#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

CD39 Expression Identifies Terminally Exhausted CD8 T Cells


Chronic viral infection induces an acquired state of T cell dysfunction known as exhaustion. Discovering surface markers of exhausted T cells is important for both to identify exhausted T cells as well as to develop potential therapies. We report that the ectonucleotidase CD39 is expressed by T cells specific for chronic viral infections in humans and a mouse model, but is rare in T cells following clearance of acute infections. In the mouse model of chronic viral infection, CD39 demarcates a subpopulation of dysfunctional, exhausted CD8+ T cells with the phenotype of irreversible exhaustion. CD39 expression therefore identifies terminal CD8+ T cell exhaustion in mice and humans, and implicates the purinergic pathway in the regulation of exhaustion.


Vyšlo v časopise: CD39 Expression Identifies Terminally Exhausted CD8 T Cells. PLoS Pathog 11(10): e32767. doi:10.1371/journal.ppat.1005177
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1005177

Souhrn

Chronic viral infection induces an acquired state of T cell dysfunction known as exhaustion. Discovering surface markers of exhausted T cells is important for both to identify exhausted T cells as well as to develop potential therapies. We report that the ectonucleotidase CD39 is expressed by T cells specific for chronic viral infections in humans and a mouse model, but is rare in T cells following clearance of acute infections. In the mouse model of chronic viral infection, CD39 demarcates a subpopulation of dysfunctional, exhausted CD8+ T cells with the phenotype of irreversible exhaustion. CD39 expression therefore identifies terminal CD8+ T cell exhaustion in mice and humans, and implicates the purinergic pathway in the regulation of exhaustion.


Zdroje

1. Kaech SM, Cui W (2012) Transcriptional control of effector and memory CD8+ T cell differentiation. Nat Rev Immunol 12: 749–761. doi: 10.1038/nri3307 23080391

2. Wherry EJ (2011) T cell exhaustion. Nat Immunol 12: 492–499. 21739672

3. Day CL, Kaufmann DE, Kiepiela P, Brown JA, Moodley ES, et al. (2006) PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443: 350–354. 16921384

4. Lechner F, Wong DK, Dunbar PR, Chapman R, Chung RT, et al. (2000) Analysis of successful immune responses in persons infected with hepatitis C virus. J Exp Med 191: 1499–1512. 10790425

5. Wherry EJ, Ha SJ, Kaech SM, Haining WN, Sarkar S, et al. (2007) Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 27: 670–684. 17950003

6. Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, et al. (2006) Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439: 682–687. 16382236

7. Kroy DC, Ciuffreda D, Cooperrider JH, Tomlinson M, Hauck GD, et al. (2014) Liver environment and HCV replication affect human T-cell phenotype and expression of inhibitory receptors. Gastroenterology 146: 550–561. doi: 10.1053/j.gastro.2013.10.022 24148617

8. Duraiswamy J, Ibegbu CC, Masopust D, Miller JD, Araki K, et al. (2011) Phenotype, function, and gene expression profiles of programmed death-1(hi) CD8 T cells in healthy human adults. J Immunol 186: 4200–4212. doi: 10.4049/jimmunol.1001783 21383243

9. Paley MA, Kroy DC, Odorizzi PM, Johnnidis JB, Dolfi DV, et al. (2012) Progenitor and terminal subsets of CD8+ T cells cooperate to contain chronic viral infection. Science 338: 1220–1225. doi: 10.1126/science.1229620 23197535

10. Buggert M, Tauriainen J, Yamamoto T, Frederiksen J, Ivarsson MA, et al. (2014) T-bet and Eomes are differentially linked to the exhausted phenotype of CD8+ T cells in HIV infection. PLoS Pathog 10: e1004251. doi: 10.1371/journal.ppat.1004251 25032686

11. Kurktschiev PD, Raziorrouh B, Schraut W, Backmund M, Wachtler M, et al. (2014) Dysfunctional CD8+ T cells in hepatitis B and C are characterized by a lack of antigen-specific T-bet induction. J Exp Med 211: 2047–2059. doi: 10.1084/jem.20131333 25225458

12. Blackburn SD, Shin H, Freeman GJ, Wherry EJ (2008) Selective expansion of a subset of exhausted CD8 T cells by alphaPD-L1 blockade. Proc Natl Acad Sci U S A 105: 15016–15021. doi: 10.1073/pnas.0801497105 18809920

13. Kaczmarek E, Koziak K, Sevigny J, Siegel JB, Anrather J, et al. (1996) Identification and characterization of CD39/vascular ATP diphosphohydrolase. J Biol Chem 271: 33116–33122. 8955160

14. Kansas GS, Wood GS, Tedder TF (1991) Expression, distribution, and biochemistry of human CD39. Role in activation-associated homotypic adhesion of lymphocytes. J Immunol 146: 2235–2244. 1672348

15. Deaglio S, Dwyer KM, Gao W, Friedman D, Usheva A, et al. (2007) Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med 204: 1257–1265. 17502665

16. Borsellino G, Kleinewietfeld M, Di Mitri D, Sternjak A, Diamantini A, et al. (2007) Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression. Blood 110: 1225–1232. 17449799

