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mRNA Structural Constraints on EBNA1 Synthesis Impact on Antigen Presentation and Early Priming of CD8 T Cells


Maintenance proteins of viruses establishing latent infections regulate their synthesis to levels sufficient for maintaining persistent infection but below threshold levels for host immune detection. The Epstein-Barr virus maintenance protein, EBNA1, has recently been shown to contain unusual G-quadruplex structures within its repeat mRNA that reduces its translational efficiency. In this study we assess how modification of the EBNA1 mRNA repeat sequence to destabilize the native G-quadruplex structures and thereby increase translation, impacts on the activation of EBNA1-specific T cells in vivo. Mice primed with viral vectors encoding a more efficiently translated EBNA1 mRNA revealed increased trafficking of EBNA1-specific T cells, an enhanced functional profile and increased expression of transcription factors providing evidence for a potential link between mRNA translational efficiency and antigen presentation in vivo and the resultant impact on the functional programming of effector T cells. These findings suggest a novel approach to therapeutic development through the use of antisense strategies or small molecules targeting EBNA1 mRNA structure.


Vyšlo v časopise: mRNA Structural Constraints on EBNA1 Synthesis Impact on Antigen Presentation and Early Priming of CD8 T Cells. PLoS Pathog 10(10): e32767. doi:10.1371/journal.ppat.1004423
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004423

Souhrn

Maintenance proteins of viruses establishing latent infections regulate their synthesis to levels sufficient for maintaining persistent infection but below threshold levels for host immune detection. The Epstein-Barr virus maintenance protein, EBNA1, has recently been shown to contain unusual G-quadruplex structures within its repeat mRNA that reduces its translational efficiency. In this study we assess how modification of the EBNA1 mRNA repeat sequence to destabilize the native G-quadruplex structures and thereby increase translation, impacts on the activation of EBNA1-specific T cells in vivo. Mice primed with viral vectors encoding a more efficiently translated EBNA1 mRNA revealed increased trafficking of EBNA1-specific T cells, an enhanced functional profile and increased expression of transcription factors providing evidence for a potential link between mRNA translational efficiency and antigen presentation in vivo and the resultant impact on the functional programming of effector T cells. These findings suggest a novel approach to therapeutic development through the use of antisense strategies or small molecules targeting EBNA1 mRNA structure.


Zdroje

1. DohertyPC, ChristensenJP, BelzGT, StevensonPG, SangsterMY (2001) Dissecting the host response to a gamma-herpesvirus. Philosophical transactions of the Royal Society of London Series B, Biological sciences 356: 581–593.

2. TellamJ, ConnollyG, GreenKJ, MilesJJ, MossDJ, et al. (2004) Endogenous presentation of CD8+ T cell epitopes from Epstein-Barr virus-encoded nuclear antigen 1. J Exp Med 199: 1421–1431.

3. VooKS, FuT, WangHY, TellamJ, HeslopHE, et al. (2004) Evidence for the presentation of major histocompatibility complex class I-restricted Epstein-Barr virus nuclear antigen 1 peptides to CD8+ T lymphocytes. J Exp Med 199: 459–470.

4. YewdellJW (2005) Serendipity strikes twice: the discovery and rediscovery of defective ribosomal products (DRiPS). Cell Mol Biol (Noisy-le-grand) 51: 635–641.

5. YewdellJW, AntonLC, BenninkJR (1996) Defective ribosomal products (DRiPs): a major source of antigenic peptides for MHC class I molecules? J Immunol 157: 1823–1826.

6. YinY, ManouryB, FahraeusR (2003) Self-inhibition of synthesis and antigen presentation by Epstein-Barr virus-encoded EBNA1. Science 301: 1371–1374.

7. RyanAA, NambiarJK, WozniakTM, RoedigerB, ShklovskayaE, et al. (2009) Antigen load governs the differential priming of CD8 T cells in response to the bacille Calmette Guerin vaccine or Mycobacterium tuberculosis infection. J Immunol 182: 7172–7177.

8. RussellMS, IskandarM, MykytczukOL, NashJH, KrishnanL, et al. (2007) A reduced antigen load in vivo, rather than weak inflammation, causes a substantial delay in CD8+ T cell priming against Mycobacterium bovis (bacillus Calmette-Guerin). J Immunol 179: 211–220.

9. ZhengH, JinB, HenricksonSE, PerelsonAS, von AndrianUH, et al. (2008) How antigen quantity and quality determine T-cell decisions in lymphoid tissue. Mol Cell Biol 28: 4040–4051.

10. KhannaR, BurrowsSR, MossDJ (1995) Immune regulation in Epstein-Barr virus-associated diseases. Microbiol Rev 59: 387–405.

11. MunzC (2004) Epstein-barr virus nuclear antigen 1: from immunologically invisible to a promising T cell target. J Exp Med 199: 1301–1304.

12. LevitskayaJ, CoramM, LevitskyV, ImrehS, Steigerwald-MullenPM, et al. (1995) Inhibition of antigen processing by the internal repeat region of the Epstein-Barr virus nuclear antigen-1. Nature 375: 685–688.

