randall TD. CD4+ T helper cells use CD154-CD40 interactions to counteract T reg cell-mediated suppression of CD8+ T cell responses to influenza. J Exp Med (2013) 210:1591-601. doi:10.1084/jem.20130097
140. Srivastava S, Koch MA, Pepper M, Campbell DJ. Type I interferons directly inhibit regulatory T cells to allow optimal antiviral T cell responses during acute LCMV infection. J Exp Med (2014). doi:10.1084/jem.20131556
141. Schneider A, Long SA, Cerosaletti K, Ni CT, Samuels P, Kita M, et al. Active relapsing-remitting multiple sclerosis, effector T cell resistance to adaptive Tregs involves IL-6-mediated signaling. Sci Transl Med (2013) 5:170ra15. doi:10.1126/scitranslmed.3004970
142. Cervantes-Barragán L, Firner S, Bechmann I, Waisman A, Lahl K, Sparwasser T, et al. Regulatory T cells selectively preserve immune privilege of self-antigens during viral central nervous system infection. J Immunol (2012) 188:3678-85. doi:10.4049/jimmunol.1102422
143. Onishi Y, Fehervari Z, Yamaguchi T, Sakaguchi S. Foxp3+ natural regulatory T cells preferentially form aggregates on dendritic cells in vitro and actively inhibit their maturation. Proc Natl Acad Sci U S A (2008) 105:10113-8. doi:10.1073/pnas.0711106105
144. Setiady YY, Ohno K, Samy ET, Bagavant H, Qiao H, Sharp C, et al. Physiologic self antigens rapidly capacitate autoimmune disease-specific polyclonal CD4+CD25+ regulatory T cells. Blood (2006) 107:1056-62. doi:10.1182/blood-2005-08-3088
145. Samy ET, Parker LA, Sharp CP, Tung KSK. Continuous control of autoimmune disease by antigen-dependent polyclonal CD4+CD25+ regulatory T cells in the regional lymph node. J Exp Med (2005) 202:771-81. doi:10.1084/jem.20041033
146. 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) 207:1879-89. doi:10.1084/jem.20100205
147. Burzyn D, Kuswanto W, Kolodin D, Shadrach JL, Cerletti M, Jang Y, et al. A special population of regulatory T cells potentiates muscle repair. Cell (2013) 155:1282-95. doi:10.1016/j.cell.2013.10.054
148. Cipolletta D, Feuerer M, Li A, Kamei N, Lee J, Shoelson SE, et al. PPAR-γ is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature (2012) 486:549-53. doi:10.1038/nature11132
149. Burzyn D, Benoist C, Mathis D. Regulatory T cells in nonlymphoid tissues. Nat Immunol (2013) 14:1007-13. doi:10.1038/ni.2683
150. Rowe JH, Ertelt JM, Xin L, Way SS. Pregnancy imprints regulatory memory that sustains anergy to fetal antigen. Nature (2012) 490:102-6. doi:10.1038/nature11462
151. Kinder JM, Jiang TT, Clark DR, Chaturvedi V, Xin L, Ertelt JM, et al. Pregnancy-induced maternal regulatory T cells, bona fide memory or maintenance by antigenic reminder from fetal cell microchimerism? Chimerism (2014) 5:16-9. doi:10.4161/chim.28241
152. Samstein RM, Josefowicz SZ, Arvey A, Treuting PM, Rudensky AY. Extrathymic generation of regulatory T cells in placental mammals mitigates maternal-fetal conflict. Cell (2012) 150:29-38. doi:10.1016/j.cell.2012.05.031
153. Sabatos-Peyton CA, Verhagen J, Wraith DC. Antigen-specific immunotherapy of autoimmune and allergic diseases. Curr Opin Immunol (2010) 22:609-15. doi:10.1016/j.coi.2010.08.006
154. Plock JA, Schnider JT, Solari MG, Zheng XX, Gorantla VS. Perspectives on the use of mesenchymal stem cells in vascularized composite allotransplantation. Front Immunol (2013) 4:175. doi:10.3389/fimmu.2013.00175
155. English K, Ryan JM, Tobin L, Murphy MJ, Barry FP, Mahon BP. Cell contact, prostaglandin E(2) and transforming growth factor beta 1 play non-redundant roles in human mesenchymal stem cell induction of CD4+CD25(High) forkhead box P3+ regulatory T cells. Clin Exp Immunol (2009) 156:149-60. doi:10.1111/j.1365-2249.2009.03874.x
156. Stagg J, Galipeau J. Mechanisms of immune modulation by mesenchymal stromal cells and clinical translation. Curr Mol Med (2013) 13:856-67. doi:10.2174/1566524011313050016
157. Zou L, Barnett B, Safah H, Larussa VF, Evdemon-Hogan M, Mottram P, et al. Bone marrow is a reservoir for CD4+CD25+ regulatory T cells that traffic through CXCL12/CXCR4 signals. Cancer Res (2004) 64:8451-5. doi:10.1158/0008-5472.CAN-04-1987
158. Fujisaki J, Wu J, Carlson AL, Silberstein L, Putheti P, Larocca R, et al. In vivo imaging of Treg cells providing immune privilege to the haematopoietic stem-cell niche. Nature (2011) 474:216-9. doi:10.1038/nature10160
