Advertisement

Human Type 1 T Regulatory Cells

  • Manuela Battaglia
  • Silvia Gregori
  • Rosa Bacchetta
  • Maria Grazia Roncarolo
Chapter

Abstract

IL-10 producing T regulatory type 1 (Tr1) cells were first identified in 1994 in severe combined immunodeficient patients successfully transplanted with allogeneic hemtaopoietic stem cells. Interestingly, the presence of Tr1 cells in vivo correlated with long term allograft tolerance without the need of immunosuppressive treatment. Since then, Tr1 cells were further characterized and efficient ways for their in vitro generation were developed. It is now evident that Tr1 cells represent a unique T cell subset, distinct from Th1, Th2, and Th17 cells and also from other T regulatory cells. Tr1 cells arise from naïve precursors and are characterized by the production of high levels of IL-10 in the absence of IL-4. They are anergic cells which suppress proliferation of T cells via an IL-10-dependent mechanism. Human Tr1 cells have been clearly shown to maintain tolerance to self and non-self non harmful antigens, and to allo-antigens but also to infectious agents and tumor-bearing cells. In some clinical settings, transfer of ex vivo generated Tr1 cells can be envisaged as an efficient and safe approach to promote or restore immunological tolerance. One clinical trial with transfer of Tr1 cells in patients transplanted with hematopoietic stem cells is already ongoing at our institute and it will pave the road for future clinical Tr1 cell applications.

