Interleukin 21 Signaling in B Cells Is Required for Efficient Establishment of Murine Gammaherpesvirus Latency

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Gammaherpesviruses establish life-long infection in B cells by taking advantage of the host immune response that is generated during primary infection. During initial infection, the immune system responds by inducing rapid proliferation of responding B cells during the germinal center reaction. This response is highly coordinated and relies on the interplay of multiple cell types. CD4 T helper cells are an important component of the germinal center reaction in that they communicate with B cells by providing both proliferation and survival signals. Gammaherpesviruses infect B cells that receive these signals, resulting in proliferation and survival of infected cells, allowing the virus to establish life-long infection. Here we show that interleukin 21 (IL-21), one of the signaling factors produced by CD4 T cells, is required for efficient establishment of infection in a mouse model of gammaherpesvirus infection. In the absence of IL-21 signaling, the viral load is markedly reduced and the composition of the infected cell population is altered to cell types that are less proliferative and produce less virus. These results demonstrate how gammaherpesviruses are able to take advantage of the immune response being generated against it to establish lifelong infection.

Vyšlo v časopise: Interleukin 21 Signaling in B Cells Is Required for Efficient Establishment of Murine Gammaherpesvirus Latency. PLoS Pathog 11(4): e32767. doi:10.1371/journal.ppat.1004831
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004831

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Zdroje

1. Thorley-Lawson DA (2001) Epstein-Barr virus: exploiting the immune system. Nat Rev Immunol 1: 75–82. 11905817

2. Uchida J, Yasui T, Takaoka-Shichijo Y, Muraoka M, Kulwichit W, et al. (1999) Mimicry of CD40 signals by Epstein-Barr virus LMP1 in B lymphocyte responses. Science 286: 300–303. 10514374

3. Caldwell RG, Wilson JB, Anderson SJ, Longnecker R (1998) Epstein-Barr virus LMP2A drives B cell development and survival in the absence of normal B cell receptor signals. Immunity 9: 405–411. 9768760

4. Collins CM, Boss JM, Speck SH (2009) Identification of infected B-cell populations by using a recombinant murine gammaherpesvirus 68 expressing a fluorescent protein. J Virol 83: 6484–6493. doi: 10.1128/JVI.00297-09 19386718

5. Collins CM, Speck SH (2012) Tracking murine gammaherpesvirus 68 infection of germinal center B cells in vivo. PLoS One 7: e33230. doi: 10.1371/journal.pone.0033230 22427999

6. Flano E, Kim IJ, Woodland DL, Blackman MA (2002) Gamma-herpesvirus latency is preferentially maintained in splenic germinal center and memory B cells. J Exp Med 196: 1363–1372. 12438427

7. Marques S, Efstathiou S, Smith KG, Haury M, Simas JP (2003) Selective gene expression of latent murine gammaherpesvirus 68 in B lymphocytes. J Virol 77: 7308–7318. 12805429

8. Willer DO, Speck SH (2003) Long-term latent murine Gammaherpesvirus 68 infection is preferentially found within the surface immunoglobulin D-negative subset of splenic B cells in vivo. J Virol 77: 8310–8321. 12857900

9. Collins CM, Speck SH (2014) Expansion of murine gammaherpesvirus latently infected B cells requires T follicular help. PLoS Pathog 10: e1004106. doi: 10.1371/journal.ppat.1004106 24789087

10. Takemori T, Kaji T, Takahashi Y, Shimoda M, Rajewsky K (2014) Generation of memory B cells inside and outside germinal centers. Eur J Immunol 44: 1258–1264. doi: 10.1002/eji.201343716 24610726

11. Oracki SA, Walker JA, Hibbs ML, Corcoran LM, Tarlinton DM (2010) Plasma cell development and survival. Immunol Rev 237: 140–159. doi: 10.1111/j.1600-065X.2010.00940.x 20727034

12. Victora GD, Nussenzweig MC (2012) Germinal centers. Annu Rev Immunol 30: 429–457. doi: 10.1146/annurev-immunol-020711-075032 22224772

13. Zotos D, Tarlinton DM (2012) Determining germinal centre B cell fate. Trends Immunol 33: 281–288. doi: 10.1016/j.it.2012.04.003 22595532

