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Immunosuppressive Mechanisms During Viral Infectious Diseases

  • Ghanashyam Sarikonda
  • Matthias G. von HerrathEmail author
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 677)

Abstract

For a virus to establish persistence in the host, it has to exploit the host immune system such that the active T-cell responses against the virus are curbed. On the other hand, the goal of the immune system is to clear the virus, following which the immune responses need to be downregulated, by a process known as immunoregulation. There are multiple known immunoregulatory mechanisms that appear to play a role in persistent viral infections. In the recent past, IL-10 and PD-1 have been identified to be playing a significant role in the regulation of antiviral immune responses. The evidence that viruses can escape immunologic attack by taking advantage of the host’s immune system is found in LCMV infection of mice and in humans persistently infected with HIV and HCV. The recent observation that the functionally inactive T-cells during chronic viral infections can be made to regain their cytokine secretion and cytolytic abilities is very encouraging. Thus, it would be likely that neutralization negative immune regulation during persistent viral infection would result in the preservation of effector T-cell responses against the virus, thereby resulting in the elimination of the persistent infection.

Key words

Immunoregulation Persistent infection IL-10 PD-1 LCMV 

References

  1. 1.
    Oldstone, M. B. (2009) Anatomy of viral persistence, PLoS Pathog 5, e1000523.PubMedCrossRefGoogle Scholar
  2. 2.
    McGill, J., Heusel, J. W., and Legge, K. L. (2009) Innate immune control and regulation of influenza virus infections, J Leukoc Biol 86, 803–812.PubMedCrossRefGoogle Scholar
  3. 3.
    Khanolkar, A., Hartwig, S. M., Haag, B. A., Meyerholz, D. K., Epping, L. L., Haring, J. S., Varga, S. M., and Harty, J. T. (2009) Protective and pathologic roles of the immune response to mouse hepatitis virus type 1: implications for severe acute respiratory syndrome, J Virol 83, 9258–9272.PubMedCrossRefGoogle Scholar
  4. 4.
    Fung-Leung, W. P., Kundig, T. M., Zinkernagel, R. M., and Mak, T. W. (1991) Immune response against lymphocytic choriomeningitis virus infection in mice without CD8 expression, J Exp Med 174, 1425–1429.PubMedCrossRefGoogle Scholar
  5. 5.
    Gottwein, E., and Cullen, B. R. (2008) Viral and cellular microRNAs as determinants of viral pathogenesis and immunity, Cell Host Microbe 3, 375–387.PubMedCrossRefGoogle Scholar
  6. 6.
    Huang, J., Wang, F., Argyris, E., Chen, K., Liang, Z., Tian, H., Huang, W., Squires, K., Verlinghieri, G., and Zhang, H. (2007) Cellular microRNAs contribute to HIV-1 latency in resting primary CD4+ T lymphocytes, Nat Med 13, 1241–1247.PubMedCrossRefGoogle Scholar
  7. 7.
    de Jong, M. D., Simmons, C. P., Thanh, T. T., Hien, V. M., Smith, G. J., Chau, T. N., Hoang, D. M., Chau, N. V., Khanh, T. H., Dong, V. C., Qui, P. T., Cam, B. V., Ha do, Q., Guan, Y., Peiris, J. S., Chinh, N. T., Hien, T. T., and Farrar, J. (2006) Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia, Nat Med 12, 1203–1207.PubMedCrossRefGoogle Scholar
  8. 8.
    Cameron, M. J., Ran, L., Xu, L., Danesh, A., Bermejo-Martin, J. F., Cameron, C. M., Muller, M. P., Gold, W. L., Richardson, S. E., Poutanen, S. M., Willey, B. M., DeVries, M. E., Fang, Y., Seneviratne, C., Bosinger, S. E., Persad, D., Wilkinson, P., Greller, L. D., Somogyi, R., Humar, A., Keshavjee, S., Louie, M., Loeb, M. B., Brunton, J., McGeer, A. J., and Kelvin, D. J. (2007) Interferon-mediated immunopathological events are associated with atypical innate and adaptive immune responses in patients with severe acute respiratory syndrome, J Virol 81, 8692–8706.PubMedCrossRefGoogle Scholar
  9. 9.
