New insights into regulatory T cells: Exosome- and non-coding RNA-mediated regulation of homeostasis and resident treg cells

Frontiers in Immunology

Volumn 7, Issue DEC, 2016, Pages

  Li, Peiyao ^a,b   Liu, Changhong ^a,b   Yu, Zhibin ^a,b   Wu, Minghua ^a,b  

^a CENTRAL SOUTH UNIVERSITY   (China)

^b CENTRAL SOUTH UNIVERSITY   (China)

Author keywords

Exosome; Non coding RNA; Resident Treg cell; Treg cell; Treg homeostasis

Indexed keywords

CD28 ANTIGEN; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; INTERLEUKIN 2; MICRORNA; TOLL LIKE RECEPTOR; TRANSCRIPTION FACTOR FOXP3; TUMOR NECROSIS FACTOR; UNTRANSLATED RNA;

ADAPTIVE IMMUNITY; AUTOIMMUNITY; CD25+ T LYMPHOCYTE; CELLULAR IMMUNITY; CYTOTOXIC T LYMPHOCYTE; EXOSOME; GENE MUTATION; HUMAN; IMMUNOLOGICAL TOLERANCE; IMMUNOREGULATION; IMMUNOSUPPRESSIVE TREATMENT; INFLAMMATION; IPEX SYNDROME; NONHUMAN; REGULATORY T LYMPHOCYTE; REVIEW;

EID: 85009412700     PISSN: None     EISSN: 16643224     Source Type: Journal    
DOI: 10.3389/fimmu.2016.00574     Document Type: Review

References (100)

