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Mechanism of T cell exhaustion in a chronic environment

  • Jin, Hyun-Tak (Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine) ;
  • Jeong, Yun-Hee (Department of Biochemistry, College of Life Science and Engineering, Yonsei University) ;
  • Park, Hyo-Jin (Department of Biochemistry, College of Life Science and Engineering, Yonsei University) ;
  • Ha, Sang-Jun (Department of Biochemistry, College of Life Science and Engineering, Yonsei University)
  • Accepted : 2011.03.28
  • Published : 2011.04.30
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Abstract

T cell exhaustion develops under conditions of antigen-persistence caused by infection with various chronic pathogens, such as human immunodeficiency virus (HIV) and myco-bacterium tuberculosis (TB), or by the development of cancer. T cell exhaustion is characterized by stepwise and progressive loss of T cell function, which is probably the main reason for the failed immunological control of chronic pathogens and cancers. Recent observations have detailed some of the intrinsic and extrinsic factors that influence the severity of T cell exhaustion. Duration and magnitude of antigenic activation of T cells might be associated with up-regulation of inhibitory receptors, which is a major intrinsic factor of T cell exhaustion. Extrinsic factors might include the production of suppressive cytokines, T cell priming by either non-professional antigenpresenting cells (APCs) or tolerogenic dendritic cells (DCs), and alteration of regulatory T (Treg) cells. Further investigation of the cellular and molecular processes behind the development of T cell exhaustion can reveal therapeutic targets and strategies for the treatment of chronic infections and cancers. Here, we report the properties and the mechanisms of T cell exhaustion in a chronic environment.

Keywords

References

  1. Badovinac, V. P. and Harty, J. T. (2002) CD8(+) T-cell homeostasis after infection: setting the 'curve'. Microbes Infect. 4, 441-447. https://doi.org/10.1016/S1286-4579(02)01558-7
  2. Kaech, S. M., Hemby, S., Kersh, E. and Ahmed, R. (2002) Molecular and functional profiling of memory CD8 T cell differentiation. Cell 111, 837-851. https://doi.org/10.1016/S0092-8674(02)01139-X
  3. Lechner, F., Wong, D. K., Dunbar, P. R., Chapman, R.,Chung, R. T., Dohrenwend, P., Robbins, G., Phillips, R.,Klenerman, P. and Walker, B. D. (2000) Analysis of successful immune responses in persons infected with hepatitis C virus. J. Exp. Med. 191, 1499-1512. https://doi.org/10.1084/jem.191.9.1499
  4. Mongkolsapaya, J., Dejnirattisai, W., Xu, X. N., Vasanawathana,S., Tangthawornchaikul, N., Chairunsri, A.,Sawasdivorn, S., Duangchinda, T., Dong, T., Rowland-Jones, S., Yenchitsomanus, P. T., McMichael, A., Malasit,P. and Screaton, G. (2003) Original antigenic sin and apoptosis in the pathogenesis of dengue hemorrhagic fever. Nat. Med. 9, 921-927. https://doi.org/10.1038/nm887
  5. Van Epps, H. L., Terajima, M., Mustonen, J., Arstila, T.P., Corey, E. A., Vaheri, A. and Ennis, F. A. (2002) Long-lived memory T lymphocyte responses after hantavirus infection. J. Exp. Med. 196, 579-588. https://doi.org/10.1084/jem.20011255
  6. Wherry, E. J. and Ahmed, R. (2004) Memory CD8 T-cell differentiation during viral infection. J. Virol. 78, 5535-5545. https://doi.org/10.1128/JVI.78.11.5535-5545.2004
  7. Kaech, S. M., Wherry, E. J. and Ahmed, R. (2002) Effector and memory T-cell differentiation: implications for vaccine development. Nat. Rev. Immunol. 2, 251- 262. https://doi.org/10.1038/nri778
  8. Schluns, K. S. and Lefrancois, L. (2003) Cytokine control of memory T-cell development and survival. Nat. Rev. Immunol. 3, 269-279. https://doi.org/10.1038/nri1052
  9. Klenerman, P. and Hill, A. (2005) T cells and viral persistence: lessons from diverse infections. Nat. Immunol. 6, 873-879. https://doi.org/10.1038/ni1241
  10. Anichini, A., Vegetti, C. and Mortarini, R. (2004) The paradox of T-cell-mediated antitumor immunity in spite of poor clinical outcome in human melanoma. Cancer Immunol. Immunother. 53, 855-864.
  11. den Boer, A. T., van Mierlo, G. J., Fransen, M. F., Melief,C. J., Offringa, R. and Toes, R. E. (2004) The tumoricidal activity of memory CD8+ T cells is hampered by persistent systemic antigen, but full functional capacity is regained in an antigen-free environment. J. Immunol. 172, 6074-6079. https://doi.org/10.4049/jimmunol.172.10.6074
  12. Zippelius, A., Batard, P., Rubio-Godoy, V., Bioley, G.,Lienard, D., Lejeune, F., Rimoldi, D., Guillaume, P.,Meidenbauer, N., Mackensen, A., Rufer, N., Lubenow,N., Speiser, D., Cerottini, J. C., Romero, P. and Pittet, M.J. (2004) Effector function of human tumor-specific CD8 T cells in melanoma lesions: a state of local functional tolerance. Cancer Res. 64, 2865-2873. https://doi.org/10.1158/0008-5472.CAN-03-3066
  13. Coussens, L. M. and Werb, Z. (2002) Inflammation and cancer. Nature 420, 860-867. https://doi.org/10.1038/nature01322
  14. Virgin, H. W., Wherry, E. J. and Ahmed, R. (2009) Redefining chronic viral infection. Cell 138, 30-50. https://doi.org/10.1016/j.cell.2009.06.036
  15. Zajac, A. J., Blattman, J. N., Murali-Krishna, K., Sourdive,D. J., Suresh, M., Altman, J. D. and Ahmed, R. (1998) Viral immune evasion due to persistence of activated T cells without effector function. J. Exp. Med. 188, 2205-2213. https://doi.org/10.1084/jem.188.12.2205
  16. Crawford, A. and Wherry, E. J. (2009) The diversity of costimulatory and inhibitory receptor pathways and the regulation of antiviral T cell responses. Curr. Opin. Immunol. 21, 179-186. https://doi.org/10.1016/j.coi.2009.01.010
  17. Wherry, E. J., Blattman, J. N., Murali-Krishna, K., van derMost, R. and 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. https://doi.org/10.1128/JVI.77.8.4911-4927.2003
  18. Wherry, E. J., Ha, S. J., Kaech, S. M., Haining, W. N.,Sarkar, S., Kalia, V., Subramaniam, S., Blattman, J. N.,Barber, D. L. and Ahmed, R. (2007) Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 27, 670-684. https://doi.org/10.1016/j.immuni.2007.09.006
  19. Shin, H. and Wherry, E. J. (2007) CD8 T cell dysfunction during chronic viral infection. Curr. Opin. Immunol. 19, 408-415. https://doi.org/10.1016/j.coi.2007.06.004
  20. Shin, H., Blackburn, S. D., Blattman, J. N. and Wherry,E. J. (2007) Viral antigen and extensive division maintain virus-specific CD8 T cells during chronic infection. J. Exp. Med. 204, 941-949. https://doi.org/10.1084/jem.20061937
  21. Mumprecht, S., Schurch, C., Schwaller, J., Solenthaler,M. and Ochsenbein, A. F. (2009) Programmed death 1 signaling on chronic myeloid leukemia-specific T cells results in T-cell exhaustion and disease progression. Blood 114, 1528-1536. https://doi.org/10.1182/blood-2008-09-179697
  22. Fourcade, J., Sun, Z., Benallaoua, M., Guillaume, P.,Luescher, I. F., Sander, C., Kirkwood, J. M., Kuchroo, V.and Zarour, H. M. (2010) Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients. J. Exp. Med. 207, 2175-2186. https://doi.org/10.1084/jem.20100637
  23. Ahmadzadeh, M., Johnson, L. A., Heemskerk, B., Wunderlich,J. R., Dudley, M. E., White, D. E. and Rosenberg,S. A. (2009) Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood 114, 1537-1544. https://doi.org/10.1182/blood-2008-12-195792
  24. Barber, D. L., Wherry, E. J., Masopust, D., Zhu, B.,Allison, J. P., Sharpe, A. H., Freeman, G. J. and Ahmed, R. (2006) Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439, 682-687. https://doi.org/10.1038/nature04444
  25. Sharpe, A. H., Wherry, E. J., Ahmed, R. and Freeman, G.J. (2007) The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat. Immunol. 8, 239-245. https://doi.org/10.1038/ni1443
  26. Jin, H. T., Ahmed, R. and Okazaki, T. (2010) Role of PD-1 in Regulating T-Cell Immunity. Curr. Top. Microbiol. Immunol. [Epub ahead of print].