    Jones, B. M., Ma, E. S., Peiris, J. S., Wong, P. C., Ho, J. C., Lam, B., Lai, K. N., and Tsang, K. W. (2004) Prolonged disturbances of in vitro cytokine production in patients with severe acute respiratory syndrome (SARS) treated with ribavirin and steroids, Clin Exp Immunol 135, 467–473.PubMedCrossRefGoogle Scholar
  10. 10.
    Hussell, T., Pennycook, A., and Openshaw, P. J. (2001) Inhibition of tumor necrosis factor reduces the severity of virus-specific lung immunopathology, Eur J Immunol 31, 2566–2573.PubMedCrossRefGoogle Scholar
  11. 11.
    Oldstone, M. B. (2002) Biology and pathogenesis of lymphocytic choriomeningitis virus infection, Curr Top Microbiol Immunol 263, 83–117.PubMedCrossRefGoogle Scholar
  12. 12.
    Suvas, S., Azkur, A. K., Kim, B. S., Kumaraguru, U., and Rouse, B. T. (2004) CD4+CD25+ regulatory T cells control the severity of viral immunoinflammatory lesions, J Immunol 172, 4123–4132.PubMedGoogle Scholar
  13. 13.
    De Albuquerque, N., Baig, E., Ma, X., Zhang, J., He, W., Rowe, A., Habal, M., Liu, M., Shalev, I., Downey, G. P., Gorczynski, R., Butany, J., Leibowitz, J., Weiss, S. R., McGilvray, I. D., Phillips, M. J., Fish, E. N., and Levy, G. A. (2006) Murine hepatitis virus strain 1 produces a clinically relevant model of severe acute respiratory syndrome in A/J mice, J Virol 80, 10382–10394.PubMedCrossRefGoogle Scholar
  14. 14.
    Bot, A., Rodrigo, E., Wolfe, T., Bot, S., and Von Herrath, M. G. (2003) Infection-triggered regulatory mechanisms override the role of STAT 4 in control of the immune response to influenza virus antigens, J Virol 77, 5794–5800.PubMedCrossRefGoogle Scholar
  15. 15.
    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.PubMedCrossRefGoogle Scholar
  16. 16.
    Ejrnaes, M., von Herrath, M. G., and Christen, U. (2006) Cure of chronic viral infection and virus-induced type 1 diabetes by neutralizing antibodies, Clin Dev Immunol 13, 337–347.PubMedCrossRefGoogle Scholar
  17. 17.
    Filippi, C. M., and von Herrath, M. G. (2008) IL-10 and the resolution of infections, J Pathol 214, 224–230.PubMedCrossRefGoogle Scholar
  18. 18.
    Homann, D., Dummer, W., Wolfe, T., Rodrigo, E., Theofilopoulos, A. N., Oldstone, M. B., and von Herrath, M. G. (2006) Lack of intrinsic CTLA-4 expression has minimal effect on regulation of antiviral T-cell immunity, J Virol 80, 270–280.PubMedCrossRefGoogle Scholar
  19. 19.
    von Herrath, M. G., Berger, D. P., Homann, D., Tishon, T., Sette, A., and Oldstone, M. B. (2000) Vaccination to treat persistent viral infection, Virology 268, 411–419.CrossRefGoogle Scholar
  20. 20.
    Wolfe, T., Asseman, C., Hughes, A., Matsue, H., Takashima, A., and von Herrath, M. G. (2002) Reduction of antiviral CD8 lymphocytes in vivo with dendritic cells expressing Fas ligand-increased survival of viral (lymphocytic choriomeningitis virus) central nervous system infection, J Immunol 169, 4867–4872.PubMedGoogle Scholar
  21. 21.
