Breaking free of control: How conventional T cells overcome regulatory T cell suppression

Frontiers in Immunology

Volumn 7, Issue MAY, 2016, Pages

  Mercadante, Emily R ^a   Lorenz, Ulrike M ^a  

^a UNIVERSITY OF VIRGINIA   (United States)

Author keywords

Autoimmune disease; Conventional T cells; Immune tolerance; Immunotherapy; PI3K Akt pathway; Treg cells

Indexed keywords

B7 ANTIGEN; CD134 ANTIGEN; CD137 LIGAND; CD28 ANTIGEN; CD86 ANTIGEN; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; GLUCOCORTICOID INDUCED TUMOR NECROSIS FACTOR RECEPTOR; INTERLEUKIN 15; INTERLEUKIN 1BETA; INTERLEUKIN 2; INTERLEUKIN 21; INTERLEUKIN 4; INTERLEUKIN 6; INTERLEUKIN 7; MAJOR HISTOCOMPATIBILITY ANTIGEN CLASS 1; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN KINASE B; PROTEIN TYROSINE PHOSPHATASE SHP 1; TOLL LIKE RECEPTOR; TRANSFORMING GROWTH FACTOR BETA; TUMOR NECROSIS FACTOR ALPHA; TUMOR NECROSIS FACTOR RECEPTOR ASSOCIATED FACTOR 6;

APOPTOSIS; AUTOIMMUNE DISEASE; AUTOIMMUNITY; CANCER IMMUNOTHERAPY; CD8+ T LYMPHOCYTE; CELL PROLIFERATION; CELL SUPPRESSION; CELL SURVIVAL; CELLULAR, SUBCELLULAR AND MOLECULAR BIOLOGICAL PHENOMENA AND FUNCTIONS; CYTOKINE PRODUCTION; HUMAN; IMMUNE RESPONSE; INTRACELLULAR SIGNALING; NONHUMAN; PROTEIN EXPESSION; REGULATORY T LYMPHOCYTE; REVIEW; T LYMPHOCYTE;

EID: 84973517700     PISSN: None     EISSN: 16643224     Source Type: Journal    
DOI: 10.3389/fimmu.2016.00193     Document Type: Review

References (187)

1. Sakaguchi S, Wing K, Miyara M. Regulatory T cells-a brief history and perspective. Eur J Immunol (2007) 37(Suppl 1):S116-23. doi:10.1002/eji.200737593
2. Shevach EM. Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity (2009) 30:636-45. doi:10.1016/j.immuni.2009.04.010
3. Campbell DJ, Koch MA. Phenotypical and functional specialization of FOXP3+ regulatory T cells. Nat Rev Immunol (2011) 11:119-30. doi:10.1038/nri2916
4. Buckner JH. Mechanisms of impaired regulation by CD4(+)CD25(+)FOXP3(+) regulatory T cells in human autoimmune diseases. Nat Rev Immunol (2010) 10:849-59. doi:10.1038/nri2889
5. del Rio R, Sun Y, Alard P, Tung KS, Teuscher C. H2 control of natural T regulatory cell frequency in the lymph node correlates with susceptibility to day three thymectomy induced autoimmune disease. J Immunol (2011) 186:382-9. doi:10.4049/jimmunol.1002110
6. 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
7. Ziegler SF. FOXP3: of mice and men. Annu Rev Immunol (2006) 24:209-26. doi:10.1146/annurev.immunol.24.021605.090547
8. Lahl K, Loddenkemper C, Drouin C, Freyer J, Arnason J, Eberl G, et al. Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease. J Exp Med (2007) 204:57-63. doi:10.1084/jem.20061852
9. 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
10. 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
11. Annacker O, Pimenta-Araujo R, Burlen-Defranoux O, Barbosa TC, Cumano A, Bandeira A. CD25+ CD4+ T cells regulate the expansion of peripheral CD4 T cells through the production of IL-10. J Immunol (2001) 166:3008-18. doi:10.4049/jimmunol.166.5.3008
12. Long SA, Buckner JH. CD4+FOXP3+ Treg in human autoimmunity: more than a numbers game. J Immunol (2011) 187:2061-6. doi:10.4049/jimmunol.1003224
13. Grant CR, Liberal R, Mieli-Vergani G, Vergani D, Longhi MS. Regulatory T-cells in autoimmune diseases: challenges, controversies and-yet-unanswered questions. Autoimmun Rev (2015) 14:105-16. doi:10.1016/j.autrev.2014.10.012
14. Monk CR, Spachidou M, Rovis F, Leung E, Botto M, Lechler RI, et al. MRL/Mp CD4+,CD25-T cells show reduced sensitivity to suppression by CD4+,CD25+ regulatory T cells in vitro: a novel defect of T cell regulation in systemic lupus erythematosus. Arthritis Rheum (2005) 52:1180-4. doi:10.1002/art.20976
15. You S, Belghith M, Cobbold S, Alyanakian MA, Gouarin C, Barriot S, et al. Autoimmune diabetes onset results from qualitative rather than quantitative age-dependent changes in pathogenic T-cells. Diabetes (2005) 54:1415-22. doi:10.2337/diabetes.54.5.1415
16. 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
17. O'Connor RA, Malpass KH, Anderton SM. The inflamed central nervous system drives the activation and rapid proliferation of Foxp3+ regulatory T cells. J Immunol (2007) 179:958-66. doi:10.4049/jimmunol.179.2.958
18. Clough LE, Wang CJ, Schmidt EM, Booth G, Hou TZ, Ryan GA, et al. Release from regulatory T cell-mediated suppression during the onset of tissue-specific autoimmunity is associated with elevated IL-21. J Immunol (2008) 180:5393-401. doi:10.4049/jimmunol.180.8.5393
19. Parietti V, Monneaux F, Décossas M, Muller S. Function of CD4+,CD25+ Treg cells in MRL/lpr mice is compromised by intrinsic defects in antigen-presenting cells and effector T cells. Arthritis Rheum (2008) 58:1751-61. doi:10.1002/art.23464
20. D'Alise AM, Auyeung V, Feuerer M, Nishio J, Fontenot J, Benoist C, et al. The defect in T-cell regulation in NOD mice is an effect on the T-cell effectors. Proc Natl Acad Sci U S A (2008) 105:19857-62. doi:10.1073/pnas.0810713105