  27. Ha, S. J., Mueller, S. N., Wherry, E. J., Barber, D. L.,Aubert, R. D., Sharpe, A. H., Freeman, G. J. and Ahmed, R. (2008) Enhancing therapeutic vaccination by blocking PD-1-mediated inhibitory signals during chronic infection. J. Exp. Med. 205, 543-555. https://doi.org/10.1084/jem.20071949
  28. Boni, C., Fisicaro, P., Valdatta, C., Amadei, B., Di Vincenzo,P., Giuberti, T., Laccabue, D., Zerbini, A., Cavalli,A., Missale, G., Bertoletti, A. and Ferrari, C. (2007) Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic HBV infection. J. Virol. 81, 4215-4225. https://doi.org/10.1128/JVI.02844-06
  29. Day, C. L., Kaufmann, D. E., Kiepiela, P., Brown, J. A.,Moodley, E. S., Reddy, S., Mackey, E. W., Miller, J. D.,Leslie, A. J., DePierres, C., Mncube, Z., Duraiswamy, J.,Zhu, B., Eichbaum, Q., Altfeld, M., Wherry, E. J.,Coovadia, H. M., Goulder, P. J., Klenerman, P., Ahmed,R., Freeman, G. J. and Walker, B. D. (2006) PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443, 350-354. https://doi.org/10.1038/nature05115
  30. Freeman, G. J., Wherry, E. J., Ahmed, R. and Sharpe, A.H. (2006) Reinvigorating exhausted HIV-specific T cells via PD-1-PD-1 ligand blockade. J. Exp. Med. 203, 2223-2227. https://doi.org/10.1084/jem.20061800
  31. Petrovas, C., Casazza, J. P., Brenchley, J. M., Price, D.A., Gostick, E., Adams, W. C., Precopio, M. L., Schacker,T., Roederer, M., Douek, D. C. and Koup, R. A. (2006) PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection. J. Exp. Med. 203, 2281-2292. https://doi.org/10.1084/jem.20061496
  32. Radziewicz, H., Ibegbu, C. C., Fernandez, M. L.,Workowski, K. A., Obideen, K., Wehbi, M., Hanson, H.L., Steinberg, J. P., Masopust, D., Wherry, E. J., Altman,J. D., Rouse, B. T., Freeman, G. J., Ahmed, R. andGrakoui, A. (2007) Liver-infiltrating lymphocytes in chronic human hepatitis C virus infection display an exhausted phenotype with high levels of PD-1 and low levels of CD127 expression. J. Virol. 81, 2545-2553. https://doi.org/10.1128/JVI.02021-06
  33. Trautmann, L., Janbazian, L., Chomont, N., Said, E. A.,Gimmig, S., Bessette, B., Boulassel, M. R., Delwart, E.,Sepulveda, H., Balderas, R. S., Routy, J. P., Haddad, E. K.and Sekaly, R. P. (2006) Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat. Med. 12, 1198-1202. https://doi.org/10.1038/nm1482
  34. Urbani, S., Amadei, B., Tola, D., Massari, M., Schivazappa,S., Missale, G. and Ferrari, C. (2006) PD-1 expression in acute hepatitis C virus (HCV) infection is associated with HCV-specific CD8 exhaustion. J. Virol. 80, 11398-11403. https://doi.org/10.1128/JVI.01177-06
  35. Velu, V., Titanji, K., Zhu, B., Husain, S., Pladevega, A.,Lai, L., Vanderford, T. H., Chennareddi, L., Silvestri, G.,Freeman, G. J., Ahmed, R. and Amara, R. R. (2009) Enhancing SIV-specific immunity in vivo by PD-1 blockade. Nature 458, 206-210. https://doi.org/10.1038/nature07662
  36. D'Souza, M., Fontenot, A. P., Mack, D. G., Lozupone,C., Dillon, S., Meditz, A., Wilson, C. C., Connick, E. andPalmer, B. E. (2007) Programmed death 1 expression on HIV-specific CD4+ T cells is driven by viral replication and associated with T cell dysfunction. J. Immunol. 179, 1979-1987. https://doi.org/10.4049/jimmunol.179.3.1979
  37. Golden-Mason, L., Palmer, B., Klarquist, J., Mengshol, J.A., Castelblanco, N. and Rosen, H. R. (2007) Upregulation of PD-1 expression on circulating and intrahepatic hepatitis C virus-specific CD8+ T cells associated with reversible immune dysfunction. J. Virol. 81, 9249-9258. https://doi.org/10.1128/JVI.00409-07
  38. Hamanishi, J., Mandai, M., Iwasaki, M., Okazaki, T.,Tanaka, Y., Yamaguchi, K., Higuchi, T., Yagi, H.,Takakura, K., Minato, N., Honjo, T. and Fujii, S. (2007) Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc. Natl. Acad. Sci. U.S.A. 104, 3360-3365. https://doi.org/10.1073/pnas.0611533104
  39. Hino, R., Kabashima, K., Kato, Y., Yagi, H., Nakamura,M., Honjo, T., Okazaki, T. and Tokura, Y. (2010) Tumor cell expression of programmed cell death-1 ligand 1 is a prognostic factor for malignant melanoma. Cancer 116, 1757-1766. https://doi.org/10.1002/cncr.24899
  40. Nakanishi, J., Wada, Y., Matsumoto, K., Azuma, M.,Kikuchi, K. and Ueda, S. (2007) Overexpression of B7-H1 (PD-L1) significantly associates with tumor grade and postoperative prognosis in human urothelial cancers. Cancer Immunol. Immunother. 56, 1173-1182. https://doi.org/10.1007/s00262-006-0266-z
  41. Nomi, T., Sho, M., Akahori, T., Hamada, K., Kubo, A.,Kanehiro, H., Nakamura, S., Enomoto, K., Yagita, H.,Azuma, M. and Nakajima, Y. (2007) Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clin. Cancer Res. 13, 2151-2157. https://doi.org/10.1158/1078-0432.CCR-06-2746
  42. Ohigashi, Y., Sho, M., Yamada, Y., Tsurui, Y., Hamada,K., Ikeda, N., Mizuno, T., Yoriki, R., Kashizuka, H.,Yane, K., Tsushima, F., Otsuki, N., Yagita, H., Azuma,M. and Nakajima, Y. (2005) Clinical significance of programmed death-1 ligand-1 and programmed death-1 ligand-2 expression in human esophageal cancer. Clin. Cancer Res. 11, 2947-2953. https://doi.org/10.1158/1078-0432.CCR-04-1469
  43. Thompson, R. H., Gillett, M. D., Cheville, J. C., Lohse,C. M., Dong, H., Webster, W. S., Krejci, K. G., Lobo, J.R., Sengupta, S., Chen, L., Zincke, H., Blute, M. L.,Strome, S. E., Leibovich, B. C. and Kwon, E. D. (2004) Costimulatory B7-H1 in renal cell carcinoma patients: Indicator of tumor aggressiveness and potential therapeutic target. Proc. Natl. Acad. Sci. U.S.A. 101, 17174-17179. https://doi.org/10.1073/pnas.0406351101
  44. Wu, C., Zhu, Y., Jiang, J., Zhao, J., Zhang, X. G. and Xu,N. (2006) Immunohistochemical localization of programmed death-1 ligand-1 (PD-L1) in gastric carcinoma and its clinical significance. Acta Histochem. 108, 19-24. https://doi.org/10.1016/j.acthis.2006.01.003
  45. Fourcade, J., Kudela, P., Sun, Z., Shen, H., Land, S. R., Lenzner, D., Guillaume, P., Luescher, I. F., Sander, C.,Ferrone, S., Kirkwood, J. M. and Zarour, H. M. (2009) PD-1 is a regulator of NY-ESO-1-specific CD8+ T cell expansion in melanoma patients. J. Immunol. 182, 5240-5249. https://doi.org/10.4049/jimmunol.0803245