    Fuller, M. J., Khanolkar, A., Tebo, A. E., and Zajac, A. J. (2004) Maintenance, loss, and resurgence of T cell responses during acute, protracted, and chronic viral infections, J Immunol 172, 4204–4214.PubMedGoogle Scholar
  22. 22.
    Oldstone, M. B. (2007) A suspenseful game of “hide and seek” between virus and host, Nat Immunol 8, 325–327.PubMedCrossRefGoogle Scholar
  23. 23.
    Brooks, D. G., Teyton, L., Oldstone, M. B., and McGavern, D. B. (2005) Intrinsic functional dysregulation of CD4 T cells occurs rapidly following persistent viral infection, J Virol 79, 10514–10527.PubMedCrossRefGoogle Scholar
  24. 24.
    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.PubMedCrossRefGoogle Scholar
  25. 25.
    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.PubMedCrossRefGoogle Scholar
  26. 26.
    Ou, R., Zhou, S., Huang, L., and Moskophidis, D. (2001) Critical role for alpha/beta and gamma interferons in persistence of lymphocytic choriomeningitis virus by clonal exhaustion of cytotoxic T cells, J Virol 75, 8407–8423.PubMedCrossRefGoogle Scholar
  27. 27.
    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.PubMedCrossRefGoogle Scholar
  28. 28.
    Kannanganat, S., Kapogiannis, B. G., Ibegbu, C., Chennareddi, L., Goepfert, P., Robinson, H. L., Lennox, J., and Amara, R. R. (2007) Human immunodeficiency virus type 1 controllers but not noncontrollers maintain CD4 T cells coexpressing three cytokines, J Virol 81, 12071–12076.PubMedCrossRefGoogle Scholar
  29. 29.
    Brooks, D. G., McGavern, D. B., and Oldstone, M. B. (2006) Reprogramming of antiviral T cells prevents inactivation and restores T cell activity during persistent viral infection, J Clin Invest 116, 1675–1685.PubMedCrossRefGoogle Scholar
  30. 30.
    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.PubMedCrossRefGoogle Scholar
  31. 31.
    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.PubMedCrossRefGoogle Scholar
  32. 32.
    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.PubMedCrossRefGoogle Scholar
  33. 33.
    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.PubMedCrossRefGoogle Scholar
  34. 34.
    Barrett, L., Gallant, M., Howley, C., Bowmer, M. I., Hirsch, G., Peltekian, K., and Grant, M. (2008) Enhanced IL-10 production in response to hepatitis C virus proteins by peripheral blood mononuclear cells from human immunodeficiency virus-monoinfected individuals, BMC Immunol 9, 28.PubMedCrossRefGoogle Scholar
  35. 35.
    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.PubMedCrossRefGoogle Scholar
  36. 36.
    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.PubMedCrossRefGoogle Scholar
  37. 37.
    Landay, A. L., Clerici, M., Hashemi, F., Kessler, H., Berzofsky, J. A., and Shearer, G. M. (1996) In vitro restoration of T cell immune function in human immunodeficiency virus-positive persons: effects of interleukin (IL)-12 and anti-IL-10, J Infect Dis 173, 1085–1091.PubMedCrossRefGoogle Scholar
  38. 38.
    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.PubMedCrossRefGoogle Scholar
  39. 39.
    Thepen, T., Van Rooijen, N., and Kraal, G. (1989) Alveolar macrophage elimination in vivo is associated with an increase in pulmonary immune response in mice, J Exp Med 170, 499–509.PubMedCrossRefGoogle Scholar
  40. 40.
    Holt, P. G. (1978) Inhibitory activity of unstimulated alveolar macrophages on T-lymphocyte blastogenic response, Am Rev Respir Dis 118, 791–793.PubMedGoogle Scholar
  41. 41.
    Dillon, S., Agrawal, S., Banerjee, K., Letterio, J., Denning, T. L., Oswald-Richter, K., Kasprowicz, D. J., Kellar, K., Pare, J., van Dyke, T., Ziegler, S., Unutmaz, D., and Pulendran, B. (2006) Yeast zymosan, a stimulus for TLR2 and dectin-1, induces regulatory antigen-presenting cells and immunological tolerance, J Clin Invest 116, 916–928.PubMedCrossRefGoogle Scholar
  42. 42.