17. Junger WG (2011) Immune cell regulation by autocrine purinergic signalling. Nature Publishing Group: Nature Publishing Group. pp. 201–212. doi: 10.1038/nri2938 21331080

18. Zarek PE, Huang CT, Lutz ER, Kowalski J, Horton MR, et al. (2008) A2A receptor signaling promotes peripheral tolerance by inducing T-cell anergy and the generation of adaptive regulatory T cells. Blood 111: 251–259. 17909080

19. Huang S, Apasov S, Koshiba M, Sitkovsky M (1997) Role of A2a extracellular adenosine receptor-mediated signaling in adenosine-mediated inhibition of T-cell activation and expansion. Blood 90: 1600–1610. 9269779

20. Lokshin A, Raskovalova T, Huang X, Zacharia LC, Jackson EK, et al. (2006) Adenosine-mediated inhibition of the cytotoxic activity and cytokine production by activated natural killer cells. Cancer Res 66: 7758–7765. 16885379

21. Moncrieffe H, Nistala K, Kamhieh Y, Evans J, Eddaoudi A, et al. (2010) High Expression of the Ectonucleotidase CD39 on T Cells from the Inflamed Site Identifies Two Distinct Populations, One Regulatory and One Memory T Cell Population. The Journal of Immunology. pp. 134–143. doi: 10.4049/jimmunol.0803474 20498355

22. Pulte D, Furman RR, Broekman MJ, Drosopoulos JH, Ballard HS, et al. (2011) CD39 expression on T lymphocytes correlates with severity of disease in patients with chronic lymphocytic leukemia. Clin Lymphoma Myeloma Leuk 11: 367–372. doi: 10.1016/j.clml.2011.06.005 21816376

23. Boer MC, van Meijgaarden KE, Bastid J, Ottenhoff TH, Joosten SA (2013) CD39 is involved in mediating suppression by Mycobacterium bovis BCG-activated human CD8(+) CD39(+) regulatory T cells. Eur J Immunol 43: 1925–1932. doi: 10.1002/eji.201243286 23606272

24. Robson SC, Kaczmarek E, Siegel JB, Candinas D, Koziak K, et al. (1997) Loss of ATP diphosphohydrolase activity with endothelial cell activation. J Exp Med 185: 153–163. 8996251

25. Papanikolaou A, Papafotika A, Murphy C, Papamarcaki T, Tsolas O, et al. (2005) Cholesterol-dependent lipid assemblies regulate the activity of the ecto-nucleotidase CD39. J Biol Chem 280: 26406–26414. 15890655

26. Wu Y, Sun X, Kaczmarek E, Dwyer KM, Bianchi E, et al. (2006) RanBPM associates with CD39 and modulates ecto-nucleotidase activity. Biochem J 396: 23–30. 16478441

27. Kasprowicz V, Schulze Zur Wiesch J, Kuntzen T, Nolan BE, Longworth S, et al. (2008) High level of PD-1 expression on hepatitis C virus (HCV)-specific CD8+ and CD4+ T cells during acute HCV infection, irrespective of clinical outcome. J Virol 82: 3154–3160. 18160439

28. Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, et al. (2000) Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet 25: 25–29. 10802651

29. Doering TA, Crawford A, Angelosanto JM, Paley MA, Ziegler CG, et al. (2012) Network analysis reveals centrally connected genes and pathways involved in CD8+ T cell exhaustion versus memory. Immunity 37: 1130–1144. doi: 10.1016/j.immuni.2012.08.021 23159438

30. Quigley M, Pereyra F, Nilsson B, Porichis F, Fonseca C, et al. (2010) Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF. Nat Med 16: 1147–1151. doi: 10.1038/nm.2232 20890291

31. Baitsch L, Baumgaertner P, Devevre E, Raghav SK, Legat A, et al. (2011) Exhaustion of tumor-specific CD8(+) T cells in metastases from melanoma patients. J Clin Invest 121: 2350–2360. doi: 10.1172/JCI46102 21555851

32. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, et al. (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A 102: 15545–15550. 16199517

33. Blackburn SD, Shin H, Haining WN, Zou T, Workman CJ, et al. (2009) Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol 10: 29–37. doi: 10.1038/ni.1679 19043418

34. Trautmann L, Janbazian L, Chomont N, Said EA, Gimmig S, et al. (2006) Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat Med 12: 1198–1202. 16917489

35. Jenabian MA, Seddiki N, Yatim A, Carriere M, Hulin A, et al. (2013) Regulatory T cells negatively affect IL-2 production of effector T cells through CD39/adenosine pathway in HIV infection. PLoS Pathog 9: e1003319. doi: 10.1371/journal.ppat.1003319 23658513

36. Petrovas C, Casazza JP, Brenchley JM, Price DA, Gostick E, et al. (2006) PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection. J Exp Med 203: 2281–2292. 16954372

37. Pita-Lopez ML, Gayoso I, DelaRosa O, Casado JG, Alonso C, et al. (2009) Effect of ageing on CMV-specific CD8 T cells from CMV seropositive healthy donors. Immun Ageing 6: 11. doi: 10.1186/1742-4933-6-11 19715573

