Regulatory T-cell-mediated suppression of conventional T-cells and dendritic cells by different cAMP intracellular pathways

Frontiers in Immunology

Volumn 7, Issue JUN, 2016, Pages

  Rueda, Cesar M ^a   Jackson, Courtney M ^a   Chougnet, Claire A ^a  

^a UNIVERSITY OF CINCINNATI COLLEGE OF MEDICINE   (United States)

Author keywords

Cyclic adenosine monophosphate; Dendritic cells; Suppression; T cells; T regulatory cells

Indexed keywords

5' NUCLEOTIDASE; ADENOSINE; ADENOSINE TRIPHOSPHATE; ADENYLATE CYCLASE; CD39 ANTIGEN; CYCLIC AMP; CYCLIC AMP DEPENDENT PROTEIN KINASE; PHOSPHODIESTERASE; RAP PROTEIN; TRANSCRIPTION FACTOR FOXP3;

ACTIN POLYMERIZATION; CELL ADHESION; CELL MIGRATION; CELL PHAGOCYTOSIS; CELL PROLIFERATION; CHEMOTAXIS; CYTOKINE PRODUCTION; DENDRITIC CELL; HUMAN; IMMUNE DEFICIENCY; IMMUNOGENICITY; NONHUMAN; PHENOTYPE; PROTEIN EXPRESSION; REGULATORY T LYMPHOCYTE; REVIEW; SIGNAL TRANSDUCTION; T LYMPHOCYTE; TARGET CELL; UPREGULATION;

EID: 84977561458     PISSN: None     EISSN: 16643224     Source Type: Journal    
DOI: 10.3389/fimmu.2016.00216     Document Type: Review

References (81)