  46. Brahmer, J. R., Drake, C. G., Wollner, I., Powderly, J. D.,Picus, J., Sharfman, W. H., Stankevich, E., Pons, A.,Salay, T. M., McMiller, T. L., Gilson, M. M., Wang, C.,Selby, M., Taube, J. M., Anders, R., Chen, L., Korman, A.J., Pardoll, D. M., Lowy, I. and Topalian, S. L. (2010) Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J. Clin. Oncol. 28, 3167-3175. https://doi.org/10.1200/JCO.2009.26.7609
  47. Berger, R., Rotem-Yehudar, R., Slama, G., Landes, S.,Kneller, A., Leiba, M., Koren-Michowitz, M., Shimoni, A.and Nagler, A. (2008) Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. Clin. Cancer Res. 14, 3044-3051. https://doi.org/10.1158/1078-0432.CCR-07-4079
  48. Blackburn, S. D., Shin, H., Haining, W. N., Zou, T.,Workman, C. J., Polley, A., Betts, M. R., Freeman, G. J.,Vignali, D. A. and Wherry, E. J. (2009) Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat. Immunol. 10, 29-37. https://doi.org/10.1038/ni.1679
  49. Golden-Mason, L., Palmer, B. E., Kassam, N., Townshend-Bulson, L., Livingston, S., McMahon, B. J.,Castelblanco, N., Kuchroo, V., Gretch, D. R. and Rosen, H. R. (2009) Negative immune regulator Tim-3 is overexpressed on T cells in hepatitis C virus infection and its blockade rescues dysfunctional CD4+ and CD8+ T cells. J. Virol. 83, 9122-9130. https://doi.org/10.1128/JVI.00639-09
  50. Jin, H. T., Anderson, A. C., Tan, W. G., West, E. E., Ha,S. J., Araki, K., Freeman, G. J., Kuchroo, V. K. and Ahmed, R. (2010) Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection. Proc. Natl. Acad. Sci. U.S.A. 107, 14733-14738. https://doi.org/10.1073/pnas.1009731107
  51. Jones, R. B., Ndhlovu, L. C., Barbour, J. D., Sheth, P. M.,Jha, A. R., Long, B. R., Wong, J. C., Satkunarajah, M.,Schweneker, M., Chapman, J. M., Gyenes, G., Vali, B.,Hyrcza, M. D., Yue, F. Y., Kovacs, C., Sassi, A., Loutfy,M., Halpenny, R., Persad, D., Spotts, G., Hecht, F. M.,Chun, T. W., McCune, J. M., Kaul, R., Rini, J. M., Nixon,D. F. and Ostrowski, M. A. (2008) Tim-3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV-1 infection. J. Exp. Med. 205, 2763-2779. https://doi.org/10.1084/jem.20081398
  52. Sakuishi, K., Apetoh, L., Sullivan, J. M., Blazar, B. R.,Kuchroo, V. K. and Anderson, A. C. (2010) Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J. Exp. Med. 207, 2187-2194. https://doi.org/10.1084/jem.20100643
  53. Shin, H., Blackburn, S. D., Intlekofer, A. M., Kao, C.,Angelosanto, J. M., Reiner, S. L. and Wherry, E. J. (2009) A role for the transcriptional repressor Blimp-1 in CD8(+) T cell exhaustion during chronic viral infection. Immunity 31, 309-320. https://doi.org/10.1016/j.immuni.2009.06.019
  54. Agnellini, P., Wolint, P., Rehr, M., Cahenzli, J., Karrer,U. and Oxenius, A. (2007) Impaired NFAT nuclear translocation results in split exhaustion of virus-specific CD8+ T cell functions during chronic viral infection. Proc. Natl. Acad. Sci. U.S.A. 104, 4565-4570. https://doi.org/10.1073/pnas.0610335104
  55. Quigley, M., Pereyra, F., Nilsson, B., Porichis, F.,Fonseca, C., Eichbaum, Q., Julg, B., Jesneck, J. L., Brosnahan,K., Imam, S., Russell, K., Toth, I., Piechocka-Trocha, A., Dolfi, D., Angelosanto, J., Crawford, A.,Shin, H., Kwon, D. S., Zupkosky, J., Francisco, L.,Freeman, G. J., Wherry, E. J., Kaufmann, D. E., Walker,B. D., Ebert, B. and Haining, W. N. (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. https://doi.org/10.1038/nm.2232
  56. Pellegrini, M., Calzascia, T., Toe, J. G., Preston, S. P.,Lin, A. E., Elford, A. R., Shahinian, A., Lang, P. A., Lang,K. S., Morre, M., Assouline, B., Lahl, K., Sparwasser, T.,Tedder, T. F., Paik, J. H., DePinho, R. A., Basta, S.,Ohashi, P. S. and Mak, T. W. (2011) IL-7 engages multiple mechanisms to overcome chronic viral infection and limit organ pathology. Cell 144, 601-613. https://doi.org/10.1016/j.cell.2011.01.011
  57. Abbas, A. K. and Sharpe, A. H. (2005) Dendritic cells giveth and taketh away. Nat. Immunol. 6, 227-228. https://doi.org/10.1038/ni0305-227
  58. Lore, K., Sonnerborg, A., Brostrom, C., Goh, L. E.,Perrin, L., McDade, H., Stellbrink, H. J., Gazzard, B.,Weber, R., Napolitano, L. A., van Kooyk, Y. and Andersson,J. (2002) Accumulation of DC-SIGN+CD40+ dendritic cells with reduced CD80 and CD86 expression in lymphoid tissue during acute HIV-1 infection. AIDS 16, 683-692. https://doi.org/10.1097/00002030-200203290-00003
  59. Redpath, S., Angulo, A., Gascoigne, N. R. and Ghazal, P. (2001) Immune checkpoints in viral latency. Annu. Rev. Microbiol. 55, 531-560. https://doi.org/10.1146/annurev.micro.55.1.531
  60. Tortorella, D., Gewurz, B., Schust, D., Furman, M. andPloegh, H. (2000) Down-regulation of MHC class I antigen presentation by HCMV; lessons for tumor immunology. Immunol. Invest. 29, 97-100. https://doi.org/10.3109/08820130009062289
  61. Fuller, M. J. and Zajac, A. J. (2003) Ablation of CD8 and CD4 T cell responses by high viral loads. J. Immunol. 170, 477-486. https://doi.org/10.4049/jimmunol.170.1.477
  62. Moskophidis, D., Lechner, F., Pircher, H. and Zinkernagel, R. M. (1993) Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells. Nature 362, 758-761. https://doi.org/10.1038/362758a0
  63. Mueller, S. N. and Ahmed, R. (2009) High antigen levels are the cause of T cell exhaustion during chronic viral infection. Proc. Natl. Acad. Sci. U.S.A. 106, 8623-8628. https://doi.org/10.1073/pnas.0809818106
  64. Schacker, T. W., Brenchley, J. M., Beilman, G. J., Reilly,C., Pambuccian, S. E., Taylor, J., Skarda, D., Larson, M.,Douek, D. C. and Haase, A. T. (2006) Lymphatic tissue fibrosis is associated with reduced numbers of naive CD4+ T cells in human immunodeficiency virus type 1 infection. Clin. Vaccine Immunol. 13, 556-560. https://doi.org/10.1128/CVI.13.5.556-560.2006
  65. Mueller, S. N., Matloubian, M., Clemens, D. M., Sharpe,A. H., Freeman, G. J., Gangappa, S., Larsen, C. P. and Ahmed, R. (2007) Viral targeting of fibroblastic reticular cells contributes to immunosuppression and persistence during chronic infection. Proc. Natl. Acad. Sci. U.S.A. 104, 15430-15435. https://doi.org/10.1073/pnas.0702579104
  66. Zhang, M., Tang, H., Guo, Z., An, H., Zhu, X., Song, W.,Guo, J., Huang, X., Chen, T., Wang, J. and Cao, X.(2004) Splenic stroma drives mature dendritic cells to differentiate into regulatory dendritic cells. Nat. Immunol. 5, 1124-1133. https://doi.org/10.1038/ni1130
