Regulatory T Cells Negatively Affect IL-2 Production of Effector T Cells through CD39/Adenosine Pathway in HIV Infection

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The mechanisms by which Regulatory T cells suppress IL-2 production of effector CD4+ T cells in pathological conditions are unclear. A subpopulation of human Treg expresses the ectoenzyme CD39, which in association with CD73 converts ATP/ADP/AMP to adenosine. We show here that Treg/CD39+ suppress IL-2 expression of activated CD4+ T-cells more efficiently than Treg/CD39−. This inhibition is due to the demethylation of an essential CpG site of the il-2 gene promoter, which was reversed by an anti-CD39 mAb. By recapitulating the events downstream CD39/adenosine receptor (A2AR) axis, we show that A2AR agonist and soluble cAMP inhibit CpG site demethylation of the il-2 gene promoter. A high frequency of Treg/CD39+ is associated with a low clinical outcome in HIV infection. We show here that CD4+ T-cells from HIV-1 infected individuals express high levels of A2AR and intracellular cAMP. Following in vitro stimulation, these cells exhibit a lower degree of demethylation of il-2 gene promoter associated with a lower expression of IL-2, compared to healthy individuals. These results extend previous data on the role of Treg in HIV infection by filling the gap between expansion of Treg/CD39+ in HIV infection and the suppression of CD4+ T-cell function through inhibition of IL-2 production.

Vyšlo v časopise: Regulatory T Cells Negatively Affect IL-2 Production of Effector T Cells through CD39/Adenosine Pathway in HIV Infection. PLoS Pathog 9(4): e32767. doi:10.1371/journal.ppat.1003319
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1003319

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1. VignaliDA, CollisonLW, WorkmanCJ (2008) How regulatory T cells work. Nat Rev Immunol 8: 523–532.

2. FehervariZ, SakaguchiS (2004) Development and function of CD25+CD4+ regulatory T cells. Curr Opin Immunol 16: 203–208.

3. O'GarraA, VieiraP (2004) Regulatory T cells and mechanisms of immune system control. Nat Med 10: 801–805.

4. LiuW, PutnamAL, Xu-YuZ, SzotGL, LeeMR, et al. (2006) CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med 203: 1701–1711.

5. SeddikiN, Santner-NananB, MartinsonJ, ZaundersJ, SassonS, et al. (2006) Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J Exp Med 203: 1693–1700.

6. WeinerHL (2001) Induction and mechanism of action of transforming growth factor-beta-secreting Th3 regulatory cells. Immunol Rev 182: 207–214.

7. VieiraPL, ChristensenJR, MinaeeS, O'NeillEJ, BarratFJ, et al. (2004) IL-10-secreting regulatory T cells do not express Foxp3 but have comparable regulatory function to naturally occurring CD4+CD25+ regulatory T cells. J Immunol 172: 5986–5993.

8. DeaglioS, DwyerKM, GaoW, FriedmanD, UshevaA, et al. (2007) Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med 204: 1257–1265.

9. BluestoneJA (2011) The yin and yang of interleukin-2-mediated immunotherapy. N Engl J Med 365: 2129–2131.

10. WeissL, Donkova-PetriniV, CaccavelliL, BalboM, CarbonneilC, et al. (2004) Human immunodeficiency virus-driven expansion of CD4+CD25+ regulatory T cells, which suppress HIV-specific CD4 T-cell responses in HIV-infected patients. Blood 104: 3249–3256.

11. KaredH, LelievreJD, Donkova-PetriniV, AoubaA, MelicaG, et al. (2008) HIV-specific regulatory T cells are associated with higher CD4 cell counts in primary infection. AIDS 22: 2451–2460.

12. BiX, SuzukiY, GatanagaH, OkaS (2009) High frequency and proliferation of CD4+ FOXP3+ Treg in HIV-1-infected patients with low CD4 counts. Eur J Immunol 39: 301–309.

13. AandahlEM, MichaelssonJ, MorettoWJ, HechtFM, NixonDF (2004) Human CD4+ CD25+ regulatory T cells control T-cell responses to human immunodeficiency virus and cytomegalovirus antigens. J Virol 78: 2454–2459.