14. Gitlin AD, Shulman Z, Nussenzweig MC (2014) Clonal selection in the germinal centre by regulated proliferation and hypermutation. Nature 509: 637–640. doi: 10.1038/nature13300 24805232

15. Chtanova T, Tangye SG, Newton R, Frank N, Hodge MR, et al. (2004) T follicular helper cells express a distinctive transcriptional profile, reflecting their role as non-Th1/Th2 effector cells that provide help for B cells. J Immunol 173: 68–78. 15210760

16. Nurieva RI, Chung Y, Hwang D, Yang XO, Kang HS, et al. (2008) Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. Immunity 29: 138–149. doi: 10.1016/j.immuni.2008.05.009 18599325

17. Rasheed AU, Rahn HP, Sallusto F, Lipp M, Muller G (2006) Follicular B helper T cell activity is confined to CXCR5(hi)ICOS(hi) CD4 T cells and is independent of CD57 expression. Eur J Immunol 36: 1892–1903. 16791882

18. Vogelzang A, McGuire HM, Yu D, Sprent J, Mackay CR, et al. (2008) A fundamental role for interleukin-21 in the generation of T follicular helper cells. Immunity 29: 127–137. doi: 10.1016/j.immuni.2008.06.001 18602282

19. Bessa J, Kopf M, Bachmann MF (2010) Cutting edge: IL-21 and TLR signaling regulate germinal center responses in a B cell-intrinsic manner. J Immunol 184: 4615–4619. doi: 10.4049/jimmunol.0903949 20368279

20. Linterman MA, Beaton L, Yu D, Ramiscal RR, Srivastava M, et al. (2010) IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses. J Exp Med 207: 353–363. doi: 10.1084/jem.20091738 20142429

21. Zotos D, Coquet JM, Zhang Y, Light A, D'Costa K, et al. (2010) IL-21 regulates germinal center B cell differentiation and proliferation through a B cell-intrinsic mechanism. J Exp Med 207: 365–378. doi: 10.1084/jem.20091777 20142430

22. Jin H, Carrio R, Yu A, Malek TR (2004) Distinct activation signals determine whether IL-21 induces B cell costimulation, growth arrest, or Bim-dependent apoptosis. J Immunol 173: 657–665. 15210829

23. Rasheed MA, Latner DR, Aubert RD, Gourley T, Spolski R, et al. (2013) Interleukin-21 is a critical cytokine for the generation of virus-specific long-lived plasma cells. J Virol 87: 7737–7746. doi: 10.1128/JVI.00063-13 23637417

24. Zeng R, Spolski R, Casas E, Zhu W, Levy DE, et al. (2007) The molecular basis of IL-21-mediated proliferation. Blood 109: 4135–4142. 17234735

25. Konforte D, Paige CJ (2006) Identification of cellular intermediates and molecular pathways induced by IL-21 in human B cells. J Immunol 177: 8381–8392. 17142735

26. Fornek JL, Tygrett LT, Waldschmidt TJ, Poli V, Rickert RC, et al. (2006) Critical role for Stat3 in T-dependent terminal differentiation of IgG B cells. Blood 107: 1085–1091. 16223771

27. Ozaki K, Spolski R, Ettinger R, Kim HP, Wang G, et al. (2004) Regulation of B cell differentiation and plasma cell generation by IL-21, a novel inducer of Blimp-1 and Bcl-6. J Immunol 173: 5361–5371. 15494482

28. Arguni E, Arima M, Tsuruoka N, Sakamoto A, Hatano M, et al. (2006) JunD/AP-1 and STAT3 are the major enhancer molecules for high Bcl6 expression in germinal center B cells. Int Immunol 18: 1079–1089. 16702165

29. Dent AL, Shaffer AL, Yu X, Allman D, Staudt LM (1997) Control of inflammation, cytokine expression, and germinal center formation by BCL-6. Science 276: 589–592. 9110977

30. Liang X, Collins CM, Mendel JB, Iwakoshi NN, Speck SH (2009) Gammaherpesvirus-driven plasma cell differentiation regulates virus reactivation from latently infected B lymphocytes. PLoS Pathog 5: e1000677. doi: 10.1371/journal.ppat.1000677 19956661