1. 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.
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. 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
4. Tang Q, Krummel MF. Imaging the function of regulatory T cells in vivo. Curr Opin Immunol (2006) 18:496-502. doi:10.1016/j.coi.2006.05.007
5. 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
6. Tang Q, Boden EK, Henriksen KJ, Bour-Jordan H, Bi M, Bluestone JA. Distinct roles of CTLA-4 and TGF-beta in CD4+CD25+ regulatory T cell function. Eur J Immunol (2004) 34:2996-3005. doi:10.1002/eji.200425143
7. 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
8. Bopp T, Becker C, Klein M, Klein-Hessling S, Palmetshofer A, Serfling E, et al. Cyclic adenosine monophosphate is a key component of regulatory T cell-mediated suppression. J Exp Med (2007) 204:1303-10. doi:10.1084/jem.20062129
9. Sutherland EW, Rall TW. Fractionation and characterization of a cyclic adenine ribonucleotide formed by tissue particles. J Biol Chem (1958) 232:1077-92.
10. Beavo JA, Brunton LL. Cyclic nucleotide research-still expanding after half a century. Nat Rev Mol Cell Biol (2002) 3:710-8. doi:10.1038/nrm911
11. Cheng X, Ji Z, Tsalkova T, Mei F. Epac and PKA: a tale of two intracellular cAMP receptors. Acta Biochim Biophys Sin (Shanghai) (2008) 40:651-62. doi:10.1111/j.1745-7270.2008.00438.x
12. Vang AG, Housley W, Dong H, Basole C, Ben-Sasson SZ, Kream BE, et al. Regulatory T-cells and cAMP suppress effector T-cells independently of PKA-CREM/ICER: a potential role for Epac. Biochem J (2013) 456:463-73. doi:10.1042/BJ20130064
13. Huang B, Zhao J, Lei Z, Shen S, Li D, Shen G-X, et al. miR-142-3p restricts cAMP production in CD4(+)CD25(-) T cells and CD4(+)CD25(+) T(REG) cells by targeting AC9 mRNA. EMBO Rep (2009) 10:180-5. doi:10.1038/embor.2008.224
14. Duan B, Davis R, Sadat EL, Collins J, Sternweis PC, Yuan D, et al. Distinct roles of adenylyl cyclase VII in regulating the immune responses in mice. J Immunol (2010) 185:335-44. doi:10.4049/jimmunol.0903474
15. Giembycz MA, Corrigan CJ, Seybold J, Newton R, Barnes PJ. Identification of cyclic AMP phosphodiesterases 3, 4 and 7 in human CD4+ and CD8+ T-lymphocytes: role in regulating proliferation and the biosynthesis of interleukin-2. Br J Pharmacol (1996) 118:1945-58. doi:10.1111/j.1476-5381.1996.tb15629.x
16. Glavas NA, Ostenson C, Schaefer JB, Vasta V, Beavo JA. T cell activation up-regulates cyclic nucleotide phosphodiesterases 8A1 and 7A3. Proc Natl Acad Sci USA (2001) 98:6319-24. doi:10.1073/pnas.101131098
17. Peter D, Jin SLC, Conti M, Hatzelmann A, Zitt C. Differential expression and function of phosphodiesterase 4 (PDE4) subtypes in human primary CD4+ T cells: predominant role of PDE4D. J Immunol (2007) 178:4820-31. doi:10.4049/jimmunol.178.8.4820
18. Bazhin AV, Kahnert S, Kimpfler S, Schadendorf D, Umansky V. Distinct metabolism of cyclic adenosine monophosphate in regulatory and helper CD4+ T cells. Mol Immunol (2010) 47:678-84. doi:10.1016/j.molimm.2009.10.032
19. Klein M, Vaeth M, Scheel T, Grabbe S, Baumgrass R, Berberich-Siebelt F, et al. Repression of cyclic adenosine monophosphate upregulation disarms and expands human regulatory T cells. J Immunol (2012) 188:1091-7. doi:10.4049/jimmunol.1102045
20. Birzele F, Fauti T, Stahl H, Lenter MC, Simon E, Knebel D, et al. Next-generation insights into regulatory T cells: expression profiling and FoxP3 occupancy in Human. Nucleic Acids Res (2011) 39:7946-60. doi:10.1093/nar/gkr444