21. Wu G, Lu ZH, Gabius HJ, Ledeen RW, Bleich D. Ganglioside GM1 deficiency in effector T cells from NOD mice induces resistance to regulatory T-cell suppression. Diabetes (2011) 60:2341-9. doi:10.2337/db10-1309
22. Wilhelm AJ, Rhoads JP, Wade NS, Major AS. Dysregulated CD4+ T cells from SLE-susceptible mice are sufficient to accelerate atherosclerosis in LDLr-/-mice. Ann Rheum Dis (2015) 74:778-85. doi:10.1136/annrheumdis-2013-203759
23. Haufe S, Haug M, Schepp C, Kuemmerle-Deschner J, Hansmann S, Rieber N, et al. Impaired suppression of synovial fluid CD4+CD25-T cells from patients with juvenile idiopathic arthritis by CD4+CD25+ Treg cells. Arthritis Rheum (2011) 63:3153-62. doi:10.1002/art.30503
24. Wehrens EJ, Mijnheer G, Duurland CL, Klein M, Meerding J, van Loosdregt J, et al. Functional human regulatory T cells fail to control autoimmune inflammation due to PKB/c-akt hyperactivation in effector cells. Blood (2011) 118:3538-48. doi:10.1182/blood-2010-12-328187
25. Wehrens EJ, Vastert SJ, Mijnheer G, Meerding J, Klein M, Wulffraat NM, et al. Anti-tumor necrosis factor a targets protein kinase B/c-Akt-induced resistance of effector cells to suppression in juvenile idiopathic arthritis. Arthritis Rheum (2013) 65:3279-84. doi:10.1002/art.38132
26. Xiao H, Wang S, Miao R, Kan W. TRAIL is associated with impaired regulation of CD4+CD25-T cells by regulatory T cells in patients with rheumatoid arthritis. J Clin Immunol (2011) 31:1112-9. doi:10.1007/s10875-011-9559-x
27. Schneider A, Rieck M, Sanda S, Pihoker C, Greenbaum C, Buckner JH. The effector T cells of diabetic subjects are resistant to regulation via CD4+FoxP3+ Treg. J Immunol (2008) 181:7350-5. doi:10.4049/jimmunol.181.10.7350
28. Lawson JM, Tremble J, Dayan C, Beyan H, Leslie RD, Peakman M, et al. Increased resistance to CD4+CD25hi regulatory T cell-mediated suppression in patients with type 1 diabetes. Clin Exp Immunol (2008) 154:353-9. doi:10.1111/j.1365-2249.2008.03810.x
29. Venigalla RK, Tretter T, Krienke S, Max R, Eckstein V, Blank N, et al. Reduced CD4+,CD25-T cell sensitivity to the suppressive function of CD4+,CD25high,CD127-/low regulatory T cells in patients with active systemic lupus erythematosus. Arthritis Rheum (2008) 58:2120-30. doi:10.1002/art.23556
30. Vargas-Rojas MI, Crispín JC, Richaud-Patin Y, Alcocer-Varela J. Quantitative and qualitative normal regulatory T cells are not capable of inducing suppression in SLE patients due to T-cell resistance. Lupus (2008) 17:289-94. doi:10.1177/0961203307088307
31. Trinschek B, Luessi F, Haas J, Wildemann B, Zipp F, Wiendl H, et al. Kinetics of IL-6 production defines T effector cell responsiveness to regulatory T cells in multiple sclerosis. PLoS One (2013) 8:e77634. doi:10.1371/journal.pone.0077634
32. Schneider A, Long SA, Cerosaletti K, Ni CT, Samuels P, Kita M, et al. In active relapsing-remitting multiple sclerosis, effector T cell resistance to adaptive T(regs) involves IL-6-mediated signaling. Sci Transl Med (2013) 5:170ra15. doi:10.1126/scitranslmed.3004970
33. Bhela S, Kempsell C, Manohar M, Dominguez-Villar M, Griffin R, Bhatt P, et al. Nonapoptotic and extracellular activity of granzyme B mediates resistance to regulatory T cell (Treg) suppression by HLA-DR-CD25hiCD127lo Tregs in multiple sclerosis and in response to IL-6. J Immunol (2015) 194(5):2180-9. doi:10.4049/jimmunol.1303257
34. Hmida NB, Ben Ahmed M, Moussa A, Rejeb MB, Said Y, Kourda N, et al. Impaired control of effector T cells by regulatory T cells: a clue to loss of oral tolerance and autoimmunity in celiac disease? Am J Gastroenterol (2012) 107:604-11. doi:10.1038/ajg.2011.397
35. Fantini MC, Rizzo A, Fina D, Caruso R, Sarra M, Stolfi C, et al. Smad7 controls resistance of colitogenic T cells to regulatory T cell-mediated suppression. Gastroenterology (2009) 136(1308-16):e1-3. doi:10.1053/j.gastro.2008.12.053
36. Fontenot JD, Dooley JL, Farr AG, Rudensky AY. Developmental regulation of Foxp3 expression during ontogeny. J Exp Med (2005) 202:901-6. doi:10.1084/jem.20050784
37. Larosa DF, Gelman AE, Rahman AH, Zhang J, Turka LA, Walsh PT. CpG DNA inhbiits CD4+CD25+ Treg suppression through direct MyD88-dependent costimulation of effector CD4+ T cells. Immunol Lett (2007) 108:183-8. doi:10.1016/j.imlet.2006.12.007
38. Thornton BAM, Shevach EM. CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J Exp Med (1998) 188:287-96. doi:10.1084/jem.188.2.287
39. Baecher-Allan C, Brown JA, Freeman GJ, Hafler DA. CD4+CD25 high regulatory cells in human peripheral blood. J Immunol (2001) 167:1245-53. doi:10.4049/jimmunol.167.3.1245
40. Takahashi T, Kuniyasu Y, Toda M, Sakaguchi N, Itoh M, Iwata M, et al. Immunologic self-tolerance maintained by suppressive T cells: induction of autoimmune disease by breaking their anergic/suppressive state. Int Immunol (1998) 10:1969-80. doi:10.1093/intimm/10.12.1969
41. Sojka DK, Hughson A, Sukiennicki TL, Fowell DJ. Early kinetic window of target T cell susceptibility to CD25+ regulatory T cell activity. J Immunol (2005) 175:7274-80. doi:10.4049/jimmunol.175.11.7274
42. Song J, Lei FT, Xiong X, Haque R. Intracellular signals of T cell costimulation. Cell Mol Immunol (2008) 5:239-47. doi:10.1038/cmi.2008.30