  67. Svensson, M., Maroof, A., Ato, M. and Kaye, P. M.(2004) Stromal cells direct local differentiation of regulatory dendritic cells. Immunity 21, 805-816. https://doi.org/10.1016/j.immuni.2004.10.012
  68. Benedict, C. A., De Trez, C., Schneider, K., Ha, S.,Patterson, G. and Ware, C. F. (2006) Specific remodeling of splenic architecture by cytomegalovirus. PLoS Pathog. 2, e16. https://doi.org/10.1371/journal.ppat.0020016
  69. Donaghy, H., Pozniak, A., Gazzard, B., Qazi, N.,Gilmour, J., Gotch, F. and Patterson, S. (2001) Loss of blood CD11c(+) myeloid and CD11c(-) plasmacytoid dendritic cells in patients with HIV-1 infection correlates with HIV-1 RNA virus load. Blood 98, 2574-2576. https://doi.org/10.1182/blood.V98.8.2574
  70. Pacanowski, J., Kahi, S., Baillet, M., Lebon, P., Deveau,C., Goujard, C., Meyer, L., Oksenhendler, E., Sinet, M. and Hosmalin, A. (2001) Reduced blood CD123+ (lymphoid) and CD11c+ (myeloid) dendritic cell numbers in primary HIV-1 infection. Blood 98, 3016-3021. https://doi.org/10.1182/blood.V98.10.3016
  71. Kanto, T., Inoue, M., Miyatake, H., Sato, A., Sakakibara,M., Yakushijin, T., Oki, C., Itose, I., Hiramatsu, N.,Takehara, T., Kasahara, A. and Hayashi, N. (2004) Reduced numbers and impaired ability of myeloid and plasmacytoid dendritic cells to polarize T helper cells in chronic hepatitis C virus infection. J. Infect. Dis. 190, 1919-1926. https://doi.org/10.1086/425425
  72. Smed-Sorensen, A., Lore, K., Vasudevan, J., Louder, M.K., Andersson, J., Mascola, J. R., Spetz, A. L. and Koup,R. A. (2005) Differential susceptibility to human immunodeficiency virus type 1 infection of myeloid and plasmacytoid dendritic cells. J. Virol. 79, 8861-8869. https://doi.org/10.1128/JVI.79.14.8861-8869.2005
  73. Lore, K., Smed-Sorensen, A., Vasudevan, J., Mascola, J.R. and Koup, R. A. (2005) Myeloid and plasmacytoid dendritic cells transfer HIV-1 preferentially to antigenspecific CD4+ T cells. J. Exp. Med. 201, 2023-2033. https://doi.org/10.1084/jem.20042413
  74. Schmitt, N., Nugeyre, M. T., Scott-Algara, D., Cumont,M. C., Barre-Sinoussi, F., Pancino, G. and Israel, N.(2006) Differential susceptibility of human thymic dendritic cell subsets to X4 and R5 HIV-1 infection. AIDS 20, 533-542. https://doi.org/10.1097/01.aids.0000210607.63138.bc
  75. Cameron, P. U., Handley, A. J., Baylis, D. C., Solomon,A. E., Bernard, N., Purcell, D. F. and Lewin, S. R. (2007) Preferential infection of dendritic cells during human immunodeficiency virus type 1 infection of blood leukocytes. J. Virol. 81, 2297-2306. https://doi.org/10.1128/JVI.01795-06
  76. Groot, F., van Capel, T. M., Kapsenberg, M. L.,Berkhout, B. and de Jong, E. C. (2006) Opposing roles of blood myeloid and plasmacytoid dendritic cells in HIV-1 infection of T cells: transmission facilitation versus replication inhibition. Blood 108, 1957-1964. https://doi.org/10.1182/blood-2006-03-010918
  77. Cavaleiro, R., Baptista, A. P., Soares, R. S., Tendeiro, R.,Foxall, R. B., Gomes, P., Victorino, R. M. and Sousa, A.E. (2009) Major depletion of plasmacytoid dendritic cells in HIV-2 infection, an attenuated form of HIV disease. PLoS Pathog. 5, e1000667. https://doi.org/10.1371/journal.ppat.1000667
  78. Blackburn, S. D., Crawford, A., Shin, H., Polley, A.,Freeman, G. J. and Wherry, E. J. (2010) Tissue-specific differences in PD-1 and PD-L1 expression during chronic viral infection: implications for CD8 T-cell exhaustion. J. Virol. 84, 2078-2089. https://doi.org/10.1128/JVI.01579-09
  79. Sevilla, N., Kunz, S., Holz, A., Lewicki, H., Homann, D.,Yamada, H., Campbell, K. P., de La Torre, J. C. andOldstone, M. B. (2000) Immunosuppression and resultant viral persistence by specific viral targeting of dendritic cells. J. Exp. Med. 192, 1249-1260. https://doi.org/10.1084/jem.192.9.1249
  80. Sevilla, N., Kunz, S., McGavern, D. and Oldstone, M. B.(2003) Infection of dendritic cells by lymphocytic choriomeningitis virus. Curr. Top. Microbiol. Immunol. 276, 125-144.
  81. Homann, D., McGavern, D. B. and Oldstone, M. B.(2004) Visualizing the viral burden: phenotypic and functional alterations of T cells and APCs during persistent infection. J. Immunol. 172, 6239-6250. https://doi.org/10.4049/jimmunol.172.10.6239
  82. Sevilla, N., McGavern, D. B., Teng, C., Kunz, S. andOldstone, M. B. (2004) Viral targeting of hematopoietic progenitors and inhibition of DC maturation as a dual strategy for immune subversion. J. Clin. Invest. 113, 737-745. https://doi.org/10.1172/JCI20243
  83. Wang, X., Zhang, Z., Zhang, S., Fu, J., Yao, J., Jiao, Y.,Wu, H. and Wang, F. S. (2008) B7-H1 up-regulation impairs myeloid DC and correlates with disease progression in chronic HIV-1 infection. Eur. J. Immunol. 38, 3226-3236. https://doi.org/10.1002/eji.200838285
  84. Rodrigue-Gervais, I. G., Rigsby, H., Jouan, L., Sauve, D.,Sekaly, R. P., Willems, B. and Lamarre, D. (2010)Dendritic cell inhibition is connected to exhaustion of CD8+ T cell polyfunctionality during chronic hepatitis C virus infection. J. Immunol. 184, 3134-3144. https://doi.org/10.4049/jimmunol.0902522
  85. Rodrigue-Gervais, I. G., Rigsby, H., Jouan, L., Sauve, D.,Sekaly, R. P., Willems, B. and Lamarre, D. (2010) Dendritic cell inhibition is connected to exhaustion of CD8+ T cell polyfunctionality during chronic hepatitis C virus infection. J. Immunol. 184, 3134-3144. https://doi.org/10.4049/jimmunol.0902522
  86. Chen, L., Zhang, Z., Chen, W., Li, Y., Shi, M., Zhang, J.,Wang, S. and Wang, F. S. (2007) B7-H1 up-regulation on myeloid dendritic cells significantly suppresses T cell immune function in patients with chronic hepatitis B. J. Immunol. 178, 6634-6641. https://doi.org/10.4049/jimmunol.178.10.6634
  87. Averill, L., Lee, W. M. and Karandikar, N. J. (2007)Differential dysfunction in dendritic cell subsets during chronic HCV infection. Clin. Immunol. 123, 40-49. https://doi.org/10.1016/j.clim.2006.12.001
  88. Probst, H. C., McCoy, K., Okazaki, T., Honjo, T. andvan den Broek, M. (2005) Resting dendritic cells induce peripheral CD8+ T cell tolerance through PD-1 and CTLA-4. Nat. Immunol. 6, 280-286.