38. Rey J, Giustiniani J, Mallet F, Schiavon V, Boumsell L, et al. (2006) The co-expression of 2B4 (CD244) and CD160 delineates a subpopulation of human CD8+ T cells with a potent CD160-mediated cytolytic effector function. Eur J Immunol 36: 2359–2366. 16917959

39. Shin H, Blackburn SD, Intlekofer AM, Kao C, Angelosanto JM, et al. (2009) A role for the transcriptional repressor Blimp-1 in CD8(+) T cell exhaustion during chronic viral infection. Immunity 31: 309–320. doi: 10.1016/j.immuni.2009.06.019 19664943

40. Migueles SA, Laborico AC, Shupert WL, Sabbaghian MS, Rabin R, et al. (2002) HIV-specific CD8+ T cell proliferation is coupled to perforin expression and is maintained in nonprogressors. Nat Immunol 3: 1061–1068. 12368910

41. Shin H, Blackburn SD, Blattman JN, Wherry EJ (2007) Viral antigen and extensive division maintain virus-specific CD8 T cells during chronic infection. J Exp Med 204: 941–949. 17420267

42. Cox AL, Mosbruger T, Lauer GM, Pardoll D, Thomas DL, et al. (2005) Comprehensive analyses of CD8+ T cell responses during longitudinal study of acute human hepatitis C. Hepatology 42: 104–112. 15962289

43. Zajac AJ, Blattman JN, Murali-Krishna K, Sourdive DJ, Suresh M, et al. (1998) Viral immune evasion due to persistence of activated T cells without effector function. J Exp Med 188: 2205–2213. 9858507

44. Moskophidis D, Lechner F, Pircher H, Zinkernagel RM (1993) Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells. Nature 362: 758–761. 8469287

45. Seddiki N, Brezar V, Draenert R (2014) Cell exhaustion in HIV-1 infection: role of suppressor cells. Curr Opin HIV AIDS 9: 452–458. doi: 10.1097/COH.0000000000000087 25010895

46. Toth I, Le AQ, Hartjen P, Thomssen A, Matzat V, et al. (2013) Decreased frequency of CD73+CD8+ T cells of HIV-infected patients correlates with immune activation and T cell exhaustion. J Leukoc Biol 94: 551–561. doi: 10.1189/jlb.0113018 23709688

47. Leisner C, Loeth N, Lamberth K, Justesen S, Sylvester-Hvid C, et al. (2008) One-pot, mix-and-read peptide-MHC tetramers. PLoS One 3: e1678. doi: 10.1371/journal.pone.0001678 18301755

48. Wherry EJ, Blattman JN, Murali-Krishna K, van der Most R, Ahmed R (2003) Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment. J Virol 77: 4911–4927. 12663797

49. Murali-Krishna K, Altman JD, Suresh M, Sourdive DJ, Zajac AJ, et al. (1998) Counting antigen-specific CD8 T cells: a reevaluation of bystander activation during viral infection. Immunity 8: 177–187. 9491999

50. Ahmed R, Salmi A, Butler LD, Chiller JM, Oldstone MB (1984) Selection of genetic variants of lymphocytic choriomeningitis virus in spleens of persistently infected mice. Role in suppression of cytotoxic T lymphocyte response and viral persistence. J Exp Med 160: 521–540. 6332167

51. Lazarowski ER, Tarran R, Grubb BR, van Heusden CA, Okada S, et al. (2004) Nucleotide release provides a mechanism for airway surface liquid homeostasis. J Biol Chem 279: 36855–36864. 15210701

52. Chen Y, Corriden R, Inoue Y, Yip L, Hashiguchi N, et al. (2006) ATP release guides neutrophil chemotaxis via P2Y2 and A3 receptors. Science 314: 1792–1795. 17170310

53. Haining WN, Ebert BL, Subrmanian A, Wherry EJ, Eichbaum Q, et al. (2008) Identification of an evolutionarily conserved transcriptional signature of CD8 memory differentiation that is shared by T and B cells. J Immunol 181: 1859–1868. 18641323

54. Monti S TP, Mesirov J, Golub T (2003) Consensus Clustering: A Resampling-Based Method for Class Discovery and Visualization of Gene Expression Microarray Data. Machine Learning 52: 91–118.

55. Liberzon A (2014) A description of the Molecular Signatures Database (MSigDB) Web site. Methods Mol Biol 1150: 153–160. doi: 10.1007/978-1-4939-0512-6_9 24743996

56. Merico D, Isserlin R, Stueker O, Emili A, Bader GD (2010) Enrichment map: a network-based method for gene-set enrichment visualization and interpretation. PLoS One 5: e13984. doi: 10.1371/journal.pone.0013984 21085593

Štítky
Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

Článok vyšiel v časopise

PLOS Pathogens


2015 Číslo 10
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Aktuální možnosti diagnostiky a léčby litiáz
nový kurz
Autori: MUDr. Tomáš Ürge, PhD.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#