43. George TC, Bilsborough J, Viney JL, Norment AM. High antigen dose and activated dendritic cells enable Th cells to escape regulatory T cell-mediated suppression in vitro. Eur J Immunol (2003) 33:502-11. doi:10.1002/immu.200310026
44. Miller SD, Turley DM, Podojil JR. Antigen-specific tolerance strategies for the prevention and treatment of autoimmune disease. Nat Rev Immunol (2007) 7:665-77. doi:10.1038/nri2153
45. 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
46. Goodman WA, Levine AD, Massari JV, Sugiyama H, McCormick TS, Cooper KD. IL-6 signaling in psoriarsis prevents immune suppression by regulatory T cells. J Immunol (2009) 183:3170-6. doi:10.4049/jimmunol.0803721
47. Goodman WA, Young AB, McCormick TS, Cooper KD, Levine AD. Stat3 phosphorylation mediates resistance of primary human T cells to regulatory T cell suppression. J Immunol (2011) 186:3336-45. doi:10.4049/jimmunol.1001455
48. Riella LV, Yang J, Chock S, Safa K, Magee CN, Vanguri V, et al. Jagged2-signaling promotes IL-6-dependent transplant rejection. Eur J Immunol (2013) 43:1449-58. doi:10.1002/eji.201243151
49. Chen Y, Jian Y, Liu M, Zhong L, Zhang F, Yang W, et al. Gr-1+CD11b+ immature myeloid cells (IMC) promote resistance of pro-inflammatory T cells to suppression by regulatory T cells in atherosclerotic Apo E-deficient mice. PLoS One (2014) 9:e108620. doi:10.1371/journal.pone.0108620
50. Valencia X, Stephens G, Goldbach-Mansky R, Wilson M, Shevach EM, Lipsky PE. TNF downmodulates the function of human CD4+ CD25 hi T-regulatory cells. Immunobiology (2006) 108:253-61. doi:10.1182/blood-2005-11-4567
51. van Amelsfort JM, van Roon JA, Noordegraaf M, Jacobs KM, Bijlsma JW, Lafeber FP, et al. Proinflammatory mediator-induced reversal of CD4+,CD25+ regulatory T cell-mediated suppression in rheumatoid arthritis. Arthritis Rheum (2007) 56:732-42. doi:10.1002/art.22414
52. Ben Ahmed M, Belhadj Hmida N, Moes N, Buyse S, Abdeladhim M, Louzir H, et al. IL-15 renders conventional lymphocytes resistant to suppressive functions of regulatory T cells through activation of the phosphatidylinositol 3-kinase pathway. J Immunol (2009) 182:6763-70. doi:10.4049/jimmunol.0801792
53. Ruprecht CR, Gattorno M, Ferlito F, Gregorio A, Martini A, Lanzavecchia A, et al. Coexpression of CD25 and CD27 identifies FoxP3+ regulatory T cells in inflamed synovia. J Exp Med (2005) 201:1793-803. doi:10.1084/jem.20050085
54. Peluso I, Fantini MC, Fina D, Caruso R, Boirivant M, MacDonald TT, et al. IL-21 counteracts the regulatory T cell-mediated suppression of human CD4+ T lymphocytes. J Immunol (2007) 178:732-9. doi:10.4049/jimmunol.178.2.732
55. Ostiguy V, Allard EL, Marquis M, Leignadier J, Labrecque N. IL-21 promotes T lymphocyte survival by activating the phosphatidylinositol-3 kinase signaling cascade. J Leukoc Biol (2007) 82:645-56. doi:10.1189/jlb.0806494
56. O'Sullivan BJ, Thomas HE, Pai S, Santamaria P, Iwakura Y, Steptoe RJ, et al. IL-1 beta breaks tolerance through expansion of CD25+ effector T cells. J Immunol (2006) 176:7278-87. doi:10.4049/jimmunol.176.12.7278
57. 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
58. Pace L, Rizzo S, Palombi C, Brombacher F, Doria G. Cutting edge: IL-4-induced protection of CD4+CD25-Th cells from CD4+CD25+ regulatory T cell-mediated suppression. J Immunol (2006) 176:3900-4. doi:10.4049/jimmunol.176.7.3900
59. Pillemer BB, Qi Z, Melgert B, Oriss TB, Ray P, Ray A. STAT6 activation confers upon T helper cells resistance to suppression by regulatory T cells. J Immunol (2009) 183:155-63. doi:10.4049/jimmunol.0803733
60. Yao X, Huang J, Zhong H, Shen N, Faggioni R, Fung M, et al. Targeting interleukin-6 in inflammatory autoimmune diseases and cancers. Pharmacol Ther (2014) 141:125-9. doi:10.1016/j.pharmthera.2013.09.004
61. Trinschek B, Luessi F, Gross CC, Wiendl H, Jonuleit H. Interferon-beta therapy of multiple sclerosis patients improves the responsiveness of T cells for immune suppression by regulatory T cells. Int J Mol Sci (2015) 16:16330-46. doi:10.3390/ijms160716330
62. Herrath J, Müller M, Amoudruz P, Janson P, Michaëlsson J, Larsson PT, et al. The inflammatory milieu in the rheumatic joint reduces regulatory T-cell function. Eur J Immunol (2011) 41:2279-90. doi:10.1002/eji.201041004
63. Taylor PC, Feldmann M. Anti-TNF biologic agents: still the therapy of choice for rheumatoid arthritis. Nat Rev Rheumatol (2009) 5:578-82. doi:10.1038/nrrheum.2009.181
64. Rochman Y, Spolski R, Leonard WJ. New insights into the regulation of T cells by gamma(c) family cytokines. Nat Rev Immunol (2009) 9:480-90. doi:10.1038/nri2580
65. McInnes IB, Gracie JA. Interleukin-15: a new cytokine target for the treatment of inflammatory diseases. Curr Opin Pharmacol (2004) 4:392-7. doi:10.1016/j.coph.2004.04.003
66. Wang XS, Li BZ, Hu LF, Wen PF, Zhang M, Pan HF, et al. Perspectives of the relationship between IL-7 and autoimmune diseases. Clin Rheumatol (2013) 32:1703-9. doi:10.1007/s10067-013-2360-x