159. Riley JL, June CH, Blazar BR. Human T regulatory cell therapy: take a billion or so and call me in the morning. Immunity (2009) 30:656-65. doi:10.1016/j.immuni.2009.04.006
160. Boyman O, Krieg C, Homann D, Sprent J. Homeostatic maintenance of T cells and natural killer cells. Cell Mol Life Sci (2012) 69:1597-608. doi:10.1007/s00018-012-0968-7
161. + regulatory T cells. Nat Immunol (2013) 14:959-65. doi:10.1038/ni.2649
162. Setoguchi R, Hori S, Takahashi T, Sakaguchi S. 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 (2005) 201:723-35. doi:10.1084/jem.20041982
163. Tai X, Erman B, Alag A, Mu J, Kimura M, Katz G, et al. Foxp3 transcription factor is proapoptotic and lethal to developing regulatory T cells unless counterbalanced by cytokine survival signals. Immunity (2013) 38:1116-28. doi:10.1016/j.immuni.2013.02.022
164. Boyman O, Kovar M, Rubinstein MP, Surh CD, Sprent J. Selective stimulation of T cell subsets with antibody-cytokine immune complexes. Science (2006) 311:1924-7. doi:10.1126/science.1122927
165. Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol (2005) 6:1142-51. doi:10.1038/ni1263
166. Soper DM, Kasprowicz DJ, Ziegler SF. IL-2Rbeta links IL-2R signaling with Foxp3 expression. Eur J Immunol (2007) 37:1817-26. doi:10.1002/eji.200737101
167. Barron L, Dooms H, Hoyer KK, Kuswanto W, Hofmann J, O'Gorman WE, et al. Cutting edge: mechanisms of IL-2-dependent maintenance of functional regulatory T cells. J Immunol (2010) 185:6426-30. doi:10.4049/jimmunol.0903940
168. Zou T, Satake A, Corbo-Rodgers E, Schmidt AM, Farrar MA, Maltzman JS, et al. Cutting edge: IL-2 signals determine the degree of TCR signaling necessary to support regulatory T cell proliferation in vivo. J Immunol (2012) 189:28-32. doi:10.4049/jimmunol.1200507
169. Tang Q, Henriksen KJ, Boden EK, Tooley AJ, Ye J, Subudhi SK, et al. Cutting edge: CD28 controls peripheral homeostasis of CD4+CD25+ regulatory T cells. J Immunol (2003) 171:3348-52. doi:10.4049/jimmunol.171.7.3348
170. Zhang R, Huynh A, Whitcher G, Chang J, Maltzman JS, Turka LA. An obligate cell-intrinsic function for CD28 in Tregs. J Clin Invest (2013) 123:580-93. doi:10.1172/JCI65013
171. Herman AE, Freeman GJ, Mathis D, Benoist C. CD4+CD25+ T regulatory cells dependent on ICOS promote regulation of effector cells in the prediabetic lesion. J Exp Med (2004) 199:1479-89. doi:10.1084/jem.20040179
172. Josefowicz SZ, Lu L-F, Rudensky AY. Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol (2012) 30:531-64. doi:10.1146/annurev.immunol.25.022106.141623
173. Ouyang W, Li MO. Foxo: in command of T lymphocyte homeostasis and tolerance. Trends Immunol (2011) 32:26-33. doi:10.1016/j.it.2010.10.005
174. Liu W, Putnam AL, Xu-Yu Z, Szot GL, Lee MR, Zhu S, et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med (2006) 203:1701-11. doi:10.1084/jem.20060772
175. Rosenblum MD, Gratz IK, Paw JS, Abbas AK. Treating human autoimmunity: current practice and future prospects. Sci Transl Med (2012) 4:125sr1. doi:10.1126/scitranslmed.3003504
176. Tang Q, Bluestone JA. Regulatory T-cell therapy in transplantation: moving to the clinic. Cold Spring Harb Perspect Med (2013):3(11):a015552. doi:10.1101/cshperspect.a015552
177. Zillikens D. BP180 as the common autoantigen in blistering diseases with different clinical phenotypes. Keio J Med (2002) 51:21-8. doi:10.2302/kjm.51.21
178. Amagai M, Klaus-Kovtun V, Stanley JR. Autoantibodies against a novel epithelial cadherin in pemphigus vulgaris, a disease of cell adhesion. Cell (1991) 67:869-77. doi:10.1016/0092-8674(91)90360-B
179. Roep BO, Peakman M. Antigen targets of type 1 diabetes autoimmunity. Cold Spring Harb Perspect Med (2012) 2:a007781. doi:10.1101/cshperspect.a007781
180. Putnam AL, Safinia N, Medvec A, Laszkowska M, Wray M, Mintz MA, et al. Clinical grade manufacturing of human alloantigen-reactive regulatory T cells for use in transplantation. Am J Transplant (2013) 13:3010-20. doi:10.1111/ajt.12433
181. Delgoffe GM, Woo S-R, Turnis ME, Gravano DM, Guy C, Overacre AE, et al. Stability and function of regulatory T cells is maintained by a neuropilin-1-semaphorin-4a axis. Nature (2013) 501:252-6. doi:10.1038/nature12428