13. LevitskayaJ, SharipoA, LeonchiksA, CiechanoverA, MasucciMG (1997) Inhibition of ubiquitin/proteasome-dependent protein degradation by the Gly-Ala repeat domain of the Epstein-Barr virus nuclear antigen 1. Proc Natl Acad Sci U S A 94: 12616–12621.

14. TellamJ, SherrittM, ThomsonS, TellamR, MossDJ, et al. (2001) Targeting of EBNA1 for rapid intracellular degradation overrides the inhibitory effects of the Gly-Ala repeat domain and restores CD8+ T cell recognition. J Biol Chem 276: 33353–33360.

15. ApcherS, DaskalogianniC, ManouryB, FahraeusR (2010) Epstein Barr virus-encoded EBNA1 interference with MHC class I antigen presentation reveals a close correlation between mRNA translation initiation and antigen presentation. PLoS Pathog 6: e1001151.

16. MackayLK, LongHM, BrooksJM, TaylorGS, LeungCS, et al. (2009) T cell detection of a B-cell tropic virus infection: newly-synthesised versus mature viral proteins as antigen sources for CD4 and CD8 epitope display. PLoS pathogens 5: e1000699.

17. TellamJ, FoggMH, RistM, ConnollyG, TscharkeD, et al. (2007) Influence of translation efficiency of homologous viral proteins on the endogenous presentation of CD8+ T cell epitopes. J Exp Med 204: 525–532.

18. TellamJ, RistM, ConnollyG, WebbN, FazouC, et al. (2007) Translation efficiency of EBNA1 encoded by lymphocryptoviruses influences endogenous presentation of CD8+ T cell epitopes. Eur J Immunol 37: 328–337.

19. TellamJT, LekieffreL, ZhongJ, LynnDJ, KhannaR (2012) Messenger RNA Sequence Rather than Protein Sequence Determines the Level of Self-synthesis and Antigen Presentation of the EBV-encoded Antigen, EBNA1. PLoS Pathog 8: e1003112.

20. CardinaudS, StarckSR, ChandraP, ShastriN (2010) The synthesis of truncated polypeptides for immune surveillance and viral evasion. PLoS One 5: e8692.

21. ApcherS, KomarovaA, DaskalogianniC, YinY, Malbert-ColasL, et al. (2009) mRNA translation regulation by the Gly-Ala repeat of Epstein-Barr virus nuclear antigen 1. J Virol 83: 1289–1298.

22. TellamJ, SmithC, RistM, WebbN, CooperL, et al. (2008) Regulation of protein translation through mRNA structure influences MHC class I loading and T cell recognition. Proc Natl Acad Sci U S A 105: 9319–9324.

23. MuratP, ZhongJ, LekieffreL, CowiesonNP, ClancyJL, et al. (2014) G-quadruplexes regulate Epstein-Barr virus-encoded nuclear antigen 1 mRNA translation. Nature chemical biology 10: 358–364 doi:10.1038/nchembio.1479

24. ChengLE, OhlenC, NelsonBH, GreenbergPD (2002) Enhanced signaling through the IL-2 receptor in CD8+ T cells regulated by antigen recognition results in preferential proliferation and expansion of responding CD8+ T cells rather than promotion of cell death. Proc Natl Acad Sci U S A 99: 3001–3006.

25. PipkinME, SacksJA, Cruz-GuillotyF, LichtenheldMG, BevanMJ, et al. (2010) Interleukin-2 and inflammation induce distinct transcriptional programs that promote the differentiation of effector cytolytic T cells. Immunity 32: 79–90.

26. HendriksJ, GravesteinLA, TesselaarK, van LierRA, SchumacherTN, et al. (2000) CD27 is required for generation and long-term maintenance of T cell immunity. Nature immunology 1: 433–440.

27. van GisbergenKP, KlarenbeekPL, KragtenNA, UngerPP, NieuwenhuisMB, et al. (2011) The costimulatory molecule CD27 maintains clonally diverse CD8(+) T cell responses of low antigen affinity to protect against viral variants. Immunity 35: 97–108.

28. BanerjeeA, GordonSM, IntlekoferAM, PaleyMA, MooneyEC, et al. (2010) Cutting edge: The transcription factor eomesodermin enables CD8+ T cells to compete for the memory cell niche. J Immunol 185: 4988–4992.

29. IntlekoferAM, TakemotoN, WherryEJ, LongworthSA, NorthrupJT, et al. (2005) Effector and memory CD8+ T cell fate coupled by T-bet and eomesodermin. Nat Immunol 6: 1236–1244.

30. JoshiNS, CuiW, ChandeleA, LeeHK, UrsoDR, et al. (2007) Inflammation directs memory precursor and short-lived effector CD8(+) T cell fates via the graded expression of T-bet transcription factor. Immunity 27: 281–295.

31. PearceEL, MullenAC, MartinsGA, KrawczykCM, HutchinsAS, et al. (2003) Control of effector CD8+ T cell function by the transcription factor Eomesodermin. Science 302: 1041–1043.