1. Sakaguchi S. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol (2005) 6(4):345-52. doi: 10.1038/ni1178
2. Linehan DC, Goedegebuure PS. CD25+ CD4+ regulatory T-cells in cancer. Immunol Res (2005) 32(1-3):155-68. doi:10.1385/IR:32:1-3:155
3. Belkaid Y. Regulatory T cells and infection: a dangerous necessity. Nat Rev Immunol (2007) 7(11):875-88. doi:10.1038/nri2189
4. Loser K, Beissert S. Regulatory T cells: banned cells for decades. J Invest Dermatol (2012) 132(3 Pt 2):864-71. doi:10.1038/jid.2011.375
5. Penaloza-MacMaster P, Kamphorst AO, Wieland A, Araki K, Iyer SS, West EE. Interplay between regulatory T cells and PD-1 in modulating T cell exhaustion and viral control during chronic LCMV infection. J Exp Med (2014) 211(9):1905-18. doi:10.1084/jem.20132577
6. Tan T, Xiang Y, Chang C, Zhou Z. Alteration of regulatory T cells in type 1 diabetes mellitus: a comprehensive review. Clin Rev Allergy Immunol (2014) 47(2):234-43. doi:10.1007/s12016-014-8440-0
7. Furtado GC, Curotto DLM, Kutchukhidze N, Lafaille JJ. Interleukin 2 signaling is required for CD4(+) regulatory T cell function. J Exp Med (2002) 196(6):851-7. doi:10.1084/jem.20020190
8. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol (2003) 4(4):330-6. doi:10.1038/ni904
9. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science (2003) 299(5609):1057-61. doi:10.1126/science.1079490
10. Sun L, Wu J, Yi S. Foxp3 is critical for human natural CD4+CD25+ regulatory T cells to suppress alloimmune response. Transpl Immunol (2012) 26(2-3):71-80. doi:10.1016/j.trim.2011.10.005
11. Zhao M, Liang GP, Tang MN, Luo SY, Zhang J, Cheng WJ. Total glucosides of paeony induces regulatory CD4(+)CD25(+) T cells by increasing Foxp3 demethylation in lupus CD4(+) T cells. Clin Immunol (2012) 143(2):180-7. doi:10.1016/j.clim.2012.02.002
12. Gavin MA, Torgerson TR, Houston E, DeRoos P, Ho WY, Stray-Pedersen A. Single-cell analysis of normal and FOXP3-mutant human T cells: FOXP3 expression without regulatory T cell development. Proc Natl Acad Sci U S A (2006) 103(17):6659-64. doi:10.1073/pnas.0509484103
13. Liu W, Putnam AL, Xu-Yu Z, Szot GL, Lee MR, Zhu S. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med (2006) 203(7):1701-11. doi:10.1084/jem.20060772
14. Schwab M, Barth S, Boffetta P, Colditz GA, Duhé RJ, Hunter K, et al. Encyclopedia of Cancer. Berlin, Heidelberg: Springer (2009).
15. Li Z, Li D, Tsun A, Li B. FOXP3+ regulatory T cells and their functional regulation. Cell Mol Immunol (2015) 12(5):558-65. doi:10.1038/cmi.2015.10
16. Liston A, Rudensky AY. Thymic development and peripheral homeostasis of regulatory T cells. Curr Opin Immunol (2007) 19(2):176-85. doi:10.1016/j.coi.2007.02.005
17. Paiva RS, Lino AC, Bergman ML, Caramalho I, Sousa AE, Zelenay S. Recent thymic emigrants are the preferential precursors of regulatory T cells differentiated in the periphery. Proc Natl Acad Sci U S A (2013) 110(16):6494-9. doi:10.1073/pnas.1221955110
18. Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N. 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(12):1875-86. doi:10.1084/jem.20030152
19. Gratz IK, Campbell DJ. Organ-specific and memory treg cells: specificity, development, function, and maintenance. Front Immunol (2014) 5:333. doi:10.3389/fimmu.2014.00333
20. Roncarolo MG, Gregori S, Battaglia M, Bacchetta R, Fleischhauer K, Levings MK. Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol Rev (2006) 212:28-50. doi:10.1111/j.0105-2896.2006.00420.x
21. Weiner HL. Induction and mechanism of action of transforming growth factor-beta-secreting Th3 regulatory cells. Immunol Rev (2001) 182:207-14. doi:10.1034/j.1600-065X.2001.1820117.x
22. Wang HY, Wang RF. Regulatory T cells and cancer. Curr Opin Immunol (2007) 19(2):217-23. doi:10.1016/j.coi.2007.02.004