    Holt, P. G., Oliver, J., Bilyk, N., McMenamin, C., McMenamin, P. G., Kraal, G., and Thepen, T. (1993) Downregulation of the antigen presenting cell function(s) of pulmonary dendritic cells in vivo by resident alveolar macrophages, J Exp Med 177, 397–407.PubMedCrossRefGoogle Scholar
  43. 43.
    Bilyk, N., and Holt, P. G. (1995) Cytokine modulation of the immunosuppressive phenotype of pulmonary alveolar macrophage populations, Immunology 86, 231–237.PubMedGoogle Scholar
  44. 44.
    Strickland, D. H., Thepen, T., Kees, U. R., Kraal, G., and Holt, P. G. (1993) Regulation of T-cell function in lung tissue by pulmonary alveolar macrophages, Immunology 80, 266–272.PubMedGoogle Scholar
  45. 45.
    Steinman, R. M., Hawiger, D., and Nussenzweig, M. C. (2003) Tolerogenic dendritic cells, Annu Rev Immunol 21, 685–711.PubMedCrossRefGoogle Scholar
  46. 46.
    Steinbrink, K., Wolfl, M., Jonuleit, H., Knop, J., and Enk, A. H. (1997) Induction of tolerance by IL-10-treated dendritic cells, J Immunol 159, 4772–4780.PubMedGoogle Scholar
  47. 47.
    Steinbrink, K., Graulich, E., Kubsch, S., Knop, J., and Enk, A. H. (2002) CD4(+) and CD8(+) anergic T cells induced by interleukin-10-treated human dendritic cells display antigen-specific suppressor activity, Blood 99, 2468–2476.PubMedCrossRefGoogle Scholar
  48. 48.
    Kubsch, S., Graulich, E., Knop, J., and Steinbrink, K. (2003) Suppressor activity of anergic T cells induced by IL-10-treated human dendritic cells: association with IL-2- and CTLA-4-dependent G1 arrest of the cell cycle regulated by p27Kip1, Eur J Immunol 33, 1988–1997.PubMedCrossRefGoogle Scholar
  49. 49.
    Penna, G., Roncari, A., Amuchastegui, S., Daniel, K. C., Berti, E., Colonna, M., and Adorini, L. (2005) Expression of the inhibitory receptor ILT3 on dendritic cells is dispensable for induction of CD4+Foxp3+ regulatory T cells by 1,25-dihydroxyvitamin D3, Blood 106, 3490–3497.PubMedCrossRefGoogle Scholar
  50. 50.
    Netea, M. G., Sutmuller, R., Hermann, C., Van der Graaf, C. A., Van der Meer, J. W., van Krieken, J. H., Hartung, T., Adema, G., and Kullberg, B. J. (2004) Toll-like receptor 2 suppresses immunity against Candida albicans through induction of IL-10 and regulatory T cells, J Immunol 172, 3712–3718.PubMedGoogle Scholar
  51. 51.
    Sutmuller, R. P., den Brok, M. H., Kramer, M., Bennink, E. J., Toonen, L. W., Kullberg, B. J., Joosten, L. A., Akira, S., Netea, M. G., and Adema, G. J. (2006) Toll-like receptor 2 controls expansion and function of regulatory T cells, J Clin Invest 116, 485–494.PubMedCrossRefGoogle Scholar
  52. 52.
    Penna, G., and Adorini, L. (2000) 1 Alpha,25-dihydroxyvitamin D3 inhibits differentiation, maturation, activation, and survival of dendritic cells leading to impaired alloreactive T cell activation, J Immunol 164, 2405–2411.PubMedGoogle Scholar
  53. 53.
    Oh, S., and Eichelberger, M. C. (1999) Influenza virus neuraminidase alters allogeneic T cell proliferation, Virology 264, 427–435.PubMedCrossRefGoogle Scholar
  54. 54.