31. Wilson SJ, Tsao EH, Webb BL, Ye H, Dalton-Griffin L, et al. (2007) X box binding protein XBP-1s transactivates the Kaposi's sarcoma-associated herpesvirus (KSHV) ORF50 promoter, linking plasma cell differentiation to KSHV reactivation from latency. J Virol 81: 13578–13586. 17928342

32. Laichalk LL, Thorley-Lawson DA (2005) Terminal differentiation into plasma cells initiates the replicative cycle of Epstein-Barr virus in vivo. J Virol 79: 1296–1307. 15613356

33. Sun CC, Thorley-Lawson DA (2007) Plasma cell-specific transcription factor XBP-1s binds to and transactivates the Epstein-Barr virus BZLF1 promoter. J Virol 81: 13566–13577. 17898050

34. Yu F, Feng J, Harada JN, Chanda SK, Kenney SC, et al. (2007) B cell terminal differentiation factor XBP-1 induces reactivation of Kaposi's sarcoma-associated herpesvirus. FEBS Lett 581: 3485–3488. 17617410

35. Bhende PM, Dickerson SJ, Sun X, Feng WH, Kenney SC (2007) X-box-binding protein 1 activates lytic Epstein-Barr virus gene expression in combination with protein kinase D. J Virol 81: 7363–7370. 17494074

36. Decalf J, Godinho-Silva C, Fontinha D, Marques S, Simas JP (2014) Establishment of murine gammaherpesvirus latency in B cells is not a stochastic event. PLoS Pathog 10: e1004269. doi: 10.1371/journal.ppat.1004269 25079788

37. Victora GD, Schwickert TA, Fooksman DR, Kamphorst AO, Meyer-Hermann M, et al. (2010) Germinal center dynamics revealed by multiphoton microscopy with a photoactivatable fluorescent reporter. Cell 143: 592–605. doi: 10.1016/j.cell.2010.10.032 21074050

38. Schwickert TA, Lindquist RL, Shakhar G, Livshits G, Skokos D, et al. (2007) In vivo imaging of germinal centres reveals a dynamic open structure. Nature 446: 83–87. 17268470

39. Suzuki K, Grigorova I, Phan TG, Kelly LM, Cyster JG (2009) Visualizing B cell capture of cognate antigen from follicular dendritic cells. J Exp Med 206: 1485–1493. doi: 10.1084/jem.20090209 19506051

40. Konforte D, Paige CJ (2009) Interleukin-21 regulates expression of the immediate-early lytic cycle genes and proteins in Epstein-Barr Virus infected B cells. Virus Res 144: 339–343. doi: 10.1016/j.virusres.2009.05.003 19447148

41. Konforte D, Simard N, Paige CJ (2008) Interleukin-21 regulates expression of key Epstein-Barr virus oncoproteins, EBNA2 and LMP1, in infected human B cells. Virology 374: 100–113. doi: 10.1016/j.virol.2007.12.027 18222514

42. Kis LL, Salamon D, Persson EK, Nagy N, Scheeren FA, et al. (2010) IL-21 imposes a type II EBV gene expression on type III and type I B cells by the repression of C- and activation of LMP-1-promoter. Proc Natl Acad Sci U S A 107: 872–877. doi: 10.1073/pnas.0912920107 20080768

43. Nagy N, Adori M, Rasul A, Heuts F, Salamon D, et al. (2012) Soluble factors produced by activated CD4+ T cells modulate EBV latency. Proc Natl Acad Sci U S A 109: 1512–1517. doi: 10.1073/pnas.1120587109 22307606

44. Ozaki K, Spolski R, Feng CG, Qi CF, Cheng J, et al. (2002) A critical role for IL-21 in regulating immunoglobulin production. Science 298: 1630–1634. 12446913

45. Weck KE, Kim SS, Virgin HI, Speck SH (1999) B cells regulate murine gammaherpesvirus 68 latency. J Virol 73: 4651–4661. 10233924

46. Weck KE, Barkon ML, Yoo LI, Speck SH, Virgin HI (1996) Mature B cells are required for acute splenic infection, but not for establishment of latency, by murine gammaherpesvirus 68. J Virol 70: 6775–6780. 8794315