23. Thornton AM, Korty PE, Tran DQ, Wohlfert EA, Murray PE, Belkaid Y. Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells. J Immunol (2010) 184(7):3433-41. doi:10.4049/jimmunol.0904028
24. Yadav M, Louvet C, Davini D, Gardner JM, Martinez-Llordella M, Bailey-Bucktrout S. Neuropilin-1 distinguishes natural and inducible regulatory T cells among regulatory T cell subsets in vivo. J Exp Med (2012) 209(10):S1-19. doi:10.1084/jem.20120822
25. Bin DK, D'Hennezel E, Nashi E, Bar-Or A, Rieder S, Shevach EM. Coexpression of TIGIT and FCRL3 identifies Helios+ human memory regulatory T cells. J Immunol (2015) 194(8):3687-96. doi:10.4049/jimmunol.1401803
26. Rosenblum MD, Way SS, Abbas AK. Regulatory T cell memory. Nat Rev Immunol (2016) 16(2):90-101. doi:10.1038/nri.2015.1
27. Liston A, Gray DH. Homeostatic control of regulatory T cell diversity. Nat Rev Immunol (2014) 14(3):154-65. doi:10.1038/nri3605
28. Campbell DJ, Koch MA. Phenotypical and functional specialization of FOXP3+ regulatory T cells. Nat Rev Immunol (2011) 11(2):119-30. doi:10.1038/nri2916
29. Mendes F, Domingues C, Rodrigues-Santos P, Abrantes AM, Goncalves AC, Estrela J. The role of immune system exhaustion on cancer cell escape and anti-tumor immune induction after irradiation. Biochim Biophys Acta (2016) 1865(2):168-75. doi:10.1016/j.bbcan.2016.02.002
30. Burzyn D, Benoist C, Mathis D. Regulatory T cells in nonlymphoid tissues. Nat Immunol (2013) 14(10):1007-13. doi:10.1038/ni.2683
31. Lu J, Meng H, Zhang A, Yang J, Zhang X. Phenotype and function of tissue-resident unconventional Foxp3-expressing CD4(+) regulatory T cells. Cell Immunol (2015) 297(1):53-9. doi:10.1016/j.cellimm.2015.06.005
32. Li X, Zheng Y. Regulatory T cell identity: formation and maintenance. Trends Immunol (2015) 36(6):344-53. doi:10.1016/j.it.2015.04.006
33. Barnaba V, Schinzari V. Induction, control, and plasticity of Treg cells: the immune regulatory network revised? Eur J Immunol (2013) 43(2):318-22. doi:10.1002/eji.201243265
34. Kleinewietfeld M, Hafler DA. The plasticity of human Treg and Th17 cells and its role in autoimmunity. Semin Immunol (2013) 25(4):305-12. doi:10.1016/j.smim.2013.10.009
35. Booth AM, Fang Y, Fallon JK, Yang JM, Hildreth JE, Gould SJ. Exosomes and HIV Gag bud from endosome-like domains of the T cell plasma membrane. J Cell Biol (2006) 172(6):923-35. doi:10.1083/jcb.200508014
36. Robbins PD, Morelli AE. Regulation of immune responses by extracellular vesicles. Nat Rev Immunol (2014) 14(3):195-208. doi:10.1038/nri3622
37. Thery C, Zitvogel L, Amigorena S. Exosomes: composition, biogenesis and function. Nat Rev Immunol (2002) 2(8):569-79. doi:10.1038/nri855
38. Li Y, Zheng Q, Bao C, Li S, Guo W, Zhao J. Circular RNA is enriched and stable in exosomes: a promising biomarker for cancer diagnosis. Cell Res (2015) 25(8):981-4. doi:10.1038/cr.2015.82
39. Balaj L, Lessard R, Dai L, Cho YJ, Pomeroy SL, Breakefield XO. Tumour microvesicles contain retrotransposon elements and amplified oncogene sequences. Nat Commun (2011) 2:180. doi:10.1038/ncomms1180
40. Okoye IS, Coomes SM, Pelly VS, Czieso S, Papayannopoulos V, Tolmachova T. MicroRNA-containing T-regulatory-cell-derived exosomes suppress pathogenic T helper 1 cells. Immunity (2014) 41(1):89-103. doi:10.1016/j.immuni.2014.05.019
41. Wang GJ, Liu Y, Qin A, Shah SV, Deng ZB, Xiang X. Thymus exosomes-like particles induce regulatory T cells. J Immunol (2008) 181(8):5242-8. doi:10.4049/jimmunol.181.8.5242
42. Mittelbrunn M, Gutierrez-Vazquez C, Villarroya-Beltri C, Gonzalez S, Sanchez-Cabo F, Gonzalez MA. Unidirectional transfer of microRNA-loaded exosomes from T cells to antigen-presenting cells. Nat Commun (2011) 2:282. doi:10.1038/ncomms1285
43. Smyth LA, Ratnasothy K, Tsang JY, Boardman D, Warley A, Lechler R. CD73 expression on extracellular vesicles derived from CD4+ CD25+ Foxp3+ T cells contributes to their regulatory function. Eur J Immunol (2013) 43(9):2430-40. doi:10.1002/eji.201242909
44. Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol (2007) 9(6):654-9. doi:10.1038/ncb1596
45. Savina A, Furlan M, Vidal M, Colombo MI. Exosome release is regulated by a calcium-dependent mechanism in K562 cells. J Biol Chem (2003) 278(22):20083-90. doi:10.1074/jbc.M301642200
46. King HW, Michael MZ, Gleadle JM. Hypoxic enhancement of exosome release by breast cancer cells. BMC Cancer (2012) 12:421. doi:10.1186/1471-2407-12-421
47. Trajkovic K, Hsu C, Chiantia S, Rajendran L, Wenzel D, Wieland F. Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science (2008) 319(5867):1244-7. doi:10.1126/science.1153124
48. Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol (2005) 6(11):1142-51. doi:10.1038/ni1263
49. Agarwal A, Fanelli G, Letizia M, Tung SL, Boardman D, Lechler R. Regulatory T cell-derived exosomes: possible therapeutic and diagnostic tools in transplantation. Front Immunol (2014) 5:555. doi:10.3389/fimmu.2014.00555
50. Clayton A, Al-Taei S, Webber J, Mason MD, Tabi Z. Cancer exosomes express CD39 and CD73, which suppress T cells through adenosine production. J Immunol (2011) 187(2):676-83. doi:10.4049/jimmunol.1003884
51. Kim SH, Bianco N, Menon R, Lechman ER, Shufesky WJ, Morelli AE. Exosomes derived from genetically modified DC expressing FasL are anti-inflammatory and immunosuppressive. Mol Ther (2006) 13(2):289-300. doi:10.1016/j.ymthe.2005.09.015
52. Mokarizadeh A, Delirezh N, Morshedi A, Mosayebi G, Farshid AA, Mardani K. Microvesicles derived from mesenchymal stem cells: potent organelles for induction of tolerogenic signaling. Immunol Lett (2012) 147(1-2):47-54. doi:10.1016/j.imlet.2012.06.001
53. Buzas EI, Gyorgy B, Nagy G, Falus A, Gay S. Emerging role of extracellular vesicles in inflammatory diseases. Nat Rev Rheumatol (2014) 10(6):356-64. doi:10.1038/nrrheum.2014.19
54. Mrizak D, Martin N, Barjon C, Jimenez-Pailhes AS, Mustapha R, Niki T. Effect of nasopharyngeal carcinoma-derived exosomes on human regulatory T cells. J Natl Cancer Inst (2015) 107(1):363. doi:10.1093/jnci/dju363
55. Yin Y, Cai X, Chen X, Liang H, Zhang Y, Li J. Tumor-secreted miR-214 induces regulatory T cells: a major link between immune evasion and tumor growth. Cell Res (2014) 24(10):1164-80. doi:10.1038/cr.2014.121
56. Yamada N, Kuranaga Y, Kumazaki M, Shinohara H, Taniguchi K, Akao Y. Colorectal cancer cell-derived extracellular vesicles induce phenotypic alteration of T cells into tumor-growth supporting cells with transforming growth factor-beta1-mediated suppression. Oncotarget (2016) 7(19):27033-43. doi:10.18632/oncotarget.7041
57. Ling H, Fabbri M, Calin GA. MicroRNAs and other non-coding RNAs as targets for anticancer drug development. Nat Rev Drug Discov (2013) 12(11):847-65. doi:10.1038/nrd4140
58. Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell (2009) 136(2):215-33. doi:10.1016/j.cell.2009.01.002
59. Fabian MR, Sonenberg N, Filipowicz W. Regulation of mRNA translation and stability by microRNAs. Annu Rev Biochem (2010) 79:351-79. doi:10.1146/annurev-biochem-060308-103103
60. Tay Y, Zhang J, Thomson AM, Lim B, Rigoutsos I. MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation. Nature (2008) 455(7216):1124-8. doi:10.1038/nature07299
61. Lytle JR, Yario TA, Steitz JA. Target mRNAs are repressed as efficiently by microRNA-binding sites in the 5' UTR as in the 3' UTR. Proc Natl Acad Sci U S A (2007) 104(23):9667-72. doi:10.1073/pnas.0703820104
62. Baumjohann D, Ansel KM. MicroRNA-mediated regulation of T helper cell differentiation and plasticity. Nat Rev Immunol (2013) 13(9):666-78. doi:10.1038/nri3494
63. Zhou L, Park JJ, Zheng Q, Dong Z, Mi Q. MicroRNAs are key regulators controlling iNKT and regulatory T-cell development and function. Cell Mol Immunol (2011) 8(5):380-7. doi:10.1038/cmi.2011.27