14. KinterAL, HennesseyM, BellA, KernS, LinY, et al. (2004) CD25(+)CD4(+) regulatory T cells from the peripheral blood of asymptomatic HIV-infected individuals regulate CD4(+) and CD8(+) HIV-specific T cell immune responses in vitro and are associated with favorable clinical markers of disease status. J Exp Med 200: 331–343.

15. ShawJM, HuntPW, CritchfieldJW, McConnellDH, GarciaJC, et al. (2011) Increased frequency of regulatory T cells accompanies increased immune activation in rectal mucosae of HIV-positive noncontrollers. J Virol 85: 11422–11434.

16. BelkaidY, RouseBT (2005) Natural regulatory T cells in infectious disease. Nat Immunol 6: 353–360.

17. Fazekas de St GrothB, LandayAL (2008) Regulatory T cells in HIV infection: pathogenic or protective participants in the immune response? AIDS 22: 671–683.

18. HuntPW, LandayAL, SinclairE, MartinsonJA, HatanoH, et al. (2011) A low T regulatory cell response may contribute to both viral control and generalized immune activation in HIV controllers. PLoS One 6: e15924.

19. SakaguchiS, MiyaraM, CostantinoCM, HaflerDA (2010) FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol 10: 490–500.

20. KaczmarekE, KoziakK, SevignyJ, SiegelJB, AnratherJ, et al. (1996) Identification and characterization of CD39/vascular ATP diphosphohydrolase. J Biol Chem 271: 33116–33122.

21. KukulskiF, LevesqueSA, SevignyJ (2011) Impact of ectoenzymes on p2 and p1 receptor signaling. Adv Pharmacol 61: 263–299.

22. BorsellinoG, KleinewietfeldM, Di MitriD, SternjakA, DiamantiniA, et al. (2007) Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression. Blood 110: 1225–1232.

23. DwyerKM, DeaglioS, GaoW, FriedmanD, StromTB, et al. (2007) CD39 and control of cellular immune responses. Purinergic Signal 3: 171–180.

24. PulteED, BroekmanMJ, OlsonKE, DrosopoulosJH, KizerJR, et al. (2007) CD39/NTPDase-1 activity and expression in normal leukocytes. Thromb Res 121: 309–317.

25. FaustherM, LeckaJ, SolimanE, KauffensteinG, PelletierJ, et al. (2012) Coexpression of ecto-5′-nucleotidase/CD73 with specific NTPDases differentially regulates adenosine formation in the rat liver. Am J Physiol Gastrointest Liver Physiol 302: G447–459.

26. OhtaA, SitkovskyM (2001) Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage. Nature 414: 916–920.

27. SitkovskyMV, LukashevD, ApasovS, KojimaH, KoshibaM, et al. (2004) Physiological control of immune response and inflammatory tissue damage by hypoxia-inducible factors and adenosine A2A receptors. Annu Rev Immunol 22: 657–682.

28. OhtaA, MadasuM, KiniR, SubramanianM, GoelN, et al. (2009) A2A adenosine receptor may allow expansion of T cells lacking effector functions in extracellular adenosine-rich microenvironments. J Immunol 183: 5487–5493.

29. Moreno-FernandezME, RuedaCM, RusieLK, ChougnetCA (2011) Regulatory T cells control HIV replication in activated T cells through a cAMP-dependent mechanism. Blood 117: 5372–5380.

30. NikolovaM, CarriereM, JenabianMA, LimouS, YounasM, et al. (2011) CD39/adenosine pathway is involved in AIDS progression. PLoS Pathog 7: e1002110.

31. VisovattiSH, HymanMC, BouisD, NeubigR, McLaughlinVV, et al. (2012) Increased CD39 nucleotidase activity on microparticles from patients with idiopathic pulmonary arterial hypertension. PLoS One 7: e40829.