21. Zheng Y, Josefowicz SZ, Kas A, Chu T-T, Gavin MA, Rudensky AY. Genome-wide analysis of Foxp3 target genes in developing and mature regulatory T cells. Nature (2007) 445:936-40. doi:10.1038/nature05563
22. Lahl K, Mayer CT, Bopp T, Huehn J, Loddenkemper C, Eberl G, et al. Nonfunctional regulatory T cells and defective control of Th2 cytokine production in natural scurfy mutant mice. J Immunol (2009) 183:5662-72. doi:10.4049/jimmunol.0803762
23. Rueda CM, Moreno-Fernandez ME, Jackson CM, Kallapur SG, Jobe AH, Chougnet CA. Neonatal regulatory T cells have reduced capacity to suppress dendritic cell function. Eur J Immunol (2015) 45:2582-92. doi:10.1002/eji.201445371
24. Levy O, Coughlin M, Cronstein BN, Roy RM, Desai A, Wessels MR. The adenosine system selectively inhibits TLR-mediated TNF-alpha production in the human newborn. J Immunol (2006) 177:1956-66. doi:10.4049/jimmunol.177.3.1956
25. Pettengill M, Robson S, Tresenriter M, Millan JL, Usheva A, Bingham T, et al. Soluble ecto-5'-nucleotidase (5'-NT), alkaline phosphatase, and adenosine deaminase (ADA1) activities in neonatal blood favor elevated extracellular adenosine. J Biol Chem (2013) 288:27315-26. doi:10.1074/jbc. M113.484212
26. Fassbender M, Gerlitzki B, Ullrich N, Lupp C, Klein M, Radsak MP, et al. Cyclic adenosine monophosphate and IL-10 coordinately contribute to nTreg cell-mediated suppression of dendritic cell activation. Cell Immunol (2010) 265:91-6. doi:10.1016/j.cellimm.2010.07.007
27. Ring S, Karakhanova S, Johnson T, Enk AH, Mahnke K. Gap junctions between regulatory T cells and dendritic cells prevent sensitization of CD8(+) T cells. J Allergy Clin Immunol (2010) 125(237-246):e231-7. doi:10.1016/j.jaci.2009.10.025
28. Fonseca PC, Nihei OK, Savino W, Spray DC, Alves LA. Flow cytometry analysis of gap junction-mediated cell-cell communication: advantages and pitfalls. Cytometry A (2006) 69:487-93. doi:10.1002/cyto.a.20255
29. Borsellino G, Kleinewietfeld M, Di Mitri D, Sternjak A, Diamantini A, Giometto R, et al. Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression. Blood (2007) 110:1225-32. doi:10.1182/blood-2006-12-064527
30. 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
31. Van Calker D, Muller M, Hamprecht B. Adenosine regulates via two different types of receptors, the accumulation of cyclic AMP in cultured brain cells. J Neurochem (1979) 33:999-1005. doi:10.1111/j.1471-4159.1979.tb05236.x
32. Londos C, Cooper DM, WolffJ. Subclasses of external adenosine receptors. Proc Natl Acad Sci U S A (1980) 77:2551-4. doi:10.1073/pnas.77.5.2551
33. Huang S, Apasov S, Koshiba M, Sitkovsky M. Role of A2A extracellular adenosine receptor-mediated signaling in adenosine-mediated inhibition of T-cell activation and expansion. Blood (1997) 90:1600-10.
34. Chen GY, Nuñez G. Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol (2010) 10:826-37. doi:10.1038/nri2873
35. Cauwels A, Rogge E, Vandendriessche B, Shiva S, Brouckaert P. Extracellular ATP drives systemic inflammation, tissue damage and mortality. Cell Death Dis (2014) 5:e1102. doi:10.1038/cddis.2014.70
36. Ohta A, Sitkovsky M. Extracellular adenosine-mediated modulation of regulatory T cells. Front Immunol (2014) 5:304. doi:10.3389/fimmu.2014.00304
37. Alam MS, Kurtz CC, Rowlett RM, Reuter BK, Wiznerowicz E, Das S, et al. CD73 is expressed by human regulatory T helper cells and suppresses proinflammatory cytokine production and Helicobacter felis-induced gastritis in mice. J Infect Dis (2009) 199:494-504. doi:10.1086/596205