    Oh, S., McCaffery, J. M., and Eichelberger, M. C. (2000) Dose-dependent changes in influenza virus-infected dendritic cells result in increased allogeneic T-cell proliferation at low, but not high, doses of virus, J Virol 74, 5460–5469.PubMedCrossRefGoogle Scholar
  55. 55.
    Dhodapkar, M. V., and Steinman, R. M. (2002) Antigen-bearing immature dendritic cells induce peptide-specific CD8(+) regulatory T cells in vivo in humans, Blood 100, 174–177.PubMedCrossRefGoogle Scholar
  56. 56.
    Dhodapkar, M. V., Steinman, R. M., Krasovsky, J., Munz, C., and Bhardwaj, N. (2001) Antigen-specific inhibition of effector T cell function in humans after injection of immature dendritic cells, J Exp Med 193, 233–238.PubMedCrossRefGoogle Scholar
  57. 57.
    Sakaguchi, S., Wing, K., and Yamaguchi, T. (2009) Dynamics of peripheral tolerance and immune regulation mediated by Treg, Eur J Immunol 39, 2331–2336.PubMedCrossRefGoogle Scholar
  58. 58.
    Hori, S., Nomura, T., and Sakaguchi, S. (2003) Control of regulatory T cell development by the transcription factor Foxp3, Science 299, 1057–1061.PubMedCrossRefGoogle Scholar
  59. 59.
    Zhou, X., Bailey-Bucktrout, S. L., Jeker, L. T., Penaranda, C., Martinez-Llordella, M., Ashby, M., Nakayama, M., Rosenthal, W., and Bluestone, J. A. (2009) Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo, Nat Immunol 10, 1000–1007.PubMedCrossRefGoogle Scholar
  60. 60.
    Toda, A., and Piccirillo, C. A. (2006) Development and function of naturally occurring CD4+CD25+ regulatory T cells, J Leukoc Biol 80, 458–470.PubMedCrossRefGoogle Scholar
  61. 61.
    Ozdemir, C., Akdis, M., and Akdis, C. A. (2009) T regulatory cells and their counterparts: masters of immune regulation, Clin Exp Allergy 39, 626–639.PubMedCrossRefGoogle Scholar
  62. 62.
    Horai, R., Asano, M., Sudo, K., Kanuka, H., Suzuki, M., Nishihara, M., Takahashi, M., and Iwakura, Y. (1998) Production of mice deficient in genes for interleukin (IL)-1alpha, IL-1beta, IL-1alpha/beta, and IL-1 receptor antagonist shows that IL-1beta is crucial in turpentine-induced fever development and glucocorticoid secretion, J Exp Med 187, 1463–1475.PubMedCrossRefGoogle Scholar
  63. 63.
    Aandahl, E. M., Michaelsson, J., Moretto, W. J., Hecht, F. M., and Nixon, D. F. (2004) Human CD4+ CD25+ regulatory T cells control T-cell responses to human immunodeficiency virus and cytomegalovirus antigens, J Virol 78, 2454–2459.PubMedCrossRefGoogle Scholar
  64. 64.
    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.PubMedCrossRefGoogle Scholar
  65. 65.
    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.PubMedGoogle Scholar
  66. 66.
    Suvas, S., Kumaraguru, U., Pack, C. D., Lee, S., and Rouse, B. T. (2003) CD4+CD25+ T cells regulate virus-specific primary and memory CD8+ T cell responses, J Exp Med 198, 889–901.PubMedCrossRefGoogle Scholar
  67. 67.
    Truong, P., and McGavern, D. B. (2008) A novel virus carrier state to evaluate immunotherapeutic regimens: regulatory T cells modulate the pathogenicity of antiviral memory cells, J Immunol 181, 1161–1169.PubMedGoogle Scholar
  68. 68.
    Belkaid, Y. (2007) Regulatory T cells and infection: a dangerous necessity, Nat Rev Immunol 7, 875–888.PubMedCrossRefGoogle Scholar
  69. 69.