32. MurayamaA, SakuraK, NakamaM, Yasuzawa-TanakaK, FujitaE, et al. (2006) A specific CpG site demethylation in the human interleukin 2 gene promoter is an epigenetic memory. Embo J 25: 1081–1092.

33. PorichisF, KaufmannDE (2011) HIV-specific CD4 T cells and immune control of viral replication. Curr Opin HIV AIDS 6: 174–180.

34. YounesSA, Yassine-DiabB, DumontAR, BoulasselMR, GrossmanZ, et al. (2003) HIV-1 viremia prevents the establishment of interleukin 2-producing HIV-specific memory CD4+ T cells endowed with proliferative capacity. J Exp Med 198: 1909–1922.

35. Schulze Zur WieschJ, ThomssenA, HartjenP, TothI, LehmannC, et al. (2011) Comprehensive analysis of frequency and phenotype of T regulatory cells in HIV infection: CD39 expression of FoxP3+ T regulatory cells correlates with progressive disease. J Virol 85: 1287–1297.

36. MandapathilM, SzczepanskiMJ, SzajnikM, RenJ, LenznerDE, et al. (2009) Increased ectonucleotidase expression and activity in regulatory T cells of patients with head and neck cancer. Clin Cancer Res 15: 6348–6357.

37. AirasL, NiemelaJ, SalmiM, PuurunenT, SmithDJ, et al. (1997) Differential regulation and function of CD73, a glycosyl-phosphatidylinositol-linked 70-kD adhesion molecule, on lymphocytes and endothelial cells. J Cell Biol 136: 421–431.

38. KleinM, VaethM, ScheelT, GrabbeS, BaumgrassR, et al. (2011) Repression of cyclic adenosine monophosphate upregulation disarms and expands human regulatory T cells. J Immunol 188: 1091–1097.

39. LiangB, WorkmanC, LeeJ, ChewC, DaleBM, et al. (2008) Regulatory T cells inhibit dendritic cells by lymphocyte activation gene-3 engagement of MHC class II. J Immunol 180: 5916–5926.

40. ThomsonLF, RuediJM, GlassA, MoldenhauerG, MollerP, et al. (1990) Production and characterization of monoclonal antibodies to the glycosyl phosphatidylinositol-anchored lymphocyte differentiation antigen ecto-5′-nucleotidase (CD73). Tissue Antigens 35: 9–19.

41. YegutkinG, BodinP, BurnstockG (2000) Effect of shear stress on the release of soluble ecto-enzymes ATPase and 5′-nucleotidase along with endogenous ATP from vascular endothelial cells. Br J Pharmacol 129: 921–926.

42. AlamMS, KurtzCC, RowlettRM, ReuterBK, WiznerowiczE, et al. (2009) CD73 is expressed by human regulatory T helper cells and suppresses proinflammatory cytokine production and Helicobacter felis-induced gastritis in mice. J Infect Dis 199: 494–504.

43. ZhangB (2010) CD73: a novel target for cancer immunotherapy. Cancer Res 70: 6407–6411.

44. JinD, FanJ, WangL, ThompsonLF, LiuA, et al. (2010) CD73 on tumor cells impairs antitumor T-cell responses: a novel mechanism of tumor-induced immune suppression. Cancer Res 70: 2245–2255.

45. ErdmannAA, GaoZG, JungU, FoleyJ, BorensteinT, et al. (2005) Activation of Th1 and Tc1 cell adenosine A2A receptors directly inhibits IL-2 secretion in vitro and IL-2-driven expansion in vivo. Blood 105: 4707–4714.

46. HuangS, ApasovS, KoshibaM, SitkovskyM (1997) Role of A2a extracellular adenosine receptor-mediated signaling in adenosine-mediated inhibition of T-cell activation and expansion. Blood 90: 1600–1610.

47. RicklesRJ, PierceLT, GiordanoTP3rd, TamWF, McMillinDW, et al. (2010) Adenosine A2A receptor agonists and PDE inhibitors: a synergistic multitarget mechanism discovered through systematic combination screening in B-cell malignancies. Blood 116: 593–602.