38. Dwyer KM, Hanidziar D, Putheti P, Hill PA, Pommey S, Mcrae JL, et al. Expression of CD39 by human peripheral blood CD4+ CD25+ T cells denotes a regulatory memory phenotype. Am J Transplant (2010) 10:2410-20. doi:10.1111/j.1600-6143.2010.03291.x
39. Mandapathil M, Hilldorfer B, Szczepanski MJ, Czystowska M, Szajnik M, Ren J, et al. Generation and accumulation of immunosuppressive adenosine by human CD4(+)CD25(high)FOXP3(+) regulatory T cells. J Biol Chem (2010) 285:7176-86. doi:10.1074/jbc. M109.047423
40. Moreno-Fernandez ME, Rueda CM, Rusie LK, Chougnet CA. Regulatory T cells control HIV replication in activated T cells through a cAMP-dependent mechanism. Blood (2011) 117:5372-80. doi:10.1182/blood-2010-12-323162
41. Schuler PJ, Schilling B, Harasymczuk M, Hoffmann TK, Johnson J, Lang S, et al. Phenotypic and functional characteristics of CD4+ CD39+ FOXP3+ and CD4+ CD39+ FOXP3neg T-cell subsets in cancer patients. Eur J Immunol (2012) 42:1876-85. doi:10.1002/eji.201142347
42. 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) 187:676-83. doi:10.4049/jimmunol.1003884
43. Smyth LA, Ratnasothy K, Tsang JY, Boardman D, Warley A, Lechler R, et al. CD73 expression on extracellular vesicles derived from CD4+ CD25+ Foxp3+ T cells contributes to their regulatory function. Eur J Immunol (2013) 43:2430-40. doi:10.1002/eji.201242909
44. Schuler PJ, Saze Z, Hong CS, Muller L, Gillespie DG, Cheng D, et al. Human CD4+ CD39+ regulatory T cells produce adenosine upon co-expression of surface CD73 or contact with CD73+ exosomes or CD73+ cells. Clin Exp Immunol (2014) 177:531-43. doi:10.1111/cei.12354
45. Panther E, Idzko M, Herouy Y, Rheinen H, Gebicke-Haerter PJ, Mrowietz U, et al. Expression and function of adenosine receptors in human dendritic cells. FASEB J (2001) 15:1963-70. doi:10.1096/fj.01-0169com
46. Ohta A, Kini R, Ohta A, Subramanian M, Madasu M, Sitkovsky M. The development and immunosuppressive functions of CD4(+) CD25(+) FoxP3(+) regulatory T cells are under influence of the adenosine-A2A adenosine receptor pathway. Front Immunol (2012) 3:190. doi:10.3389/fimmu.2012.00190
47. Zarek PE, Huang CT, Lutz ER, Kowalski J, Horton MR, Linden J, et al. A2A receptor signaling promotes peripheral tolerance by inducing T-cell anergy and the generation of adaptive regulatory T cells. Blood (2008) 111:251-9. doi:10.1182/blood-2007-03-081646
48. Ernst PB, Garrison JC, Thompson LF. Much ado about adenosine: adenosine synthesis and function in regulatory T cell biology. J Immunol (2010) 185:1993-8. doi:10.4049/jimmunol.1000108
49. Bopp T, Dehzad N, Reuter S, Klein M, Ullrich N, Stassen M, et al. Inhibition of cAMP degradation improves regulatory T cell-mediated suppression. J Immunol (2009) 182:4017-24. doi:10.4049/jimmunol.0803310
50. Feng G, Nadig SN, Bäckdahl L, Beck S, Francis RS, Schiopu A, et al. Functional regulatory T cells produced by inhibiting cyclic nucleotide phosphodiesterase type 3 prevent allograft rejection. Sci Transl Med (2011) 3:83ra40. doi:10.1126/scitranslmed.3002099
51. Bacher N, Raker V, Hofmann C, Graulich E, Schwenk M, Baumgrass R, et al. Interferon-a suppresses cAMP to disarm human regulatory T cells. Cancer Res (2013) 73:5647-56. doi:10.1158/0008-5472.CAN-12-3788
52. Umansky V, Shevchenko I, Bazhin AV, Utikal J. Extracellular adenosine metabolism in immune cells in melanoma. Cancer Immunol Immunother (2014) 63:1073-80. doi:10.1007/s00262-014-1553-8
