Mechanism of T cell exhaustion in a chronic environment

  • Accepted : 2011.03.28
  • Published : 2011.04.30


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.


Cancer;Chronic pathogen;T cell exhaustion;T cell immune response


  1. Badovinac, V. P. and Harty, J. T. (2002) CD8(+) T-cell homeostasis after infection: setting the 'curve'. Microbes Infect. 4, 441-447.
  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.
  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.
  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.
  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.
  6. Wherry, E. J. and Ahmed, R. (2004) Memory CD8 T-cell differentiation during viral infection. J. Virol. 78, 5535-5545.
  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.
  8. Schluns, K. S. and Lefrancois, L. (2003) Cytokine control of memory T-cell development and survival. Nat. Rev. Immunol. 3, 269-279.
  9. Klenerman, P. and Hill, A. (2005) T cells and viral persistence: lessons from diverse infections. Nat. Immunol. 6, 873-879.
  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.
  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.
  13. Coussens, L. M. and Werb, Z. (2002) Inflammation and cancer. Nature 420, 860-867.
  14. Virgin, H. W., Wherry, E. J. and Ahmed, R. (2009) Redefining chronic viral infection. Cell 138, 30-50.
  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.
  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.
  17. Wherry, E. J., Blattman, J. N., Murali-Krishna, K., van der Most, 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.
  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.
  19. Shin, H. and Wherry, E. J. (2007) CD8 T cell dysfunction during chronic viral infection. Curr. Opin. Immunol. 19, 408-415.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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. and Grakoui, 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.
  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.
  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.
  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.
  36. D'Souza, M., Fontenot, A. P., Mack, D. G., Lozupone, C., Dillon, S., Meditz, A., Wilson, C. C., Connick, E. and Palmer, 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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  57. Abbas, A. K. and Sharpe, A. H. (2005) Dendritic cells giveth and taketh away. Nat. Immunol. 6, 227-228.
  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.
  59. Redpath, S., Angulo, A., Gascoigne, N. R. and Ghazal, P. (2001) Immune checkpoints in viral latency. Annu. Rev. Microbiol. 55, 531-560.
  60. Tortorella, D., Gewurz, B., Schust, D., Furman, M. and Ploegh, H. (2000) Down-regulation of MHC class I antigen presentation by HCMV; lessons for tumor immunology. Immunol. Invest. 29, 97-100.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  79. Sevilla, N., Kunz, S., Holz, A., Lewicki, H., Homann, D., Yamada, H., Campbell, K. P., de La Torre, J. C. and Oldstone, M. B. (2000) Immunosuppression and resultant viral persistence by specific viral targeting of dendritic cells. J. Exp. Med. 192, 1249-1260.
  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.
  82. Sevilla, N., McGavern, D. B., Teng, C., Kunz, S. and Oldstone, 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.
  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.
  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.
  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.
  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.
  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.
  88. Probst, H. C., McCoy, K., Okazaki, T., Honjo, T. and van 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.
  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.
  91. Dolganiuc, A., Paek, E., Kodys, K., Thomas, J. and Szabo, G. (2008) Myeloid dendritic cells of patients with chronic HCV infection induce proliferation of regulatory T lymphocytes. Gastroenterology 135, 2119-2127.
  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.
  93. Asselin-Paturel, C. and Trinchieri, G. (2005) Production of type I interferons: plasmacytoid dendritic cells and beyond. J. Exp. Med. 202, 461-465.
  94. McKenna, K., Beignon, A. S. and Bhardwaj, N. (2005) Plasmacytoid dendritic cells: linking innate and adaptive immunity. J. Virol. 79, 17-27.
  95. Liu, Y. J. (2005) IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors. Annu. Rev. Immunol. 23, 275-306.
  96. Zuniga, E. I., Liou, L. Y., Mack, L., Mendoza, M. and Oldstone, 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.
  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.
  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.
  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.
  100. Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M. and Toda, 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.
  102. Sakaguchi, S., Wing, K., Onishi, Y., Prieto-Martin, P. and Yamaguchi, T. (2009) Regulatory T cells: how do they suppress immune responses? Int. Immunol. 21, 1105-1111.
  103. Vignali, D. A., Collison, L. W. and Workman, C. J. (2008) How regulatory T cells work. Nat. Rev. Immunol. 8, 523-532.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  115. Lohr, J., Knoechel, B. and Abbas, A. K. (2006) Regulatory T cells in the periphery. Immunol. Rev. 212, 149-162.
  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.
  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.
  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.
  119. Majlessi, L., Lo-Man, R. and Leclerc, C. (2008) Regulatory B and T cells in infections. Microbes Infect. 10, 1030-1035.
  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.
  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.
  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.
  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.
  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.
  125. Boettler, T., Spangenberg, H. C., Neumann-Haefelin, C., Panther, E., Urbani, S., Ferrari, C., Blum, H. E., von Weizsacker, 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.
  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.
  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.
  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.
  129. Nilsson, J., Boasso, A., Velilla, P. A., Zhang, R., Vaccari, M., Franchini, G., Shearer, G. M., Andersson, J. and Chougnet, C. (2006) HIV-1-driven regulatory T-cell accumulation in lymphoid tissues is associated with disease progression in HIV/AIDS. Blood 108, 3808-3817.
  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.
  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.
  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.
  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.
  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.
  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.
  136. Zelinskyy, G., Kraft, A. R., Schimmer, S., Arndt, T. and Dittmer, 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.
  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.
  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.
  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.
  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.
  141. Viguier, M., Lemaitre, F., Verola, O., Cho, M. S., Gorochov, G., Dubertret, L., Bachelez, H., Kourilsky, P. and Ferradini, 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.
  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.
  143. Wang, H. Y. and Wang, R. F. (2007) Regulatory T cells and cancer. Curr. Opin. Immunol. 19, 217-223.
  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.
  146. Zou, W. (2006) Regulatory T cells, tumour immunity and immunotherapy. Nat. Rev. Immunol. 6, 295-307.
  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.
  148. Camisaschi, C., Casati, C., Rini, F., Perego, M., De Filippo, 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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  158. Moore, K. W., de Waal Malefyt, R., Coffman, R. L. and O'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.
  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.
  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.
  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.
  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.
  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.
  165. Kaplan, D. E., Ikeda, F., Li, Y., Nakamoto, N., Ganesan, S., Valiga, M. E., Nunes, F. A., Rajender Reddy, K. and Chang, 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.
  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.
  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.
  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.
  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.
  170. Gorelik, L. and Flavell, R. A. (2002) Transforming growth factor-beta in T-cell biology. Nat. Rev. Immunol. 2, 46-53.
  171. Li, M. O. and Flavell, R. A. (2008) TGF-beta: a master of all T cell trades. Cell 134, 392-404.
  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.
  173. Whiteside, T. L. (2010) Immune responses to malignancies. J. Allergy. Clin. Immunol. 125, S272-283.
  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.
  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.
  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.