    Belkaid, Y., and Rouse, B. T. (2005) Natural regulatory T cells in infectious disease, Nat Immunol 6, 353–360.PubMedCrossRefGoogle Scholar
  70. 70.
    Robertson, S. J., and Hasenkrug, K. J. (2006) The role of virus-induced regulatory T cells in immunopathology, Springer Semin Immunopathol 28, 51–62.PubMedCrossRefGoogle Scholar
  71. 71.
    Iwashiro, M., Messer, R. J., Peterson, K. E., Stromnes, I. M., Sugie, T., and Hasenkrug, K. J. (2001) Immunosuppression by CD4+ regulatory T cells induced by chronic retroviral infection, Proc Natl Acad Sci U S A 98, 9226–9230.PubMedCrossRefGoogle Scholar
  72. 72.
    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.PubMedCrossRefGoogle Scholar
  73. 73.
    Luhn, K., Simmons, C. P., Moran, E., Dung, N. T., Chau, T. N., Quyen, N. T., Thao le, T. T., Van Ngoc, T., Dung, N. M., Wills, B., Farrar, J., McMichael, A. J., Dong, T., and Rowland-Jones, S. (2007) Increased frequencies of CD4+ CD25(high) regulatory T cells in acute dengue infection, J Exp Med 204, 979–985.PubMedCrossRefGoogle Scholar
  74. 74.
    Shevach, E. M. (2009) Mechanisms of foxp3+ T regulatory cell-mediated suppression, Immunity 30, 636–645.PubMedCrossRefGoogle Scholar
  75. 75.
    Tang, Q., and Bluestone, J. A. (2008) The Foxp3+ regulatory T cell: a jack of all trades, master of regulation, Nat Immunol 9, 239–244.PubMedCrossRefGoogle Scholar
  76. 76.
    Vignali, D. A., Collison, L. W., and Workman, C. J. (2008) How regulatory T cells work, Nat Rev Immunol 8, 523–532.PubMedCrossRefGoogle Scholar
  77. 77.
    Miyara, M., and Sakaguchi, S. (2007) Natural regulatory T cells: mechanisms of suppression, Trends Mol Med 13, 108–116.PubMedCrossRefGoogle Scholar
  78. 78.
    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.PubMedCrossRefGoogle Scholar
  79. 79.
    Wing, K., Onishi, Y., Prieto-Martin, P., Yamaguchi, T., Miyara, M., Fehervari, Z., Nomura, T., and Sakaguchi, S. (2008) CTLA-4 control over Foxp3+ regulatory T cell function, Science 322, 271–275.PubMedCrossRefGoogle Scholar
  80. 80.
    Onishi, Y., Fehervari, Z., Yamaguchi, T., and Sakaguchi, S. (2008) Foxp3+ natural regulatory T cells preferentially form aggregates on dendritic cells in vitro and actively inhibit their maturation, Proc Natl Acad Sci U S A 105, 10113–10118.PubMedCrossRefGoogle Scholar
  81. 81.
    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.PubMedCrossRefGoogle Scholar
  82. 82.
    Pandiyan, P., Zheng, L., Ishihara, S., Reed, J., and Lenardo, M. J. (2007) CD4+CD25+Foxp3+ regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4+ T cells, Nat Immunol 8, 1353–1362.PubMedCrossRefGoogle Scholar
  83. 83.
    Filippi, C. M., Estes, E. A., Oldham, J. E., and von Herrath, M. G. (2009) Immunoregulatory mechanisms triggered by viral infections protect from type 1 diabetes in mice, J Clin Invest 119, 1515–1523.PubMedGoogle Scholar
  84. 84.
    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.PubMedCrossRefGoogle Scholar
  85. 85.
    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.PubMedCrossRefGoogle Scholar
  86. 86.
    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.PubMedCrossRefGoogle Scholar
  87. 87.
    Fife, B. T., and Bluestone, J. A. (2008) Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways, Immunol Rev 224, 166–182.PubMedCrossRefGoogle Scholar
  88. 88.