  89. Curiel, T. J., Coukos, G., Zou, L. H., Alvarez, X., Cheng,P., Mottram, P., Evdemon-Hogan, M., Conejo-Garcia, J.R., Zhang, L., Burow, M., Zhu, Y., Wei, S., Kryczek, I.,Daniel, B., Gordon, A., Myers, L., Lackner, A., Disis, M.L., Knutson, K. L., Chen, L. P. and Zou, W. P. (2004) Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat. Med. 10, 942-949. https://doi.org/10.1038/nm1093
  90. Manches, O., Munn, D., Fallahi, A., Lifson, J., Chaperot,L., Plumas, J. and Bhardwaj, N. (2008) HIV-activated human plasmacytoid DCs induce Tregs through an indoleamine 2,3-dioxygenase-dependent mechanism. J. Clin. Invest. 118, 3431-3439. https://doi.org/10.1172/JCI34823
  91. Dolganiuc, A., Paek, E., Kodys, K., Thomas, J. andSzabo, G. (2008) Myeloid dendritic cells of patients with chronic HCV infection induce proliferation of regulatory T lymphocytes. Gastroenterology 135, 2119-2127. https://doi.org/10.1053/j.gastro.2008.07.082
  92. Sharma, M. D., Baban, B., Chandler, P., Hou, D. Y.,Singh, N., Yagita, H., Azuma, M., Blazar, B. R., Mellor,A. L. and Munn, D. H. (2007) Plasmacytoid dendritic cells from mouse tumor draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase. J. Clin. Invest. 117, 2570-2582. https://doi.org/10.1172/JCI31911
  93. Asselin-Paturel, C. and Trinchieri, G. (2005) Production of type I interferons: plasmacytoid dendritic cells and beyond. J. Exp. Med. 202, 461-465. https://doi.org/10.1084/jem.20051395
  94. McKenna, K., Beignon, A. S. and Bhardwaj, N. (2005) Plasmacytoid dendritic cells: linking innate and adaptive immunity. J. Virol. 79, 17-27. https://doi.org/10.1128/JVI.79.1.17-27.2005
  95. Liu, Y. J. (2005) IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors. Annu. Rev. Immunol. 23, 275-306. https://doi.org/10.1146/annurev.immunol.23.021704.115633
  96. Zuniga, E. I., Liou, L. Y., Mack, L., Mendoza, M. andOldstone, M. B. (2008) Persistent virus infection inhibits type I interferon production by plasmacytoid dendritic cells to facilitate opportunistic infections. Cell Host. Microbe 4, 374-386. https://doi.org/10.1016/j.chom.2008.08.016
  97. Schlender, J., Hornung, V., Finke, S., Gunthner-Biller,M., Marozin, S., Brzozka, K., Moghim, S., Endres, S.,Hartmann, G. and Conzelmann, K. K. (2005) Inhibition of toll-like receptor 7- and 9-mediated alpha/beta interferon production in human plasmacytoid dendritic cells by respiratory syncytial virus and measles virus. J. Virol. 79, 5507-5515. https://doi.org/10.1128/JVI.79.9.5507-5515.2005
  98. Seo, Y. J. and Hahm, B. (2010) Type I interferon modulates the battle of host immune system against viruses. Adv. Appl. Microbiol. 73, 83-101. https://doi.org/10.1016/S0065-2164(10)73004-5
  99. Hori, S., Nomura, T. and Sakaguchi, S. (2003) Control of regulatory T cell development by the transcription factor Foxp.3. Science 299, 1057-1061. https://doi.org/10.1126/science.1079490
  100. Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M. andToda, M. (1995) 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. 155, 1151-1164.
  101. Feuerer, M., Hill, J. A., Mathis, D. and Benoist, C. (2009)Foxp3(+) regulatory T cells: differentiation, specification, subphenotypes. Nat. Immunol. 10, 689-695. https://doi.org/10.1038/ni.1760
  102. Sakaguchi, S., Wing, K., Onishi, Y., Prieto-Martin, P. andYamaguchi, T. (2009) Regulatory T cells: how do they suppress immune responses? Int. Immunol. 21, 1105-1111. https://doi.org/10.1093/intimm/dxp095
  103. Vignali, D. A., Collison, L. W. and Workman, C. J.(2008) How regulatory T cells work. Nat. Rev. Immunol. 8, 523-532. https://doi.org/10.1038/nri2343
  104. Collison, L. W., Workman, C. J., Kuo, T. T., Boyd, K.,Wang, Y., Vignali, K. M., Cross, R., Sehy, D., Blumberg,R. S. and Vignali, D. A. (2007) The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 450, 566-569. https://doi.org/10.1038/nature06306
  105. Gondek, D. C., Lu, L. F., Quezada, S. A., Sakaguchi, S.and Noelle, R. J. (2005) Cutting edge: contact-mediated suppression by CD4+CD25+ regulatory cells involves a granzyme B-dependent, perforin-independent mechanism. J. Immunol. 174, 1783-1786. https://doi.org/10.4049/jimmunol.174.4.1783
  106. Grossman, W. J., Verbsky, J. W., Tollefsen, B. L.,Kemper, C., Atkinson, J. P. and Ley, T. J. (2004) Differential expression of granzymes A and B in human cytotoxic lymphocyte subsets and T regulatory cells. Blood 104, 2840-2848. https://doi.org/10.1182/blood-2004-03-0859
  107. de la Rosa, M., Rutz, S., Dorninger, H. and Scheffold, A.(2004) Interleukin-2 is essential for CD4+CD25+ regulatory T cell function. Eur. J. Immunol. 34, 2480-2488. https://doi.org/10.1002/eji.200425274
  108. Thornton, A. M. and Shevach, E. M. (1998) CD4+ CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J. Exp. Med. 188, 287-296. https://doi.org/10.1084/jem.188.2.287
  109. Barboza, L., Salmen, S., Goncalves, L., Colmenares, M.,Peterson, D., Montes, H., Cartagirone, R., Gutierrez, M.D. and Berrueta, L. (2007) Antigen-induced regulatory T cells in HBV chronically infected patients. Virology 368, 41-49. https://doi.org/10.1016/j.virol.2007.06.030
  110. Annacker, O., Asseman, C., Read, S. and Powrie, F.(2003) Interleukin-10 in the regulation of T cell-induced colitis. J. Autoimmun. 20, 277-279. https://doi.org/10.1016/S0896-8411(03)00045-3
  111. Dieckmann, D., Plottner, H., Berchtold, S., Berger, T.and Schuler, G. (2001) Ex vivo isolation and characterization of CD4(+)CD25(+) T cells with regulatory properties from human blood. J. Exp. Med. 193, 1303-1310. https://doi.org/10.1084/jem.193.11.1303
  112. Hawrylowicz, C. M. and O'Garra, A. (2005) Potential role of interleukin-10-secreting regulatory T cells in allergy and asthma. Nat. Rev. Immunol. 5, 271-283. https://doi.org/10.1038/nri1589
  113. Jonuleit, H., Schmitt, E., Stassen, M., Tuettenberg, A.,Knop, J. and Enk, A. H. (2001) Identification and functional characterization of human CD4(+)CD25(+) T cells with regulatory properties isolated from peripheral blood. J. Exp. Med. 193, 1285-1294. https://doi.org/10.1084/jem.193.11.1285
  114. Chen, W., Jin, W., Hardegen, N., Lei, K. J., Li, L.,Marinos, N., McGrady, G. and Wahl, S. M. (2003) Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J. Exp. Med. 198, 1875-1886. https://doi.org/10.1084/jem.20030152