67. Hofmeister R, Khaled AR, Benbernou N, Rajnavolgyi E, Muegge K, Durum SK. Interleukin-7: physiological roles and mechanisms of action. Cytokine Growth Factor Rev (1999) 10:41-60. doi:10.1016/S1359-6101(98)00025-2
68. Mishra A, Sullivan L, Caligiuri MA. Molecular pathways: interleukin-15 signaling in health and in cancer. Clin Cancer Res (2014) 20:2044-50. doi:10.1158/1078-0432.CCR-12-3603
69. Remillard B, Petrillo R, Maslinski W, Tsudo M, Strom TB, Cantley L, et al. Interleukin-2 receptor regulates activation of phosphatidylinositol 3-kinase. J Biol Chem (1991) 266:14167-70
70. Moon JJ, Nelson BH. Phosphatidylinositol 3-kinase potentiates, but does not trigger, T cell proliferation mediated by the IL-2 receptor. J Immunol (2001) 167:2714-23. doi:10.4049/jimmunol.167.5.2714
71. Boyman O, Sprent J. The role of interleukin-2 during homeostasis and activation of the immune system. Nat Rev Immunol (2012) 12:180-90. doi:10.1038/nri3156
72. Wurster AL, Withers DJ, Uchida T, White MF, Grusby MJ. Stat6 and IRS-2 cooperate in interleukin 4 (IL-4)-induced proliferation and differentiation but are dispensable for IL-4-dependent rescue from apoptosis. Mol Cell Biol (2002) 22:117-26. doi:10.1128/MCB.22.1.117-126.2002
73. Cohen P. The TLR and IL-1 signalling network at a glance. J Cell Sci (2014) 127:2383-90. doi:10.1242/jcs.149831
74. Caramalho I, Lopes-Carvalho T, Ostler D, Zelenay S, Haury M, Demengeot J. Regulatory T cells selectively express toll-like receptors and are activated by lipopolysaccharide. J Exp Med (2003) 197:403-11. doi:10.1084/jem.20021633
75. Sutmuller RP, Morgan ME, Netea MG, Grauer O, Adema GJ. Toll-like receptors on regulatory T cells: expanding immune regulation. Trends Immunol (2006) 27:387-93. doi:10.1016/j.it.2006.06.005
76. Chen Q, Davidson TS, Huter EN, Shevach EM. Engagement of TLR2 does not reverse the suppressor function of mouse regulatory T cells, but promotes their survival. J Immunol (2009) 183:4458-66. doi:10.4049/jimmunol.0901465
77. Crellin NK, Garcia RV, Hadisfar O, Allan SE, Steiner TS, Levings MK. Human CD4+ T cells express TLR5 and its ligand flagellin enhances the suppressive capacity and expression of FOXP3 in CD4+CD25+ T regulatory cells. J Immunol (2005) 175:8051-9. doi:10.4049/jimmunol.175.12.8051
78. Peng G, Guo Z, Kiniwa Y, Voo KS, Peng W, Fu T, et al. Toll-like receptor 8-mediated reversal of CD4+ regulatory T cell function. Science (2005) 309:1380-4. doi:10.1126/science.1113401
79. Oberg HH, Ly TT, Ussat S, Meyer T, Kabelitz D, Wesch D. Differential but direct abolishment of human regulatory T cell suppressive capacity by various TLR2 ligands. J Immunol (2010) 184:4733-40. doi:10.4049/jimmunol.0804279
80. Nyirenda MH, Sanvito L, Darlington PJ, O'Brien K, Zhang GX, Constantinescu CS, et al. TLR2 stimulation drives human naive and effector regulatory T cells into a Th17-like phenotype with reduced suppressive function. J Immunol (2011) 187:2278-90. doi:10.4049/jimmunol.1003715
81. Amiset L, Fend L, Gatard-Scheikl T, Rittner K, Duong V, Rooke R, et al. TLR2 ligation protects effector T cells from regulatory T-cell mediated suppression and repolarizes T helper responses following MVA-based cancer immunotherapy. Oncoimmunology (2012) 1:1271-80. doi:10.4161/onci.21479
82. Jin B, Sun T, Yu XH, Yang YX, Yeo AE. The effects of TLR activation on T-cell development and differentiation. Clin Dev Immunol (2012) 2012:836485. doi:10.1155/2012/836485
83. Rahman AH, Taylor DK, Turka LA. The contribution of direct TLR signaling to T cell responses. Immunol Res (2009) 45:25-36. doi:10.1007/s12026-009-8113-x
84. Gelman AE, LaRosa DF, Zhang J, Walsh PT, Choi Y, Sunyer JO, et al. The adaptor molecule MyD88 activates PI-3 kinase signaling in CD4+ T cells and enables CpG oligodeoxynucleotide-mediated costimulation. Immunity (2006) 25:783-93. doi:10.1016/j.immuni.2006.08.023
85. Liu H, Komai-Koma M, Xu D, Liew FY. Toll-like receptor 2 signaling modulates the functions of CD4+ CD25+ regulatory T cells. Proc Natl Acad Sci U S A (2006) 103:7048-53. doi:10.1073/pnas.0601554103
86. Sutmuller RP, den Brok MH, Kramer M, Bennink EJ, Toonen LW, Kullberg BJ, 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
87. Quigley M, Martinez J, Huang X, Yang Y. A critical role for direct TLR2-MyD88 signaling in CD8 T-cell clonal expansion and memory formation following vaccinia viral infection. Immunobiology (2009) 113:2256-64. doi:10.1182/blood-2008-03-148809
88. Chapman N, Bilal M, Cruz-Orcutt N, Knudson C, Madinaveitia S, Light J, et al. Distinct signaling pathways regulate TLR2 co-stimulatory function in human T cells. Cell Signal (2013) 25:1-24. doi:10.1016/j.cellsig.2012.11.026
89. Mikacenic C, Schneider A, Radella F, Buckner JH, Wurfel MM. Cutting edge: genetic variation in TLR1 is associated with pam3CSK4-induced effector T cell resistance to regulatory T cell suppression. J Immunol (2015) 193:5786-90. doi:10.4049/jimmunol.1401185
90. Eder C. Mechanisms of interleukin-1β release. Immunobiology (2009) 214:543-53. doi:10.1016/j.imbio.2008.11.007
91. Sims JE, Smith DE. The IL-1 family: regulators of immunity. Nat Rev Immunol (2010) 10:89-102. doi:10.1038/nri2691