64. Liston A, Lu LF, O'Carroll D, Tarakhovsky A, Rudensky AY. Dicer-dependent microRNA pathway safeguards regulatory T cell function. J Exp Med (2008) 205(9):1993-2004. doi:10.1084/jem.20081062
65. Zhou X, Jeker LT, Fife BT, Zhu S, Anderson MS, McManus MT. Selective miRNA disruption in T reg cells leads to uncontrolled autoimmunity. J Exp Med (2008) 205(9):1983-91. doi:10.1084/jem.20080707
66. Chong MM, Rasmussen JP, Rudensky AY, Littman DR. The RNAseIII enzyme Drosha is critical in T cells for preventing lethal inflammatory disease. J Exp Med (2008) 205(9):2005-17. doi:10.1084/jem.20081219
67. Marson A, Kretschmer K, Frampton GM, Jacobsen ES, Polansky JK, MacIsaac KD. Foxp3 occupancy and regulation of key target genes during T-cell stimulation. Nature (2007) 445(7130):931-5. doi:10.1038/nature05478
68. Zheng Y, Josefowicz SZ, Kas A, Chu TT, Gavin MA, Rudensky AY. Genome-wide analysis of Foxp3 target genes in developing and mature regulatory T cells. Nature (2007) 445(7130):936-40. doi:10.1038/nature05563
69. Lu LF, Thai TH, Calado DP, Chaudhry A, Kubo M, Tanaka K. Foxp3-dependent microRNA155 confers competitive fitness to regulatory T cells by targeting SOCS1 protein. Immunity (2009) 30(1):80-91. doi:10.1016/j.immuni.2008.11.010
70. Rodriguez A, Vigorito E, Clare S, Warren MV, Couttet P, Soond DR. Requirement of bic/microRNA-155 for normal immune function. Science (2007) 316(5824):608-11. doi:10.1126/science.1139253
71. Thai TH, Calado DP, Casola S, Ansel KM, Xiao C, Xue Y. Regulation of the germinal center response by microRNA-155. Science (2007) 316(5824):604-8. doi:10.1126/science.1141229
72. Jeker LT, Zhou X, Gershberg K, de Kouchkovsky D, Morar MM, Stadthagen G. MicroRNA 10a marks regulatory T cells. PLoS One (2012) 7(5):e36684. doi:10.1371/journal.pone.0036684
73. Tang X, Tang R, Xu Y, Wang Q, Hou Y, Shen S. MicroRNA networks in regulatory T cells. J Physiol Biochem (2014) 70(3):869-75. doi:10.1007/s13105-014-0348-x
74. Tsuji M, Komatsu N, Kawamoto S, Suzuki K, Kanagawa O, Honjo T. Preferential generation of follicular B helper T cells from Foxp3+ T cells in gut Peyer's patches. Science (2009) 323(5920):1488-92. doi:10.1126/science.1169152
75. Takahashi H, Kanno T, Nakayamada S, Hirahara K, Sciume G, Muljo SA. TGF-beta and retinoic acid induce the microRNA miR-10a, which targets Bcl-6 and constrains the plasticity of helper T cells. Nat Immunol (2012) 13(6):587-95. doi:10.1038/ni.2286
76. Boldin MP, Taganov KD, Rao DS, Yang L, Zhao JL, Kalwani M. miR-146a is a significant brake on autoimmunity, myeloproliferation, and cancer in mice. J Exp Med (2011) 208(6):1189-201. doi:10.1084/jem.20101823
77. Lu LF, Boldin MP, Chaudhry A, Lin LL, Taganov KD, Hanada T. Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses. Cell (2010) 142(6):914-29. doi:10.1016/j.cell.2010.08.012
78. Tang Y, Luo X, Cui H, Ni X, Yuan M, Guo Y. MicroRNA-146A contributes to abnormal activation of the type I interferon pathway in human lupus by targeting the key signaling proteins. Arthritis Rheum (2009) 60(4):1065-75. doi:10.1002/art.24436
79. Qin A, Wen Z, Zhou Y, Li Y, Li Y, Luo J. MicroRNA-126 regulates the induction and function of CD4(+) Foxp3(+) regulatory T cells through PI3K/AKT pathway. J Cell Mol Med (2013) 17(2):252-64. doi:10.1111/jcmm.12003
80. Huang B, Zhao J, Lei Z, Shen S, Li D, Shen GX. miR-142-3p restricts cAMP production in CD4+CD25-T cells and CD4+CD25+ TREG cells by targeting AC9 mRNA. EMBO Rep (2009) 10(2):180-5. doi:10.1038/embor.2008.224
81. Hu Y, Wang C, Li Y, Zhao J, Chen C, Zhou Y. MiR-21 controls in situ expansion of CCR6(+) regulatory T cells through PTEN/AKT pathway in breast cancer. Immunol Cell Biol (2015) 93(8):753-64. doi:10.1038/icb.2015.37
82. Zhao M, Wang LT, Liang GP, Zhang P, Deng XJ, Tang Q. Up-regulation of microRNA-210 induces immune dysfunction via targeting FOXP3 in CD4(+) T cells of psoriasis vulgaris. Clin Immunol (2014) 150(1):22-30. doi:10.1016/j.clim.2013.10.009