  115. Lohr, J., Knoechel, B. and Abbas, A. K. (2006) Regulatory T cells in the periphery. Immunol. Rev. 212, 149-162. https://doi.org/10.1111/j.0105-2896.2006.00414.x
  116. Grainger, J. R., Smith, K. A., Hewitson, J. P., McSorley,H. J., Harcus, Y., Filbey, K. J., Finney, C. A., Greenwood,E. J., Knox, D. P., Wilson, M. S., Belkaid, Y., Rudensky,A. Y. and Maizels, R. M. (2010) Helminth secretions induce de novo T cell Foxp3 expression and regulatory function through the TGF-beta pathway. J. Exp. Med. 207, 2331-2341. https://doi.org/10.1084/jem.20101074
  117. Layland, L. E., Mages, J., Loddenkemper, C., Hoerauf, A.,Wagner, H., Lang, R. and da Costa, C. U. (2010) Pronounced phenotype in activated regulatory T cells during a chronic helminth infection. J. Immunol. 184, 713-724. https://doi.org/10.4049/jimmunol.0901435
  118. Johanns, T. M., Ertelt, J. M., Rowe, J. H. and Way, S. S.(2010) Regulatory T Cell Suppressive Potency Dictates the Balance between Bacterial Proliferation and Clearance during Persistent Salmonella Infection. PLoS Pathog. 6, e1001043. https://doi.org/10.1371/journal.ppat.1001043
  119. Majlessi, L., Lo-Man, R. and Leclerc, C. (2008) Regulatory B and T cells in infections. Microbes Infect. 10, 1030-1035. https://doi.org/10.1016/j.micinf.2008.07.017
  120. Shafiani, S., Tucker-Heard, G., Kariyone, A., Takatsu, K.and Urdahl, K. B. (2010) Pathogen-specific regulatory T cells delay the arrival of effector T cells in the lung during early tuberculosis. J. Exp. Med. 207, 1409-1420. https://doi.org/10.1084/jem.20091885
  121. Xu, D. P., Fu, J. L., Jin, L., Zhang, H., Zhou, C. B., Zou,Z. S., Zhao, J. M., Zhang, B., Shi, M., Ding, X. L., Tang,Z. R., Fu, Y. X. and Wang, F. S. (2006) Circulating and liver resident CD4(+)CD25(+) regulatory T cells actively influence the antiviral immune response and disease progression in patients with hepatitis B-1. J. Immunol. 177, 739-747. https://doi.org/10.4049/jimmunol.177.1.739
  122. Franzese, O., Kennedy, P. T., Gehring, A. J., Gotto, J.,Williams, R., Maini, M. K. and Bertoletti, A. (2005) Modulation of the CD8+-T-cell response by CD4+ CD25+ regulatory T cells in patients with hepatitis B virus infection. J. Virol. 79, 3322-3328. https://doi.org/10.1128/JVI.79.6.3322-3328.2005
  123. Accapezzato, D., Francavilla, V., Paroli, M., Casciaro,M., Chircu, L. V., Cividini, A., Abrignani, S., Mondelli, M. U. and Barnaba, V. (2004) Hepatic expansion of a virus-specific regulatory CD8(+) T cell population in chronic hepatitis C virus infection. J. Clin. Invest. 113, 963-972. https://doi.org/10.1172/JCI200420515
  124. Nakamoto, N., Cho, H., Shaked, A., Olthoff, K., Valiga,M. E., Kaminski, M., Gostick, E., Price, D. A., Freeman,G. J., Wherry, E. J. and Chang, K. M. (2009) Synergistic reversal of intrahepatic HCV-specific CD8 T cell exhaustion by combined PD-1/CTLA-4 blockade. PLoS Pathog. 5, e1000313. https://doi.org/10.1371/journal.ppat.1000313
  125. Boettler, T., Spangenberg, H. C., Neumann-Haefelin, C.,Panther, E., Urbani, S., Ferrari, C., Blum, H. E., vonWeizsacker, F. and Thimme, R. (2005) T cells with a CD4+CD25+ regulatory phenotype suppress in vitro proliferation of virus-specific CD8+ T cells during chronic hepatitis C virus infection. J. Virol. 79, 7860-7867. https://doi.org/10.1128/JVI.79.12.7860-7867.2005
  126. MacDonald, A. J., Duffy, M., Brady, M. T., McKiernan,S., Hall, W., Hegarty, J., Curry, M. and Mills, K. H.(2002) CD4 T helper type 1 and regulatory T cells induced against the same epitopes on the core protein in hepatitis C virus-infected persons. J. Infect. Dis. 185, 720-727. https://doi.org/10.1086/339340
  127. Ebinuma, H., Nakamoto, N., Li, Y., Price, D. A., Gostick,E., Levine, B. L., Tobias, J., Kwok, W. W. and Chang, K.M. (2008) Identification and in vitro expansion of functional antigen-specific CD25+ FoxP3+ regulatory T cells in hepatitis C virus infection. J. Virol. 82, 5043-5053. https://doi.org/10.1128/JVI.01548-07
  128. Bi, X., Suzuki, Y., Gatanaga, H. and Oka, S. (2009) High frequency and proliferation of CD4+ FOXP3+ Treg in HIV-1-infected patients with low CD4 counts. Eur. J. Immunol. 39, 301-309. https://doi.org/10.1002/eji.200838667
  129. Nilsson, J., Boasso, A., Velilla, P. A., Zhang, R., Vaccari,M., Franchini, G., Shearer, G. M., Andersson, J. andChougnet, C. (2006) HIV-1-driven regulatory T-cell accumulation in lymphoid tissues is associated with disease progression in HIV/AIDS. Blood 108, 3808-3817. https://doi.org/10.1182/blood-2006-05-021576
  130. Kinter, A., McNally, J., Riggin, L., Jackson, R., Roby, G.and Fauci, A. S. (2007) Suppression of HIV-specific T cell activity by lymph node CD25+ regulatory T cells from HIV-infected individuals. Proc. Natl. Acad. Sci. U.S.A. 104, 3390-3395. https://doi.org/10.1073/pnas.0611423104
  131. Trandem, K., Anghelina, D., Zhao, J. X. and Perlman, S.(2010) Regulatory T Cells Inhibit T Cell Proliferation and Decrease Demyelination in Mice Chronically Infected with a Coronavirus. J. Immunol. 184, 4391-4400. https://doi.org/10.4049/jimmunol.0903918
  132. Dietze, K. K., Zelinskyy, G., Gibbert, K., Schimmer, S.,Francois, S., Myers, L., Sparwasser, T., Hasenkrug, K. J.and Dittmer, U. (2011) Transient depletion of regulatory T cells in transgenic mice reactivates virus-specific CD8+ T cells and reduces chronic retroviral set points. Proc. Natl. Acad. Sci. U.S.A. 108, 2420-2425. https://doi.org/10.1073/pnas.1015148108
  133. Dittmer, U., He, H., Messer, R. J., Schimmer, S.,Olbrich, A. R., Ohlen, C., Greenberg, P. D., Stromnes, I.M., Iwashiro, M., Sakaguchi, S., Evans, L. H., Peterson,K. E., Yang, G. and Hasenkrug, K. J. (2004) Functional impairment of CD8(+) T cells by regulatory T cells during persistent retroviral infection. Immunity 20, 293-303. https://doi.org/10.1016/S1074-7613(04)00054-8
  134. Myers, L., Messer, R. J., Carmody, A. B. and Hasenkrug,K. J. (2009) Tissue-Specific Abundance of Regulatory T Cells Correlates with CD8(+) T Cell Dysfunction and Chronic Retrovirus Loads. J. Immunol. 183, 1636-1643. https://doi.org/10.4049/jimmunol.0900350
  135. Robertson, S. J., Messer, R. J., Carmody, A. B. and Hasenkrug, K. J. (2006) In vitro suppression of CD8+ T cell function by Friend virus-induced regulatory T cells. J. Immunol. 176, 3342-3349. https://doi.org/10.4049/jimmunol.176.6.3342