    Williams, M. A., Onami, T. M., Adams, A. B., Durham, M. M., Pearson, T. C., Ahmed, R., and Larsen, C. P. (2002) Cutting edge: persistent viral infection prevents tolerance induction and escapes immune control following CD28/CD40 blockade-based regimen, J Immunol 169, 5387–5391.PubMedGoogle Scholar
  89. 89.
    Rudd, C. E., Taylor, A., and Schneider, H. (2009) CD28 and CTLA-4 coreceptor expression and signal transduction, Immunol Rev 229, 12–26.PubMedCrossRefGoogle Scholar
  90. 90.
    Read, S., Malmstrom, V., and Powrie, F. (2000) Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation, J Exp Med 192, 295–302.PubMedCrossRefGoogle Scholar
  91. 91.
    Takahashi, T., Tagami, T., Yamazaki, S., Uede, T., Shimizu, J., Sakaguchi, N., Mak, T. W., and Sakaguchi, S. (2000) Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4, J Exp Med 192, 303–310.PubMedCrossRefGoogle Scholar
  92. 92.
    Salomon, B., Lenschow, D. J., Rhee, L., Ashourian, N., Singh, B., Sharpe, A., and Bluestone, J. A. (2000) B7/CD28 costimulation is essential for the homeostasis of the CD4+ CD25+ immunoregulatory T cells that control autoimmune diabetes, Immunity 12, 431–440.PubMedCrossRefGoogle Scholar
  93. 93.
    Simone, R., Piatti, G., and Saverino, D. (2009) The inhibitory co-receptors: a way to save from anergy the HIV-specific T cells, Curr HIV Res 7, 266–272.PubMedCrossRefGoogle Scholar
  94. 94.
    Hryniewicz, A., Boasso, A., Edghill-Smith, Y., Vaccari, M., Fuchs, D., Venzon, D., Nacsa, J., Betts, M. R., Tsai, W. P., Heraud, J. M., Beer, B., Blanset, D., Chougnet, C., Lowy, I., Shearer, G. M., and Franchini, G. (2006) CTLA-4 blockade decreases TGF-beta, IDO, and viral RNA expression in tissues of SIVmac251-infected macaques, Blood 108, 3834–3842.PubMedCrossRefGoogle Scholar
  95. 95.
    Kaufmann, D. E., Kavanagh, D. G., Pereyra, F., Zaunders, J. J., Mackey, E. W., Miura, T., Palmer, S., Brockman, M., Rathod, A., Piechocka-Trocha, A., Baker, B., Zhu, B., Le Gall, S., Waring, M. T., Ahern, R., Moss, K., Kelleher, A. D., Coffin, J. M., Freeman, G. J., Rosenberg, E. S., and Walker, B. D. (2007) Upregulation of CTLA-4 by HIV-specific CD4+ T cells correlates with disease progression and defines a reversible immune dysfunction, Nat Immunol 8, 1246–1254.PubMedCrossRefGoogle Scholar
  96. 96.
    Krummel, M. F., and Allison, J. P. (1996) CTLA-4 engagement inhibits IL-2 accumulation and cell cycle progression upon activation of resting T cells, J Exp Med 183, 2533–2540.PubMedCrossRefGoogle Scholar
  97. 97.
    Li, M. O., Wan, Y. Y., Sanjabi, S., Robertson, A. K., and Flavell, R. A. (2006) Transforming growth factor-beta regulation of immune responses, Annu Rev Immunol 24, 99–146.PubMedCrossRefGoogle Scholar
  98. 98.
    Gorelik, L., and Flavell, R. A. (2002) Transforming growth factor-beta in T-cell biology, Nat Rev Immunol 2, 46–53.PubMedCrossRefGoogle Scholar
  99. 99.
    Zhang, X., Giangreco, L., Broome, H. E., Dargan, C. M., and Swain, S. L. (1995) Control of CD4 effector fate: transforming growth factor beta 1 and interleukin 2 synergize to prevent apoptosis and promote effector expansion, J Exp Med 182, 699–709.PubMedCrossRefGoogle Scholar
  100. 100.