Cited by

  1. Modulation of regulatory T-cell activity in combination with interleukin-12 increases hepatic tolerogenicity in woodchucks with chronic hepatitis B vol.56, pp.2, 2012,
  2. Control of regulatory T cells is necessary for vaccine-like effects of antiviral immunotherapy by monoclonal antibodies vol.121, pp.7, 2013,
  3. Impairment of T Cell Function in Parasitic Infections vol.8, pp.2, 2014,
  4. Increased proportions of functionally impaired regulatory T cell subsets in systemic sclerosis 2017,
  5. The changing immune system in sepsis vol.5, pp.1, 2014,
  6. Increased Frequency of CD49b/LAG-3+Type 1 Regulatory T Cells in HIV-Infected Individuals vol.31, pp.12, 2015,
  7. A Parameter for IL-10 and TGF-ß Mediated Regulation of HIV-1 Specific T Cell Activation Provides Novel Information and Relates to Progression Markers vol.9, pp.1, 2014,
  8. T-cell exhaustion in allograft rejection and tolerance vol.20, pp.1, 2015,
  9. Enhancing immunogenicity and cross-reactivity of HIV-1 antigens by in vivo targeting to dendritic cells vol.7, pp.10, 2012,
  10. Salmonella impairs CD8 T cell response through PD-1: PD-L axis vol.220, pp.12, 2015,
  11. Salmonella induces PD-L1 expression in B cells vol.167, pp.2, 2015,
  12. Immunological function of Langerhans cells in HIV infection vol.87, pp.2, 2017,
  13. c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) are involved in Mycobacterium tuberculosis-induced expression of Leukotactin-1 vol.45, pp.10, 2012,
  14. Revisiting Immune-Based Therapies for Aggressive Follicular Cell–Derived Thyroid Cancers vol.23, pp.5, 2013,
  15. Negative Regulation of Type I IFN Expression by OASL1 Permits Chronic Viral Infection and CD8+ T-Cell Exhaustion vol.9, pp.7, 2013,
  16. Contribution of HIV infection to mortality among cancer patients in Uganda vol.27, pp.18, 2013,
  17. Enhancing T Cell Immune Responses by B Cell-based Therapeutic Vaccine Against Chronic Virus Infection vol.14, pp.4, 2014,
  18. CD8+ T cells of chronic HCV-infected patients express multiple negative immune checkpoints following stimulation with HCV peptides vol.313, 2017,
  19. The dynamics of T cells during persistentStaphylococcus aureusinfection: from antigen-reactivity toin vivoanergy vol.3, pp.11, 2011,
  20. In vitro T-cell profile induced by BCG Moreau in healthy Brazilian volunteers vol.11, pp.2, 2015,
  21. Cytokine production and dysregulation in HIV pathogenesis: Lessons for development of therapeutics and vaccines vol.23, pp.4-5, 2012,
  22. Clinically feasible approaches to potentiating cancer cell-based immunotherapies vol.11, pp.4, 2015,
  23. Regulation of immunity during visceral Leishmania infection vol.9, pp.1, 2016,
  24. Frequency and functional characterization of exhausted CD8+ T cells in chronic lymphocytic leukemia vol.98, pp.6, 2017,
  25. Tumor-infiltrating regulatory T cells delineated by upregulation of PD-1 and inhibitory receptors vol.278, pp.1-2, 2012,
  26. Differentiation of Antigen-Specific T Cells with Limited Functional Capacity during Mycobacterium tuberculosis Infection vol.82, pp.1, 2013,
  27. Purging Exhausted Virus-Specific CD8 T Cell Phenotypes by Somatic Cell Reprogramming vol.33, pp.S1, 2017,
  28. T cells and cytokines in systemic sclerosis pp.1040-8711, 2018,
  29. Molecular signatures of T-cell inhibition in HIV-1 infection vol.10, pp.1, 2013,