32. KurtsC, RobinsonBW, KnollePA (2010) Cross-priming in health and disease. Nature reviews Immunology 10: 403–414.

33. RestifoNP, BacikI, IrvineKR, YewdellJW, McCabeBJ, et al. (1995) Antigen processing in vivo and the elicitation of primary CTL responses. Journal of immunology 154: 4414–4422.

34. YewdellJW, HaeryfarSM (2005) Understanding presentation of viral antigens to CD8+ T cells in vivo: the key to rational vaccine design. Annual review of immunology 23: 651–682.

35. BurrowsSR, MossDJ, KhannaR (2011) Understanding human T-cell-mediated immunoregulation through herpesviruses. Immunology and cell biology 89: 352–358.

36. GandhiMK, KhannaR (2004) Human cytomegalovirus: clinical aspects, immune regulation, and emerging treatments. Lancet InfectDis 4: 725–738.

37. HillemanMR (2004) Strategies and mechanisms for host and pathogen survival in acute and persistent viral infections. Proceedings of the National Academy of Sciences of the United States of America 101 Suppl 2: 14560–14566.

38. KhannaR, BurrowsSR (2000) Role of cytotoxic T lymphocytes in Epstein-Barr virus-associated diseases. AnnuRevMicrobiol2000;54:19–48 54 19–48 19–48.

39. KhannaR, MossDJ, GandhiM (2005) Applications of emerging immunotherapeutic strategies for Epstein-Barr virus-associated malignancies. Nature Clinical Practice Oncolcogy 2: 138–149.

40. ApcherS, FahraeusR, ManouryB (2004) Epstein-Barr virus: exploiting the immune system by interfering with defective ribosomal products. Microbes Infect 6: 1212–1218.

41. LeeSP, BrooksJM, Al JarrahH, ThomasWA, HaighTA, et al. (2004) CD8 T cell recognition of endogenously expressed epstein-barr virus nuclear antigen 1. The Journal of Experimental Medicine 199: 1409–1420.

42. BickhamK, GoodmanK, PaludanC, NikiforowS, TsangML, et al. (2003) Dendritic cells initiate immune control of epstein-barr virus transformation of B lymphocytes in vitro. The Journal of experimental medicine 198: 1653–1663.

43. LimWH, KiretaS, RussGR, CoatesPT (2007) Human plasmacytoid dendritic cells regulate immune responses to Epstein-Barr virus (EBV) infection and delay EBV-related mortality in humanized NOD-SCID mice. Blood 109: 1043–1050.

44. FiolaS, GosselinD, TakadaK, GosselinJ (2010) TLR9 contributes to the recognition of EBV by primary monocytes and plasmacytoid dendritic cells. Journal of immunology 185: 3620–3631.

45. LiL, LiuD, Hutt-FletcherL, MorganA, MasucciMG, et al. (2002) Epstein-Barr virus inhibits the development of dendritic cells by promoting apoptosis of their monocyte precursors in the presence of granulocyte macrophage-colony-stimulating factor and interleukin-4. Blood 99: 3725–3734.

46. SeveraM, GiacominiE, GafaV, AnastasiadouE, RizzoF, et al. (2013) EBV stimulates TLR- and autophagy-dependent pathways and impairs maturation in plasmacytoid dendritic cells: implications for viral immune escape. European journal of immunology 43: 147–158.

47. SubkleweM, PaludanC, TsangML, MahnkeK, SteinmanRM, et al. (2001) Dendritic cells cross-present latency gene products from Epstein-Barr virus-transformed B cells and expand tumor-reactive CD8(+) killer T cells. The Journal of experimental medicine 193: 405–411.

48. SmithC, ElhassenD, GrasS, WynnKK, DasariV, et al. (2012) Endogenous antigen presentation impacts on T-box transcription factor expression and functional maturation of CD8+ T cells. Blood 120: 3237–3245.

49. YotndaP, OnishiH, HeslopHE, ShayakhmetovD, LieberA, et al. (2001) Efficient infection of primitive hematopoietic stem cells by modified adenovirus. Gene therapy 8: 930–937.

50. KarttunenJ, SandersonS, ShastriN (1992) Detection of rare antigen-presenting cells by the lacZ T-cell activation assay suggests an expression cloning strategy for T-cell antigens. Proc Natl Acad Sci U S A 89: 6020–6024.

51. NolanGP, FieringS, NicolasJF, HerzenbergLA (1988) Fluorescence-activated cell analysis and sorting of viable mammalian cells based on beta-D-galactosidase activity after transduction of Escherichia coli lacZ. Proc Natl Acad Sci U S A 85: 2603–2607.

52. SandersonS, ShastriN (1994) LacZ inducible, antigen/MHC-specific T cell hybrids. Int Immunol 6: 369–376.

53. QuahBJ, WarrenHS, ParishCR (2007) Monitoring lymphocyte proliferation in vitro and in vivo with the intracellular fluorescent dye carboxyfluorescein diacetate succinimidyl ester. Nat Protoc 2: 2049–2056.

54. ZhongJ, RistM, CooperL, SmithC, KhannaR (2008) Induction of pluripotent protective immunity following immunisation with a chimeric vaccine against human cytomegalovirus. PLoS One 3: e3256.

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Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

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PLOS Pathogens


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