    Genestier, L., Kasibhatla, S., Brunner, T., and Green, D. R. (1999) Transforming growth factor beta1 inhibits Fas ligand expression and subsequent activation-induced cell death in T cells via downregulation of c-Myc, J Exp Med 189, 231–239.PubMedCrossRefGoogle Scholar
  101. 101.
    Cerwenka, A., Kovar, H., Majdic, O., and Holter, W. (1996) Fas- and activation-induced apoptosis are reduced in human T cells preactivated in the presence of TGF-beta 1, J Immunol 156, 459–464.PubMedGoogle Scholar
  102. 102.
    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.PubMedCrossRefGoogle Scholar
  103. 103.
    Filippi, C., Bresson, D., and von Herrath, M. (2005) Antigen-specific induction of regulatory T cells for type 1 diabetes therapy, Int Rev Immunol 24, 341–360.PubMedCrossRefGoogle Scholar
  104. 104.
    Filippi, C. M., Juedes, A. E., Oldham, J. E., Ling, E., Togher, L., Peng, Y., Flavell, R. A., and von Herrath, M. G. (2008) TGF-{beta} suppresses the activation of CD8+ T cells when naive but promotes their survival and function once antigen-experienced: a two-faced impact on autoimmunity, Diabetes 57, 2684–2692.PubMedCrossRefGoogle Scholar
  105. 105.
    Piccirillo, C. A., Chang, Y., and Prud’homme, G. J. (1998) TGF-beta1 somatic gene therapy prevents autoimmune disease in nonobese diabetic mice, J Immunol 161, 3950–3956.PubMedGoogle Scholar
  106. 106.
    Bettelli, E., Carrier, Y., Gao, W., Korn, T., Strom, T. B., Oukka, M., Weiner, H. L., and Kuchroo, V. K. (2006) Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells, Nature 441, 235–238.PubMedCrossRefGoogle Scholar
  107. 107.
    Stockinger, B., and Veldhoen, M. (2007) Differentiation and function of Th17 T cells, Curr Opin Immunol 19, 281–286.PubMedCrossRefGoogle Scholar
  108. 108.
    Laurence, A., Tato, C. M., Davidson, T. S., Kanno, Y., Chen, Z., Yao, Z., Blank, R. B., Meylan, F., Siegel, R., Hennighausen, L., Shevach, E. M., and O’Shea, J. J. (2007) Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation, Immunity 26, 371–381.PubMedCrossRefGoogle Scholar
  109. 109.
    de Waal Malefyt, R., Abrams, J., Bennett, B., Figdor, C. G., and de Vries, J. E. (1991) Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes, J Exp Med 174, 1209–1220.PubMedCrossRefGoogle Scholar
  110. 110.
    Taylor, A., Akdis, M., Joss, A., Akkoc, T., Wenig, R., Colonna, M., Daigle, I., Flory, E., Blaser, K., and Akdis, C. A. (2007) IL-10 inhibits CD28 and ICOS costimulations of T cells via src homology 2 domain-containing protein tyrosine phosphatase 1, J Allergy Clin Immunol 120, 76–83.PubMedCrossRefGoogle Scholar
  111. 111.
    Brooks, D. G., Lee, A. M., Elsaesser, H., McGavern, D. B., and Oldstone, M. B. (2008) IL-10 blockade facilitates DNA vaccine-induced T cell responses and enhances clearance of persistent virus infection, J Exp Med 205, 533–541.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press 2010

Authors and Affiliations

  • Ghanashyam Sarikonda
    • 1
  • Matthias G. von Herrath
    • 2
    Email author
  1. 1.Department of Developmental Immunology-3,Diabetes Center of San DiegoLa Jolla Institute for Allergy and ImmunologyLa JollaUSA
  2. 2.Department of Developmental Immunology (D1-3), Diabetes Center of San DiegoLa Jolla Institute for Allergy and ImmunologyLa JollaUSA

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