92. O'Neill LAJ. The interleukin-1 receptor/toll-like receptor superfamily: 10 years of progress. Immunol Rev (2008) 226:10-8. doi:10.1111/j.1600-065X.2008.00701.x
93. Cavalli G, Dinarello CA. Treating rheumatological diseases and co-morbidities with interleukin-1 blocking therapies. Rheumatology (2015) 54(12):2134-44. doi:10.1093/rheumatology/kev269
94. Watts TH. TNF/TNFR family members in costimulation of T cell responses. Annu Rev Immunol (2005) 23:23-68. doi:10.1146/annurev.immunol.23.021704.115839
95. Stephens GL, McHugh RS, Whitters MJ, Young DA, Luxenberg D, Carreno BM, et al. Engagement of glucocorticoid-induced TNFR family-related receptor on effector T cells by its ligand mediates resistance to suppression by CD4+CD25+ T cells. J Immunol (2004) 173:5008-20. doi:10.4049/jimmunol.173.8.5008
96. Shimizu J, Yamazaki S, Takahashi T, Ishida Y, Sakaguchi S. Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance. Nat Immunol (2002) 3:135-42. doi:10.1038/ni759
97. Choi BK, Bae JS, Choi EM, Kang WJ, Sakaguchi S, Vinay DS, et al. 4-1BB-dependent inhibition of immunosuppression by activated CD4+ CD25+ T cells. J Leukoc Biol (2004) 75:785-91. doi:10.1189/jlb.1003491
98. Elpek KG, Yolcu ES, Franke DD, Lacelle C, Schabowsky RH, Shirwan H. Ex vivo expansion of CD4+CD25+FoxP3+ T regulatory cells based on synergy between IL-2 and 4-1BB signaling. J Immunol (2007) 179:7295-304. doi:10.4049/jimmunol.179.11.7295
99. Robertson SJ, Messer RJ, Carmody AB, Mittler RS, Burlak C, Hasenkrug KJ, et al. CD137-mediated immunotherapy for chronic viral infection. J Immunol (2008) 180:5267-74. doi:10.4049/jimmunol.180.8.5267
100. Takeda I, Ine S, Killeen N, Ndhlovu LC, Murata K, Satomi S, et al. Distinct roles for the OX40-OX40 ligand interaction in regulatory and nonregulatory T cells. J Immunol (2004) 172:3580-9. doi:10.4049/jimmunol.172.6.3580
101. Piconese S, Valzasina B, Colombo MP. OX40 triggering blocks suppression by regulatory T cells and facilitates tumor rejection. J Exp Med (2008) 205:825-39. doi:10.1084/jem.20071341
102. Voo KS, Bover L, Harline ML, Vien LT, Facchinetti V, Arima K, et al. Antibodies targeting human OX40 expand effector T cells and block inducible and natural regulatory T cell function. J Immunol (2013) 191:3641-50. doi:10.4049/jimmunol.1202752
103. So T, Croft M. Regulation of PI-3-kinase and Akt signaling in T lymphocytes and other cells by TNFR family molecules. Front Immunol (2013) 4:139. doi:10.3389/fimmu.2013.00139
104. McHugh RS, Whitters MJ, Piccirillo CA, Young DA, Shevach EM, Collins M, et al. CD4(+)CD25(+) immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity (2002) 16:311-23. doi:10.1016/S1074-7613(02)00280-7
105. Vu MD, Xiao X, Gao W, Degauque N, Chen M, Kroemer A, et al. OX40 costimulation turns off Foxp3 + Tregs. Blood (2007) 110:2501-10. doi:10.1182/blood-2007-01-070748
106. Chen X, Subleski JJ, Kopf H, Howard OM, Männel DN, Oppenheim JJ. Cutting edge: expression of TNFR2 defines a maximally suppressive subset of mouse CD4+CD25+FoxP3+ T regulatory cells: applicability to tumor-infiltrating T regulatory cells. J Immunol (2008) 180:6467-71. doi:10.4049/jimmunol.180.10.6467
107. Bremer E. Targeting of the tumor necrosis factor receptor superfamily for cancer immunotherapy. ISRN Oncol (2013) 2013:371854. doi:10.1155/2013/371854
108. Nishikawa H, Kato T, Hirayama M, Orito Y, Sato E, Harada N, et al. Regulatory T cell-resistant CD8+ T cells induced by glucocorticoid-induced tumor necrosis factor receptor signaling. Cancer Res (2008) 68:5948-54. doi:10.1158/0008-5472.CAN-07-5839
109. Wang C, Lin GHY, McPherson AJ, Watts TH. Immune regulation by 4-1BB and 4-1BBL: complexities and challenges. Immunol Rev (2009) 229:192-215. doi:10.1111/j.1600-065X.2009.00765.x
110. Stärck L, Scholz C, Dörken B, Daniel PT. Costimulation by CD137/4-1BB inhibits T cell apoptosis and induces Bcl-xL and c-FLIPshort via phosphatidylinositol 3-kinase and AKT/protein kinase B. Eur J Immunol (2005) 35:1257-66. doi:10.1002/eji.200425686
111. Valzasina B, Guiducci C, Dislich H, Killeen N, Weinberg AD, Colombo MP. Triggering of OX40 (CD134) on CD4+CD25+ T cells blocks their inhibitory activity: a novel regulatory role for OX40 and its comparison with GITR. Immunobiology (2005) 105:2845-51. doi:10.1182/blood-2004-07-2959
112. Griseri T, Asquith M, Thompson C, Powrie F. OX40 is required for regulatory T cell-mediated control of colitis. J Exp Med (2010) 207:699-709. doi:10.1084/jem.20091618
113. Xiao X, Balasubramanian S, Liu W, Chu X, Wang H, Taparowsky EJ, et al. OX40 signaling favors the induction of T(H)9 cells and airway inflammation. Nat Immunol (2012) 13:981-90. doi:10.1038/ni.2390
114. Ishii N, Takahashi T, Soroosh P, Sugamura K. OX40-OX40 ligand interaction in T-cell-mediated immunity and immunopathology. Adv Immunol (2010) 105:63-98. doi:10.1016/S0065-2776(10)05003-0
115. So T, Choi H, Croft M. OX40 complexes with phosphoinositide 3-kinase and protein kinase B (PKB) to augment TCR-dependent PKB signaling. J Immunol (2011) 186:3547-55. doi:10.4049/jimmunol.1003156