  136. Zelinskyy, G., Kraft, A. R., Schimmer, S., Arndt, T. andDittmer, U. (2006) Kinetics of CD8+ effector T cell responses and induced CD4+ regulatory T cell responses during Friend retrovirus infection. Eur. J. Immunol. 36, 2658-2670. https://doi.org/10.1002/eji.200636059
  137. Punkosdy, G. A., Blain, M., Glass, D. D., Lozano, M. M.,O'Mara, L., Dudley, J. P., Ahmed, R. and Shevach, E. M.(2011) Regulatory T-cell expansion during chronic viral infection is dependent on endogenous retroviral superantigens. Proc. Natl. Acad. Sci. U.S.A. 108, 3677-3682. https://doi.org/10.1073/pnas.1100213108
  138. Liyanage, U. K., Moore, T. T., Joo, H. G., Tanaka, Y.,Herrmann, V., Doherty, G., Drebin, J. A., Strasberg, S.M., Eberlein, T. J., Goedegebuure, P. S. and Linehan, D.C. (2002) Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J. Immunol. 169, 2756-2761. https://doi.org/10.4049/jimmunol.169.5.2756
  139. Ormandy, L. A., Hillemann, T., Wedemeyer, H., Manns,M. P., Greten, T. F. and Korangy, F. (2005) Increased populations of regulatory T cells in peripheral blood of patients with hepatocellular carcinoma. Cancer Res. 65, 2457-2464. https://doi.org/10.1158/0008-5472.CAN-04-3232
  140. Unitt, E., Rushbrook, S. M., Marshall, A., Davies, S.,Gibbs, P., Morris, L. S., Coleman, N. and Alexander, G.J. (2005) Compromised lymphocytes infiltrate hepatocellular carcinoma: the role of T-regulatory cells. Hepatology 41, 722-730. https://doi.org/10.1002/hep.20644
  141. Viguier, M., Lemaitre, F., Verola, O., Cho, M. S., Gorochov,G., Dubertret, L., Bachelez, H., Kourilsky, P. andFerradini, L. (2004) Foxp3 expressing CD4+CD25(high) regulatory T cells are overrepresented in human metastatic melanoma lymph nodes and inhibit the function of infiltrating T cells. J. Immunol. 173, 1444-1453. https://doi.org/10.4049/jimmunol.173.2.1444
  142. Wang, H. Y., Lee, D. A., Peng, G., Guo, Z., Li, Y., Kiniwa, Y., Shevach, E. M. and Wang, R. F. (2004) Tumorspecific human CD4+ regulatory T cells and their ligands: implications for immunotherapy. Immunity 20, 107-118. https://doi.org/10.1016/S1074-7613(03)00359-5
  143. Wang, H. Y. and Wang, R. F. (2007) Regulatory T cells and cancer. Curr. Opin. Immunol. 19, 217-223. https://doi.org/10.1016/j.coi.2007.02.004
  144. Woo, E. Y., Chu, C. S., Goletz, T. J., Schlienger, K., Yeh,H., Coukos, G., Rubin, S. C., Kaiser, L. R. and June, C.H. (2001) Regulatory CD4(+)CD25(+) T cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer. Cancer Res. 61, 4766-4772.
  145. Woo, E. Y., Yeh, H., Chu, C. S., Schleinger, K., Carroll,R. G., Riley, J. L., Kaiser, L. R. and June, C. H. (2002)Cutting edge: Regulatory T cells from lung cancer patients directly inhibit autologous T cell proliferation. J. Immunol. 168, 4272-4276. https://doi.org/10.4049/jimmunol.168.9.4272
  146. Zou, W. (2006) Regulatory T cells, tumour immunity and immunotherapy. Nat. Rev. Immunol. 6, 295-307. https://doi.org/10.1038/nri1806
  147. Peggs, K. S., Quezada, S. A., Chambers, C. A., Korman,A. J. and Allison, J. P. (2009) Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies. J. Exp. Med. 206, 1717-1725. https://doi.org/10.1084/jem.20082492
  148. Camisaschi, C., Casati, C., Rini, F., Perego, M., DeFilippo, A., Rini, F., Parmiani, G., Belli, F., Rivoltini, L.and Castelli, C. (2010) LAG-3 expression defines a subset of CD4(+)CD25(high)Foxp3(+) regulatory T Cells that are expanded at tumor sites. J. Immunol. 184, 6545- 6551. https://doi.org/10.4049/jimmunol.0903879
  149. Krupnick, A. S., Gelman, A. E., Barchet, W., Richardson,S., Kreisel, F. H., Turka, L. A., Colonna, M., Patterson, G.A. and Kreisel, D. (2005) Murine vascular endothelium activates and induces the generation of allogeneic CD4+25+Foxp3+ regulatory T cells. J. Immunol. 175, 6265-6270. https://doi.org/10.4049/jimmunol.175.10.6265
  150. Lu, L., Zhou, X., Wang, J., Zheng, S. G. and Horwitz, D.A. (2010) Characterization of protective human CD4 CD25 FOXP3 regulatory T cells generated with IL-2, TGF-beta and retinoic acid. PLoS One 5, e15150. https://doi.org/10.1371/journal.pone.0015150
  151. Francisco, L. M., Salinas, V. H., Brown, K. E., Vanguri,V. K., Freeman, G. J., Kuchroo, V. K. and Sharpe, A. H.(2009) PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J. Exp. Med. 206, 3015-3029. https://doi.org/10.1084/jem.20090847
  152. Wang, W., Lau, R., Yu, D., Zhu, W., Korman, A. and Weber, J. (2009) PD1 blockade reverses the suppression of melanoma antigen-specific CTL by CD4+ CD25(Hi) regulatory T cells. Int. Immunol. 21, 1065-1077. https://doi.org/10.1093/intimm/dxp072
  153. Curran, M. A. and Allison, J. P. (2009) Tumor vaccines expressing flt3 ligand synergize with ctla-4 blockade to reject preimplanted tumors. Cancer Res. 69, 7747- 7755. https://doi.org/10.1158/0008-5472.CAN-08-3289
  154. Fong, L., Kwek, S. S., O'Brien, S., Kavanagh, B., McNeel,D. G., Weinberg, V., Lin, A. M., Rosenberg, J., Ryan, C.J., Rini, B. I. and Small, E. J. (2009) Potentiating endogenous antitumor immunity to prostate cancer through combination immunotherapy with CTLA4 blockade and GM-CSF. Cancer Res. 69, 609-615. https://doi.org/10.1158/0008-5472.CAN-08-3529
  155. Klages, K., Mayer, C. T., Lahl, K., Loddenkemper, C.,Teng, M. W., Ngiow, S. F., Smyth, M. J., Hamann, A.,Huehn, J. and Sparwasser, T. (2010) Selective depletion of Foxp3+ regulatory T cells improves effective therapeutic vaccination against established melanoma. Cancer Res. 70, 7788-7799. https://doi.org/10.1158/0008-5472.CAN-10-1736
  156. Mitsui, J., Nishikawa, H., Muraoka, D., Wang, L.,Noguchi, T., Sato, E., Kondo, S., Allison, J. P., Sakaguchi,S., Old, L. J., Kato, T. and Shiku, H. (2010) Two distinct mechanisms of augmented antitumor activity by modulation of immunostimulatory/inhibitory signals. Clin. Cancer Res. 16, 2781-2791. https://doi.org/10.1158/1078-0432.CCR-09-3243
  157. Tuve, S., Chen, B. M., Liu, Y., Cheng, T. L., Toure, P.,Sow, P. S., Feng, Q., Kiviat, N., Strauss, R., Ni, S., Li, Z.Y., Roffler, S. R. and Lieber, A. (2007) Combination of tumor site-located CTL-associated antigen-4 blockade and systemic regulatory T-cell depletion induces tumor- destructive immune responses. Cancer Res. 67, 5929-5939. https://doi.org/10.1158/0008-5472.CAN-06-4296
  158. Moore, K. W., de Waal Malefyt, R., Coffman, R. L. andO'Garra, A. (2001) Interleukin-10 and the interleukin-10 receptor. Annu. Rev. Immunol. 19, 683-765.