53. Fletcher JM, Lonergan R, Costelloe L, Kinsella K, Moran B, O'Farrelly C, et al. CD39+Foxp3+ regulatory T Cells suppress pathogenic Th17 cells and are impaired in multiple sclerosis. J Immunol (2009) 183:7602-10. doi:10.4049/jimmunol.0901881
54. Jenabian MA, Seddiki N, Yatim A, Carriere M, Hulin A, Younas M, et al. Regulatory T cells negatively affect IL-2 production of effector T cells through CD39/adenosine pathway in HIV infection. PLoS Pathog (2013) 9:e1003319. doi:10.1371/journal.ppat.1003319
55. Herrath J, Chemin K, Albrecht I, Catrina AI, Malmstrom V. Surface expression of CD39 identifies an enriched Treg-cell subset in the rheumatic joint, which does not suppress IL-17A secretion. Eur J Immunol (2014) 44:2979-89. doi:10.1002/eji.201344140
56. Weber M, Lupp C, Stein P, Kreft A, Bopp T, Wehler TC, et al. Mechanisms of cyclic nucleotide phosphodiesterases in modulating T cell responses in murine graft-versus-host disease. PLoS One (2013) 8:e58110. doi:10.1371/journal.pone.0058110
57. Moreno-Fernandez ME, Joedicke JJ, Chougnet CA. Regulatory T cells diminish HIV infection in dendritic cells-conventional CD4(+) T cell clusters. Front Immunol (2014) 5:199. doi:10.3389/fimmu.2014.00199
58. Ring S, Pushkarevskaya A, Schild H, Probst HC, Jendrossek V, Wirsdorfer F, et al. Regulatory T cell-derived adenosine induces dendritic cell migration through the Epac-Rap1 pathway. J Immunol (2015) 194:3735-44. doi:10.4049/jimmunol.1401434
59. Adkins I, Kamanova J, Kocourkova A, Svedova M, Tomala J, Janova H, et al. Bordetella adenylate cyclase toxin differentially modulates toll-like receptor-stimulated activation, migration and T cell stimulatory capacity of dendritic cells. PLoS One (2014) 9:e104064. doi:10.1371/journal.pone.0104064
60. Brindle P, Linke S, Montminy M. Protein-kinase-A-dependent activator in transcription factor CREB reveals new role for CREM repressors. Nature (1993) 364:821-4. doi:10.1038/364821a0
61. Chrivia JC, Kwok RP, Lamb N, Hagiwara M, Montminy MR, Goodman RH. Phosphorylated CREB binds specifically to the nuclear protein CBP. Nature (1993) 365:855-9. doi:10.1038/365855a0
62. Yehia G, Schlotter F, Razavi R, Alessandrini A, Molina CA. Mitogen-activated protein kinase phosphorylates and targets inducible cAMP early repressor to ubiquitin-mediated destruction. J Biol Chem (2001) 276:35272-9. doi:10.1074/jbc. M105404200
63. Bodor J, Bodorova J, Bare C, Hodge DL, Young HA, Gress RE. Differential inducibility of the transcriptional repressor ICER and its role in modulation of Fas ligand expression in T and NK lymphocytes. Eur J Immunol (2002) 32:203-12. doi:10.1002/1521-4141(200201)32:1<203::AID-IMMU203>3.0.CO;2-C
64. Barabitskaja O, Foulke JS Jr, Pati S, Bodor J, Reitz MS Jr. Suppression of MIP-1beta transcription in human T cells is regulated by inducible cAMP early repressor (ICER). J Leukoc Biol (2006) 79:378-87. doi:10.1189/jlb.0505255
65. Vaeth M, Gogishvili T, Bopp T, Klein M, Berberich-Siebelt F, Gattenloehner S, et al. Regulatory T cells facilitate the nuclear accumulation of inducible cAMP early repressor (ICER) and suppress nuclear factor of activated T cell c1 (NFATc1). Proc Natl Acad Sci U S A (2011) 108:2480-5. doi:10.1073/pnas.1009463108
66. Bodor J, Fehervari Z, Diamond B, Sakaguchi S. ICER/CREM-mediated transcriptional attenuation of IL-2 and its role in suppression by regulatory T cells. Eur J Immunol (2007) 37:884-95. doi:10.1002/eji.200636510
67. Nayak A, Glockner-Pagel J, Vaeth M, Schumann JE, Buttmann M, Bopp T, et al. Sumoylation of the transcription factor NFATc1 leads to its subnuclear relocalization and interleukin-2 repression by histone deacetylase. J Biol Chem (2009) 284:10935-46. doi:10.1074/jbc. M900465200