116. Kshirsagar S, Binder E, Riedl M, Wechselberger G, Steichen E, Edelbauer M. Enhanced activity of Akt in effector T cells from children with lupus nephritis is associated with reduced induction of TRAF6 and increase in OX40. Arthritis Rheum (2013) 65(11):2996-3006. doi:10.1002/art
117. Aten J, Roos A, Claessen N, Schilder-Tol EJ, Ten Berge IJ, Weening JJ. Strong and selective glomerular localization of CD134 ligand and TNF receptor-1 in proliferative lupus nephritis. J Am Soc Nephrol (2000) 11:1426-38
118. Giacomelli R, Passacantando A, Perricone R, Parzanese I, Rascente M, Minisola G, et al. T lymphocytes in the synovial fluid of patients with active rheumatoid arthritis display CD134-OX40 surface antigen. Clin Exp Rheumatol (2001) 19:317-20
119. Souza HS, Elia CC, Spencer J, MacDonald TT. Expression of lymphocyte-endothelial receptor-ligand pairs, alpha4beta7/MAdCAM-1 and OX40/OX40 ligand in the colon and jejunum of patients with inflammatory bowel disease. Gut (1999) 45:856-63. doi:10.1136/gut.45.6.856
120. Stüber E, Büschenfeld A, Lüttges J, Von Freier A, Arendt T, Fölsch UR. The expression of OX40 in immunologically mediated diseases of the gastrointestinal tract (celiac disease, Crohn's disease, ulcerative colitis). Eur J Clin Invest (2000) 30:594-9. doi:10.1046/j.1365-2362.2000.00658.x
121. Malmström V, Shipton D, Singh B, Al-Shamkhani A, Puklavec MJ, Barclay AN, et al. CD134L expression on dendritic cells in the mesenteric lymph nodes drives colitis in T cell-restored SCID mice. J Immunol (2001) 166:6972-81. doi:10.4049/jimmunol.166.11.6972
122. Kotani A, Ishikawa T, Matsumura Y, Ichinohe T, Ohno H, Hori T, et al. Correlation of peripheral blood OX40+(CD134+) T cells with chronic graft-versus-host disease in patients who underwent allogeneic hematopoietic stem cell transplantation. Blood (2001) 98:3162-4. doi:10.1182/blood.V98.10.3162
123. Chen X, Bäumel M, Männel DN, Howard OM, Oppenheim JJ. Interaction of TNF with TNF receptor type 2 promotes expansion and function of mouse CD4+CD25+ T regulatory cells. J Immunol (2007) 179:154-61. doi:10.4049/jimmunol.179.1.154
124. Chen X, Hamano R, Subleski JJ, Hurwitz AA, Howard OM, Oppenheim JJ. Expression of costimulatory TNFR2 induces resistance of CD4+FoxP3-conventional T cells to suppression by CD4+FoxP3+ regulatory T cells. J Immunol (2010) 185:174-82. doi:10.4049/jimmunol.0903548
125. Yang J, Brook MO, Carvalho-Gaspar M, Zhang J, Ramon HE, Sayegh MH, et al. Allograft rejection mediated by memory T cells is resistant to regulation. Proc Natl Acad Sci U S A (2007) 104:19954-9. doi:10.1073/pnas.0704397104
126. Paolino M, Penninger JM. Cbl-b in T-cell activation. Semin Immunopathol (2010) 32:137-48. doi:10.1007/s00281-010-0197-9
127. Chiang YJ, Kole HK, Brown K, Naramura M, Fukuhara S, Hu RJ, et al. Cbl-b regulates the CD28 dependence of T-cell activation. Nature (2000) 403:216-20. doi:10.1038/35003235
128. Li D, Gál I, Vermes C, Alegre ML, Chong AS, Chen L, et al. Cutting edge: Cbl-b: one of the key molecules tuning CD28-and CTLA-4-mediated T cell costimulation. J Immunol (2004) 173(12):7135-9. doi:10.4049/jimmunol.173.12.7135
129. Fang D, Liu YC. Proteolysis-independent regulation of PI3K by Cbl-b-mediated ubiquitination in T cells. Nat Immunol (2001) 2:870-5. doi:10.1038/ni0901-870
130. Gruber T, Hermann-Kleiter N, Hinterleitner R, Fresser F, Schneider R, Gastl G, et al. PKC-theta modulates the strength of T cell responses by targeting Cbl-b for ubiquitination and degradation. Sci Signal (2009) 2:ra30. doi:10.1126/scisignal.2000046
131. Bachmaier K, Krawczyk C, Kozieradzki I, Kong YY, Sasaki T, Oliveira-dos-Santos A, et al. Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b. Nature (2000) 403:211-6. doi:10.1038/35003228
132. Wohlfert EA, Callahan MK, Clark RB. Resistance to CD4+CD25+ regulatory T cells and TGF-beta in Cbl-b-/-mice. J Immunol (2004) 173:1059-65. doi:10.4049/jimmunol.173.2.1059
133. Adams CO, Housley WJ, Bhowmick S, Cone RE, Rajan TV, Forouhar F, et al. Cbl-b(-/-) T cells demonstrate in vivo resistance to regulatory T cells but a context-dependent resistance to TGF-beta. J Immunol (2010) 185:2051-8. doi:10.4049/jimmunol.1001171
134. Chiang JY, Jang IK, Hodes R, Gu H. Ablation of Cbl-b provides protection against transplanted and spontaneous tumors. J Clin Invest (2007) 117:2-9. doi:10.1172/JCI29472
135. Loeser S, Loser K, Bijker MS, Rangachari M, van der Burg SH, Wada T, et al. Spontaneous tumor rejection by cbl-b-deficient CD8+ T cells. J Exp Med (2007) 204:879-91. doi:10.1084/jem.20061699
136. Wu H, Arron JR. TRAF6, a molecular bridge spanning adaptive immunity, innate immunity and osteoimmunology. Bioessays (2003) 25:1096-105. doi:10.1002/bies.10352
137. Yang WL, Wang J, Chan CH, Lee SW, Campos AD, Lamothe B, et al. The E3 ligase TRAF6 regulates Akt ubiquitination and activation. Science (2009) 325:1134-8. doi:10.1126/science.1175065
138. King CG, Kobayashi T, Cejas PJ, Kim T, Yoon K, Kim GK, et al. TRAF6 is a T cell-intrinsic negative regulator required for the maintenance of immune homeostasis. Nat Med (2006) 12:1088-92. doi:10.1038/nm1449