  159. Pestka, S., Krause, C. D., Sarkar, D., Walter, M. R., Shi,Y. and Fisher, P. B. (2004) Interleukin-10 and related cytokines and receptors. Annu. Rev. Immunol. 22, 929-979. https://doi.org/10.1146/annurev.immunol.22.012703.104622
  160. Brockman, M. A., Kwon, D. S., Tighe, D. P., Pavlik, D.F., Rosato, P. C., Sela, J., Porichis, F., Le Gall, S.,Waring, M. T., Moss, K., Jessen, H., Pereyra, F.,Kavanagh, D. G., Walker, B. D. and Kaufmann, D. E.(2009) IL-10 is up-regulated in multiple cell types during viremic HIV infection and reversibly inhibits virus-specific T cells. Blood 114, 346-356. https://doi.org/10.1182/blood-2008-12-191296
  161. Brooks, D. G., Trifilo, M. J., Edelmann, K. H., Teyton, L.,McGavern, D. B. and Oldstone, M. B. (2006) Interleukin- 10 determines viral clearance or persistence in vivo. Nat. Med. 12, 1301-1309. https://doi.org/10.1038/nm1492
  162. Clerici, M., Wynn, T. A., Berzofsky, J. A., Blatt, S. P.,Hendrix, C. W., Sher, A., Coffman, R. L. and Shearer, G.M. (1994) Role of interleukin-10 in T helper cell dysfunction in asymptomatic individuals infected with the human immunodeficiency virus. J. Clin. Invest. 93, 768-775. https://doi.org/10.1172/JCI117031
  163. Ejrnaes, M., Filippi, C. M., Martinic, M. M., Ling, E. M.,Togher, L. M., Crotty, S. and von Herrath, M. G. (2006) Resolution of a chronic viral infection after interleukin- 10 receptor blockade. J. Exp. Med. 203, 2461-2472. https://doi.org/10.1084/jem.20061462
  164. Hyodo, N., Nakamura, I. and Imawari, M. (2004) Hepatitis B core antigen stimulates interleukin-10 secretion by both T cells and monocytes from peripheral blood of patients with chronic hepatitis B virus infection. Clin. Exp. Immunol. 135, 462-466. https://doi.org/10.1111/j.1365-2249.2003.02376.x
  165. Kaplan, D. E., Ikeda, F., Li, Y., Nakamoto, N., Ganesan,S., Valiga, M. E., Nunes, F. A., Rajender Reddy, K. andChang, K. M. (2008) Peripheral virus-specific T-cell interleukin- 10 responses develop early in acute hepatitis C infection and become dominant in chronic hepatitis. J. Hepatol. 48, 903-913. https://doi.org/10.1016/j.jhep.2008.01.030
  166. Maris, C. H., Chappell, C. P. and Jacob, J. (2007) Interleukin-10 plays an early role in generating virus-specific T cell anergy. BMC Immunol. 8, 8. https://doi.org/10.1186/1471-2172-8-8
  167. Ohga, S., Nomura, A., Takada, H., Tanaka, T., Furuno, K., Takahata, Y., Kinukawa, N., Fukushima, N., Imai, S.and Hara, T. (2004) Dominant expression of interleukin-10 and transforming growth factor-beta genes in activated T-cells of chronic active Epstein-Barr virus infection. J. Med. Virol. 74, 449-458. https://doi.org/10.1002/jmv.20197
  168. Alatrakchi, N., Graham, C. S., van der Vliet, H. J.,Sherman, K. E., Exley, M. A. and Koziel, M. J. (2007) Hepatitis C virus (HCV)-specific CD8+ cells produce transforming growth factor beta that can suppress HCVspecific T-cell responses. J. Virol. 81, 5882-5892. https://doi.org/10.1128/JVI.02202-06
  169. Li, M. O., Sanjabi, S. and Flavell, R. A. (2006) Transforming growth factor-beta controls development, homeostasis, and tolerance of T cells by regulatory T cell-dependent and -independent mechanisms. Immunity 25, 455-471. https://doi.org/10.1016/j.immuni.2006.07.011
  170. Gorelik, L. and Flavell, R. A. (2002) Transforming growth factor-beta in T-cell biology. Nat. Rev. Immunol. 2, 46-53. https://doi.org/10.1038/nri704
  171. Li, M. O. and Flavell, R. A. (2008) TGF-beta: a master of all T cell trades. Cell 134, 392-404. https://doi.org/10.1016/j.cell.2008.07.025
  172. Tinoco, R., Alcalde, V., Yang, Y., Sauer, K. and Zuniga,E. I. (2009) Cell-intrinsic transforming growth factor-beta signaling mediates virus-specific CD8+ T cell deletion and viral persistence in vivo. Immunity 31, 145-157. https://doi.org/10.1016/j.immuni.2009.06.015
  173. Whiteside, T. L. (2010) Immune responses to malignancies. J. Allergy. Clin. Immunol. 125, S272-283. https://doi.org/10.1016/j.jaci.2009.09.045
  174. Kruger-Krasagakes, S., Krasagakis, K., Garbe, C., Schmitt,E., Huls, C., Blankenstein, T. and Diamantstein, T. (1994) Expression of interleukin 10 in human melanoma. Br. J. Cancer 70, 1182-1185. https://doi.org/10.1038/bjc.1994.469
  175. Steinbrink, K., Jonuleit, H., Muller, G., Schuler, G., Knop,J. and Enk, A. H. (1999) Interleukin-10-treated human dendritic cells induce a melanoma-antigen-specific anergy in CD8(+) T cells resulting in a failure to lyse tumor cells. Blood 93, 1634-1642.
  176. Qin, Z., Noffz, G., Mohaupt, M. and Blankenstein, T.(1997) Interleukin-10 prevents dendritic cell accumulation and vaccination with granulocyte-macrophage colony-stimulating factor gene-modified tumor cells. J. Immunol. 159, 770-776.
  177. Gorelik, L. and Flavell, R. A. (2001) Immune-mediated eradication of tumors through the blockade of transforming growth factor-beta signaling in T cells. Nat. Med. 7, 1118-1122. https://doi.org/10.1038/nm1001-1118
  178. Gajewski, T. F., Meng, Y., Blank, C., Brown, I., Kacha,A., Kline, J. and Harlin, H. (2006) Immune resistance orchestrated by the tumor microenvironment. Immunol. Rev. 213, 131-145. https://doi.org/10.1111/j.1600-065X.2006.00442.x

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