83. Liu X, Robinson SN, Setoyama T, Tung SS, D'Abundo L, Shah MY. FOXP3 is a direct target of miR15a/16 in umbilical cord blood regulatory T cells. Bone Marrow Transplant (2014) 49(6):793-9. doi:10.1038/bmt.2014.57
84. Zhao J, Fan Y, Wang K, Ni X, Gu J, Lu H. LncRNA HULC affects the differentiation of Treg in HBV-related liver cirrhosis. Int Immunopharmacol (2015) 28(2):901-5. doi:10.1016/j.intimp.2015.04.028
85. Xiong G, Yang L, Chen Y, Fan Z. Linc-POU3F3 promotes cell proliferation in gastric cancer via increasing T-reg distribution. Am J Transl Res (2015) 7(11):2262-9.
86. Qiao YQ, Huang ML, Xu AT, Zhao D, Ran ZH, Shen J. LncRNA DQ786243 affects Treg related CREB and Foxp3 expression in Crohn's disease. J Biomed Sci (2013) 20:87. doi:10.1186/1423-0127-20-87
87. Dudda JC, Perdue N, Bachtanian E, Campbell DJ. Foxp3+ regulatory T cells maintain immune homeostasis in the skin. J Exp Med (2008) 205(7):1559-65. doi:10.1084/jem.20072594
88. Denning TL, Kim G, Kronenberg M. Cutting edge: CD4+CD25+ regulatory T cells impaired for intestinal homing can prevent colitis. J Immunol (2005) 174(12):7487-91. doi:10.4049/jimmunol.174.12.7487
89. Cipolletta D. Adipose tissue-resident regulatory T cells: phenotypic specialization, functions and therapeutic potential. Immunology (2014) 142(4):517-25. doi:10.1111/imm.12262
90. Lathrop SK, Bloom SM, Rao SM, Nutsch K, Lio CW, Santacruz N. Peripheral education of the immune system by colonic commensal microbiota. Nature (2011) 478(7368):250-4. doi:10.1038/nature10434
91. Tanoue T, Atarashi K, Honda K. Development and maintenance of intestinal regulatory T cells. Nat Rev Immunol (2016) 16(5):295-309. doi:10.1038/nri.2016.36
92. Coombes JL, Siddiqui KR, Arancibia-Carcamo CV, Hall J, Sun CM, Belkaid Y. 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(8):1757-64. doi:10.1084/jem.20070590
93. Jaensson E, Uronen-Hansson H, Pabst O, Eksteen B, Tian J, Coombes JL. Small intestinal CD103+ dendritic cells display unique functional properties that are conserved between mice and humans. J Exp Med (2008) 205(9):2139-49. doi:10.1084/jem.20080414
94. Gajewski TF, Schreiber H, Fu YX. Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol (2013) 14(10):1014-22. doi:10.1038/ni.2703
95. Tanchot C, Terme M, Pere H, Tran T, Benhamouda N, Strioga M. Tumor-infiltrating regulatory T cells: phenotype, role, mechanism of expansion in situ and clinical significance. Cancer Microenviron (2013) 6(2):147-57. doi:10.1007/s12307-012-0122-y
96. Park HJ, Kusnadi A, Lee EJ, Kim WW, Cho BC, Lee IJ. Tumor-infiltrating regulatory T cells delineated by upregulation of PD-1 and inhibitory receptors. Cell Immunol (2012) 278(1-2):76-83. doi:10.1016/j.cellimm.2012.07.001
97. Gao X, Zhu Y, Li G, Huang H, Zhang G, Wang F. TIM-3 expression characterizes regulatory T cells in tumor tissues and is associated with lung cancer progression. PLoS One (2012) 7(2):e30676. doi:10.1371/journal.pone.0030676
98. Gobert M, Treilleux I, Bendriss-Vermare N, Bachelot T, Goddard-Leon S, Arfi V. Regulatory T cells recruited through CCL22/CCR4 are selectively activated in lymphoid infiltrates surrounding primary breast tumors and lead to an adverse clinical outcome. Cancer Res (2009) 69(5):2000-9. doi:10.1158/0008-5472.CAN-08-2360
99. Strauss L, Bergmann C, Szczepanski M, Gooding W, Johnson JT, Whiteside TL. A unique subset of CD4+CD25highFoxp3+ T cells secreting interleukin-10 and transforming growth factor-beta1 mediates suppression in the tumor microenvironment. Clin Cancer Res (2007) 13(15 Pt 1):4345-54. doi:10.1158/1078-0432.CCR-07-0472
100. Saito T, Nishikawa H, Wada H, Nagano Y, Sugiyama D, Atarashi K. Two FOXP3(+)CD4(+) T cell subpopulations distinctly control the prognosis of colorectal cancers. Nat Med (2016) 22(6):679-84. doi:10.1038/nm.4086