139. Lorenz U. SHP-1 and SHP-2 in T cells: two phosphatases functioning at many levels. Immunol Rev (2009) 228:342-59. doi:10.1111/j.1600-065X.2008.00760.x
140. Paster W, Bruger AM, Katsch K, Grégoire C, Roncagalli R, Fu G, et al. A THEMIS: SHP 1 complex promotes T-cell survival. EMBO J (2015) 34:393-409. doi:10.15252/embj.201387725
141. Cho SH, Oh SY, Lane AP, Lee J, Oh MH, Lee S, et al. Regulation of Nasal airway homeostasis and inflammation in mice by SHP-1 and Th2/Th1 signaling pathways. PLoS One (2014) 9:e103685. doi:10.1371/journal.pone.0103685
142. Johnson DJ, Pao LI, Dhanji S, Murakami K, Ohashi PS, Neel BG. Shp1 regulates T cell homeostasis by limiting IL-4 signals. J Exp Med (2013) 210:1419-31. doi:10.1084/jem.20122239
143. Mauldin IS, Tung KS, Lorenz UM. The tyrosine phosphatase SHP 1 as a new player that dampens murine Th17 development. Blood (2012) 119(19):4419-29. doi:10.1182/blood-2011-09-377069
144. Abram CL, Roberge GL, Pao LI, Neel BG, Lowell CA. Distinct roles for neutrophils and dendritic cells in inflammation and autoimmunity in motheaten mice. Immunity (2013) 38:489-501. doi:10.1016/j.immuni.2013.02.018
145. Tsui HW, Siminovitch KA, de Souza L, Tsui FW. Motheaten and viable motheaten mice have mutations in the haematopoeitic cell phosphatase gene. Nat Genet (1993) 4:124-9. doi:10.1038/ng0693-124
146. Fu G, Casas J, Rigaud S, Rybakin V, Lambolez F, Brzostek J, et al. Themis sets the signal threshold for positive and negative selection in T-cell development. Nature (2013) 504:441-5. doi:10.1038/nature12718
147. Fawcett VCJ, Lorenz U. Localization of Src homology 2 domain-containing phosphatase 1 (SHP-1) to lipid rafts in T lymphocytes: functional implications and a role for the SHP-1 carboxyl terminus. J Immunol (2005) 174:2849-59. doi:10.4049/jimmunol.174.5.2849
148. Stefanová I, Hemmer B, Vergelli M, Martin R, Biddison WE, Germain RN. TCR ligand discrimination is enforced by competing ERK positive and SHP-1 negative feedback pathways. Nat Immunol (2003) 4:248-54. doi:10.1038/ni895
149. Iype T, Sankarshanan M, Mauldin IS, Mullins DW, Lorenz U. The protein tyrosine phosphatase SHP-1 modulates the suppressive activity of regulatory T cells. J Immunol (2010) 185:6115-27. doi:10.4049/jimmunol.1000622
150. Mercadante E, Lorenz UM. SHP-1 regulates conventional T cell resistance to suppression by regulatory T cells. AAAS Annu. Meet. 2016. Washington, DC (2016)
151. Cuevas BD, Lu Y, Mao M, Zhang J, LaPushin R, Siminovitch K, et al. Tyrosine phosphorylation of p85 relieves its inhibitory activity on phosphatidylinositol 3-kinase. J Biol Chem (2001) 276:27455-61. doi:10.1074/jbc.M100556200
152. Stromnes IM, Fowler C, Casamina CC, Georgopolos CM, McAfee MS, Schmitt TM, et al. Abrogation of SRC homology region 2 domain-containing phosphatase 1 in tumor-specific T cells improves efficacy of adoptive immunotherapy by enhancing the effector function and accumulation of short-lived effector T cells in vivo. J Immunol (2012) 189:1812-25. doi:10.4049/jimmunol.1200552
153. Hebeisen M, Baitsch L, Presotto D, Baumgaertner P, Romero P, Michielin O, et al. SHP-1 phosphatase activity counteracts increased T cell receptor affinity. J Clin Invest (2013) 123(3):1044-56. doi:10.1172/JCI65325
154. Sathish JG, Johnson KG, LeRoy FG, Fuller KJ, Hallett MB, Brennan P, et al. Requirement for CD28 co-stimulation is lower in SHP-1-deficient T cells. Eur J Immunol (2001) 31:3649-58. doi:10.1002/1521-4141(200112)31:12<3649::AID-IMMU3649>3.0.CO;2-8
155. Wohlfert EA, Clark RB. 'Vive la Résistance!'-the PI3K-Akt pathway can determine target sensitivity to regulatory T cell suppression. Trends Immunol (2007) 28:154-60. doi:10.1016/j.it.2007.02.003
156. Kane LP, Weiss A. The PI-3 kinase/Akt pathway and T cell activation: pleiotropic pathways downstream of PIP3. Immunol Rev (2003) 192:7-20. doi:10.1034/j.1600-065X.2003.00008.x
157. Toker A, Marmiroli S. Signaling specificity in the Akt pathway in biology and disease. Adv Biol Regul (2014) 55:28-38. doi:10.1016/j.jbior.2014.04.001
158. Fruman DA. Phosphoinositide 3-kinase and its targets in B-cell and T-cell signaling. Curr Opin Immunol (2004) 16:314-20. doi:10.1016/j.coi.2004.03.014
159. Patel RK, Mohan C. PI3K/AKT signaling and systemic autoimmunity. Immunol Res (2005) 31:47-56. doi:10.1385/IR:31:1:47
160. 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
161. Vignali DA, Collison LW, Workman CJ. How regulatory T cells work. Nat Rev Immunol (2008) 8:523-32. doi:10.1038/nri2343
162. Bopp T, Palmetshofer A, Serfling E, Heib V, Schmitt S, Richter C, et al. NFATc2 and NFATc3 transcription factors play a crucial role in suppression of CD4+ T lymphocytes by CD4+ CD25+ regulatory T cells. J Exp Med (2005) 201:181-7. doi:10.1084/jem.20041538
163. Restifo NP, Dudley ME, Rosenberg SA. Adoptive immunotherapy for cancer: harnessing the T cell response. Nat Rev Immunol (2012) 12:269-81. doi:10.1038/nri3191
164. Oleinika K, Nibbs RJ, Graham GJ, Fraser AR. Suppression, subversion and escape: the role of regulatory T cells in cancer progression. Clin Exp Immunol (2013) 171:36-45. doi:10.1111/j.1365-2249.2012.04657.x