68. Bodor J, Bopp T, Vaeth M, Klein M, Serfling E, Hunig T, et al. Cyclic AMP underpins suppression by regulatory T cells. Eur J Immunol (2012) 42:1375-84. doi:10.1002/eji.201141578
69. Guereschi MG, Araujo LP, Maricato JT, Takenaka MC, Nascimento VM, Vivanco BC, et al. Beta2-adrenergic receptor signaling in CD4+ Foxp3+ regulatory T cells enhances their suppressive function in a PKA-dependent manner. Eur J Immunol (2013) 43:1001-12. doi:10.1002/eji.201243005
70. Hansen W, Loser K, Westendorf AM, Bruder D, Pfoertner S, Siewert C, et al. G protein-coupled receptor 83 overexpression in naive CD4+CD25-T cells leads to the induction of Foxp3+ regulatory T cells in vivo. J Immunol (2006) 177:209-15. doi:10.4049/jimmunol.177.1.209
71. Sugimoto N, Oida T, Hirota K, Nakamura K, Nomura T, Uchiyama T, et al. Foxp3-dependent and-independent molecules specific for CD25+CD4+ natural regulatory T cells revealed by DNA microarray analysis. Int Immunol (2006) 18:1197-209. doi:10.1093/intimm/dxl060
72. Almahariq M, Mei FC, Wang H, Cao AT, Yao S, Soong L, et al. Exchange protein directly activated by cAMP modulates regulatory T-cell-mediated immunosuppression. Biochem J (2015) 465:295-303. doi:10.1042/BJ20140952
73. Li L, Godfrey WR, Porter SB, Ge Y, June CH, Blazar BR, et al. CD4+CD25+ regulatory T-cell lines from human cord blood have functional and molecular properties of T-cell anergy. Blood (2005) 106:3068-73. doi:10.1182/blood-2005-04-1531
74. Li L, Greenwald RJ, Lafuente EM, Tzachanis D, Berezovskaya A, Freeman GJ, et al. Rap1-GTP is a negative regulator of Th cell function and promotes the generation of CD4+CD103+ regulatory T cells in vivo. J Immunol (2005) 175:3133-9. doi:10.4049/jimmunol.175.5.3133
75. Li L, Kim J, Boussiotis VA. Rap1A regulates generation of T regulatory cells via LFA-1-dependent and LFA-1-independent mechanisms. Cell Immunol (2010) 266:7-13. doi:10.1016/j.cellimm.2010.08.014
76. Skålhegg BS, Landmark BF, Døskeland SO, Hansson V, Lea T, Jahnsen T. Cyclic AMP-dependent protein kinase type I mediates the inhibitory effects of 3', 5'-cyclic adenosine monophosphate on cell replication in human T lymphocytes. J Biol Chem (1992) 267:15707-14.
77. AronoffDM, Canetti C, Serezani CH, Luo M, Peters-Golden M. Cutting edge: macrophage inhibition by cyclic AMP (cAMP): differential roles of protein kinase A and exchange protein directly activated by cAMP-1. J Immunol (2005) 174:595-9. doi:10.4049/jimmunol.174.2.595
78. Lorenowicz MJ, Van Gils J, De Boer M, Hordijk PL, Fernandez-Borja M. Epac1-Rap1 signaling regulates monocyte adhesion and chemotaxis. J Leukoc Biol (2006) 80:1542-52. doi:10.1189/jlb.0506357
79. Jing H, Yen JH, Ganea D. A novel signaling pathway mediates the inhibition of CCL3/4 expression by prostaglandin E2. J Biol Chem (2004) 279:55176-86. doi:10.1074/jbc. M409816200
80. Garay J, D'Angelo JA, Park Y, Summa CM, Aiken ML, Morales E, et al. Crosstalk between PKA and Epac regulates the phenotypic maturation and function of human dendritic cells. J Immunol (2010) 185:3227-38. doi:10.4049/jimmunol.0903066
81. Mei FC, Qiao J, Tsygankova OM, Meinkoth JL, Quilliam LA, Cheng X. Differential signaling of cyclic AMP: opposing effects of exchange protein directly activated by cyclic AMP and cAMP-dependent protein kinase on protein kinase B activation. J Biol Chem (2002) 277:11497-504. doi:10.1074/jbc. M110856200