48. ChernY, ChiouJY, LaiHL, TsaiMH (1995) Regulation of adenylyl cyclase type VI activity during desensitization of the A2a adenosine receptor-mediated cyclic AMP response: role for protein phosphatase 2A. Mol Pharmacol 48: 1–8.

49. KammerGM (1988) The adenylate cyclase-cAMP-protein kinase A pathway and regulation of the immune response. Immunol Today 9: 222–229.

50. AverillLE, SteinRL, KammerGM (1988) Control of human T-lymphocyte interleukin-2 production by a cAMP-dependent pathway. Cell Immunol 115: 88–99.

51. RahmouniS, AandahlEM, TrebakM, BoniverJ, TaskenK, et al. (2001) Increased cAMP levels and protein kinase (PKA) type I activation in CD4+ T cells and B cells contribute to retrovirus-induced immunodeficiency of mice (MAIDS): a useful in vivo model for drug testing. FASEB J 15: 1466–1468.

52. AandahlEM, AukrustP, SkalheggBS, MullerF, FrolandSS, et al. (1998) Protein kinase A type I antagonist restores immune responses of T cells from HIV-infected patients. FASEB J 12: 855–862.

53. RauenT, HedrichCM, JuangYT, TenbrockK, TsokosGC (2011) cAMP-responsive element modulator (CREM)alpha protein induces interleukin 17A expression and mediates epigenetic alterations at the interleukin-17A gene locus in patients with systemic lupus erythematosus. J Biol Chem 286: 43437–43446.

54. HedrichCM, RauenT, TsokosGC (2011) cAMP-responsive element modulator (CREM)alpha protein signaling mediates epigenetic remodeling of the human interleukin-2 gene: implications in systemic lupus erythematosus. J Biol Chem 286: 43429–43436.

55. BjorgoE, TaskenK (2010) Novel mechanism of signaling by CD28. Immunol Lett 129: 1–6.

56. Moreno-FernandezME, RuedaCM, VelillaPA, RugelesMT, ChougnetCA (2012) cAMP During HIV Infection: Friend or Foe? AIDS Res Hum Retroviruses 28: 49–53.

57. BoppT, BeckerC, KleinM, Klein-HesslingS, PalmetshoferA, et al. (2007) Cyclic adenosine monophosphate is a key component of regulatory T cell-mediated suppression. J Exp Med 204: 1303–1310.

58. LealDB, StreherCA, Bertoncheli CdeM, CarliLF, LealCA, et al. (2005) HIV infection is associated with increased NTPDase activity that correlates with CD39-positive lymphocytes. Biochim Biophys Acta 1746: 129–134.

59. NigamP, VeluV, KannanganatS, ChennareddiL, KwaS, et al. (2010) Expansion of FOXP3+ CD8 T cells with suppressive potential in colorectal mucosa following a pathogenic simian immunodeficiency virus infection correlates with diminished antiviral T cell response and viral control. J Immunol 184: 1690–1701.

60. NavarroJ, PunzonC, JimenezJL, Fernandez-CruzE, PizarroA, et al. (1998) Inhibition of phosphodiesterase type IV suppresses human immunodeficiency virus type 1 replication and cytokine production in primary T cells: involvement of NF-kappaB and NFAT. J Virol 72: 4712–4720.

61. SunY, LiL, LauF, BeavoJA, ClarkEA (2000) Infection of CD4+ memory T cells by HIV-1 requires expression of phosphodiesterase 4. J Immunol 165: 1755–1761.

62. EltzschigHK, IblaJC, FurutaGT, LeonardMO, JacobsonKA, et al. (2003) Coordinated adenine nucleotide phosphohydrolysis and nucleoside signaling in posthypoxic endothelium: role of ectonucleotidases and adenosine A2B receptors. J Exp Med 198: 783–796.

63. KukulskiF, LevesqueSA, LavoieEG, LeckaJ, BigonnesseF, et al. (2005) Comparative hydrolysis of P2 receptor agonists by NTPDases 1, 2, 3 and 8. Purinergic Signal 1: 193–204.