165. Nishikawa H, Sakaguchi S. Regulatory T cells in tumor immunity. Int J Cancer (2010) 127:759-67. doi:10.1002/ijc.25429
166. Ahmadzadeh M, Rosenberg SA. IL-2 administration increases CD4+ CD25 hi Foxp3+ regulatory T cells in cancer patients. Blood (2006) 107:2409-14. doi:10.1182/blood-2005-06-2399
167. Antony PA, Piccirillo CA, Akpinarli A, Finkelstein SE, Speiss PJ, Surman DR, et al. CD8+ T cell immunity against a tumor/self-antigen is augmented by CD4+ T helper cells and hindered by naturally occurring T regulatory cells. J Immunol (2005) 174:2591-601. doi:10.4049/jimmunol.174.5.2591
168. Hinrichs CS, Rosenberg SA. Exploiting the curative potential of adoptive T-cell therapy for cancer. Immunol Rev (2014) 257:56-71. doi:10.1111/imr.12132
169. Loskog A, Giandomenico V, Rossig C, Pule M, Dotti G, Brenner MK. Addition of the CD28 signaling domain to chimeric T-cell receptors enhances chimeric T-cell resistance to T regulatory cells. Leukemia (2006) 20:1819-28. doi:10.1038/sj.leu.2404366
170. Stromnes IM, Blattman JN, Tan X, Jeevanjee S. Abrogating Cbl-b in effector CD8 + T cells improves the efficacy of adoptive therapy of leukemia in mice. J Clin Invest (2010) 120:3722-34. doi:10.1172/JCI41991
171. Lutz-Nicoladoni C, Wallner S, Stoitzner P, Pircher M, Gruber T, Wolf AM, et al. Reinforcement of cancer immunotherapy by adoptive transfer of cblb-deficient CD8+ T cells combined with a DC vaccine. Immunol Cell Biol (2012) 90:130-4. doi:10.1038/icb.2011.11
172. Fan K, Zhou M, Pathak MK, Lindner DJ, Altuntas CZ, Tuohy VK, et al. Sodium stibogluconate interacts with IL-2 in anti-renca tumor action via a T cell-dependent mechanism in connection with induction of tumor-infiltrating macrophages. J Immunol (2005) 175:7003-8. doi:10.4049/jimmunol.175.10.7003
173. Naing A, Reuben JM, Camacho LH, Gao H, Lee BN, Cohen EN, et al. Phase I dose escalation study of sodium stibogluconate (SSG), a protein tyrosine phosphatase inhibitor, combined with interferon alpha for patients with solid tumors. J Cancer (2011) 2:81-9. doi:10.7150/jca.2.81
174. Yi T, Elson P, Mitsuhashi M, Jacobs B, Hollovary E, Budd TG, et al. Phosphatase inhibitor, sodium stibogluconate, in combination with interferon (IFN) alpha 2b: phase I trials to identify pharmacodynamic and clinical effects. Oncotarget (2011) 2:1155-64. doi:10.18632/oncotarget.563
175. Zhou P, L'italien L, Hodges D, Schebye XM. Pivotal roles of CD4+ effector T cells in mediating agonistic anti-GITR mAb-induced-immune activation and tumor immunity in CT26 tumors. J Immunol (2007) 179:7365-75. doi:10.4049/jimmunol.179.11.7365
176. Francisco L, Sage PT, Sharpe AH. PD-1 pathway in tolerance and autoimmunity. Immunol Rev (2010) 236:219-42. doi:10.1111/j.1600-065X.2010.00923.x
177. Zhou Q, Munger ME, Highfill SL, Tolar J, Weigel BJ, Riddle M, et al. Program death-1 (PD-1) signaling and regulatory T cells (Tregs) collaborate to resist the function of adoptively transferred cytotoxic T lymphocytes (CTLs) in advanced acute myeloid leukemia (AML). Blood (2010) 116:2484-93. doi:10.1182/blood-2010-03-275446
178. Wang W, Lau R, Yu D, Zhu W, Korman A, Weber J. PD1 blockade reverses the suppression of melanoma antigen-specific CTL by CD4+ CD25(Hi) regulatory T cells. Int Immunol (2009) 21:1065-77. doi:10.1093/intimm/dxp072
179. Kitazawa Y, Fujino M, Wang Q, Kimura H, Azuma M, Kubo M, et al. Involvement of the programmed death-1/programmed death-1 ligand pathway in CD4+CD25+ regulatory T-cell activity to suppress alloimmune responses. Transplantation (2007) 83:774-82. doi:10.1097/01.tp.0000256293.90270.e8
180. Duraiswamy J, Kaluza KM, Freeman GJ, Coukos G. Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors. Cancer Res (2013) 73:3591-603. doi:10.1158/0008-5472.CAN-12-4100
181. Wolchok JD. PD-1 blockers. Cell (2015) 162:937. doi:10.1016/j.cell.2015.07.045
182. Sun J, Dotti G, Huye LE, Foster AE, Savoldo B, Gramatges MM, et al. T cells expressing constitutively active Akt resist multiple tumor-associated inhibitory mechanisms. Mol Ther (2010) 18:2006-17. doi:10.1038/mt.2010.185
183. Chang EH, Harford JB, Eaton MAW, Boisseau PM, Dube A, Hayeshi R, et al. Nanomedicine: past, present and future-a global perspective. Biochem Biophys Res Commun (2015) 468:511-7. doi:10.1016/j.bbrc.2015.10.136
184. Marabelle A, Kohrt H, Caux C, Levy R. Intratumoral immunization: a new paradigm for cancer therapy. Clin Cancer Res (2014) 20:1747-56. doi:10.1158/1078-0432.CCR-13-2116
185. Petrelli A, Wehrens EJ, Scholman RC, Prakken BJ, Vastert SJ, van Wijk F. Self-sustained resistance to suppression of CD8+ Teff cells at the site of autoimmune inflammation can be reversed by tumor necrosis factor and interferon-γ blockade. Arthritis Rheumatol (2016) 68:229-36. doi:10.1002/art.39418
186. Cabello-Kindelan C, Mackey S, Bayer AL. Adoptive T regulatory cell therapy for tolerance induction. Curr Transplant Rep (2015) 2:191-201. doi:10.1007/s40472-015-0058-5
187. Vignali DA. Mechanisms of Treg suppression: still a long way to go. Front Immunol (2012) 3:191. doi:10.3389/fimmu.2012.00191