Keywords

Celiac Disease Graft Versus Host Disease Acute Graft Versus Host Disease Graft Versus Leukemia Cytokine Production Profile 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Gershon, R. K., and K. Kondo. 1971. Infectious immunological tolerance. Immunology 21:903–914.PubMedGoogle Scholar
  2. 2.
    Dorf, M. E., and B. Benacerraf. 1984. Suppressor cells and immunoregulation. Annu Rev Immunol 2:127–157.PubMedCrossRefGoogle Scholar
  3. 3.
    Groux, H., A. O'Garra, M. Bigler, M. Rouleau, S. Antonenko, J. E. de Vries, and M. G. Roncarolo. 1997. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389:737–742.PubMedCrossRefGoogle Scholar
  4. 4.
    Bacchetta, R., M. Bigler, J. L. Touraine, R. Parkman, P. A. Tovo, J. Abrams, R. de Waal Malefyt, J. E. de Vries, and M. G. Roncarolo. 1994. High levels of interleukin 10 production in vivo are associated with tolerance in SCID patients transplanted with HLA mismatched hematopoietic stem cells. J Exp Med 179:493–502.PubMedCrossRefGoogle Scholar
  5. 5.
    Bacchetta, R., C. Sartirana, M. K. Levings, C. Bordignon, S. Narula, and M. G. Roncarolo. 2002. Growth and expansion of human T regulatory type 1 cells are independent from TCR activation but require exogenous cytokines. Eur J Immunol 32:2237–2245.PubMedCrossRefGoogle Scholar
  6. 6.
    Gilliet, M., and Y. J. Liu. 2002. Generation of human CD8 T regulatory cells by CD40 ligand-activated plasmacytoid dendritic cells. J Exp Med 195:695–704.PubMedCrossRefGoogle Scholar
  7. 7.
    Gregori, S., P. Mangia, R. Bacchetta, E. Tresoldi, F. Kolbinger, C. Traversari, J. M. Carballido, J. E. de Vries, U. Korthauer, and M. G. Roncarolo. 2005. An anti-CD45RO/RB monoclonal antibody modulates T cell responses via induction of apoptosis and generation of regulatory T cells. J Exp Med 201:1293–1305.PubMedCrossRefGoogle Scholar
  8. 8.
    Steinbrink, K., H. Jonuleit, G. Muller, G. Schuler, J. Knop, and A. H. Enk. 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.PubMedGoogle Scholar
  9. 9.
    Groux, H., M. Bigler, J. E. de Vries, and M. G. Roncarolo. 1996. Interleukin-10 induces a long-term antigen-specific anergic state in human CD4+ T cells. J Exp Med 184: 19–29.PubMedCrossRefGoogle Scholar
  10. 10.
    Levings, M. K., S. Gregori, E. Tresoldi, S. Cazzaniga, C. Bonini, and M. G. Roncarolo. 2005. Differentiation of Tr1 cells by immature dendritic cells requires IL-10 but not CD25+CD4+ Tr cells. Blood 105:1162–1169.PubMedCrossRefGoogle Scholar
  11. 11.
    Levings, M. K., R. Sangregorio, F. Galbiati, S. Squadrone, R. de Waal Malefyt, and M. G. Roncarolo. 2001. IFN-alpha and IL-10 induce the differentiation of human type 1 T regulatory cells. J Immunol 166:5530–5539.PubMedGoogle Scholar
  12. 12.
    Sebastiani, S., P. Allavena, C. Albanesi, F. Nasorri, G. Bianchi, C. Traidl, S. Sozzani, G. Girolomoni, and A. Cavani. 2001. Chemokine receptor expression and function in CD4+ T lymphocytes with regulatory activity. J Immunol 166:996–1002.PubMedGoogle Scholar
  13. 13.
    Freeman, C. M., B. C. Chiu, V. R. Stolberg, J. Hu, K. Zeibecoglou, N. W. Lukacs, S. A. Lira, S. L. Kunkel, and S. W. Chensue. 2005. CCR8 is expressed by antigen-elicited, IL-10-producing CD4+CD25+ T cells, which regulate Th2-mediated granuloma formation in mice. J Immunol 174:1962–1970.PubMedGoogle Scholar
  14. 14.
    Papadakis, K. A., C. Landers, J. Prehn, E. A. Kouroumalis, S. T. Moreno, J. C. Gutierrez-Ramos, M. R. Hodge, and S. R. Targan. 2003. CC chemokine receptor 9 expression defines a subset of peripheral blood lymphocytes with mucosal T cell phenotype and Th1 or T-regulatory 1 cytokine profile. J Immunol 171:159–165.PubMedGoogle Scholar
  15. 15.
    Fontenot, J. D., and A. Y. Rudensky. 2005. A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3. Nat Immunol 6: 331–337.PubMedCrossRefGoogle Scholar
  16. 16.
    Hori, S., T. Nomura, and S. Sakaguchi. 2003. Control of regulatory T cell development by the transcription factor Foxp3. Science 299:1057–1061.PubMedCrossRefGoogle Scholar
  17. 17.
    Allan, S. E., L. Passerini, R. Bacchetta, N. Crellin, M. Dai, P. C. Orban, S. F. Ziegler, M. G. Roncarolo, and M. K. Levings. 2005. The role of 2 FOXP3 isoforms in the generation of human CD4+ Tregs. J Clin Invest 115:3276–3284.PubMedCrossRefGoogle Scholar
  18. 18.
    Walker, M. R., D. J. Kasprowicz, V. H. Gersuk, A. Benard, M. Van Landeghen, J. H. Buckner, and S. F. Ziegler. 2003. Induction of FoxP3 and acquisition of T regulatory activity by stimulated human CD4+CD25- T cells. J Clin Invest 112:1437–1443.PubMedGoogle Scholar
  19. 19.
    Barrat, F. J., D. J. Cua, A. Boonstra, D. F. Richards, C. Crain, H. F. Savelkoul, R. de Waal-Malefyt, R. L. Coffman, C. M. Hawrylowicz, and A. O'Garra. 2002. In vitro generation of interleukin 10-producing regulatory CD4(+) T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)- and Th2-inducing cytokines. J Exp Med 195: 603–616.PubMedCrossRefGoogle Scholar
  20. 20.
    Kitani, A., K. Chua, K. Nakamura, and W. Strober. 2000. Activated self-MHC-reactive T cells have the cytokine phenotype of Th3/T regulatory cell 1 T cells. J Immunol 165:691–702.PubMedGoogle Scholar
  21. 21.
    Steinbrink, K., M. Wolfl, H. Jonuleit, J. Knop, and A. H. Enk. 1997. Induction of tolerance by IL-10-treated dendritic cells. J Immunol 159:4772–4780.PubMedGoogle Scholar
  22. 22.
    Steinbrink, K., E. Graulich, S. Kubsch, J. Knop, and A. H. Enk. 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
  23. 23.
    Willems, F., A. Marchant, J. P. Delville, C. Gerard, A. Delvaux, T. Velu, M. de Boer, and M. Goldman. 1994. Interleukin-10 inhibits B7 and intercellular adhesion molecule-1 expression on human monocytes. Eur J Immunol 24:1007–1009.PubMedCrossRefGoogle Scholar
  24. 24.
    Fiorentino, D. F., A. Zlotnik, T. R. Mosmann, M. Howard, and A. O'Garra. 1991. IL-10 inhibits cytokine production by activated macrophages. J Immunol 147:3815–3822.PubMedGoogle Scholar
  25. 25.
    Allavena, P., L. Piemonti, D. Longoni, S. Bernasconi, A. Stoppacciaro, L. Ruco, and A. Mantovani. 1998. IL-10 prevents the differentiation of monocytes to dendritic cells but promotes their maturation to macrophages. Eur J Immunol 28:359–369.PubMedCrossRefGoogle Scholar
  26. 26.
    Li, M. O., Y. Y. Wan, S. Sanjabi, A. K. Robertson, and R. A. Flavell. 2006. Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol 24:99–146.PubMedCrossRefGoogle Scholar
  27. 27.
    Hawrylowicz, C. M., and A. O'Garra. 2005. Potential role of interleukin-10-secreting regulatory T cells in allergy and asthma. Nat Rev Immunol 5:271–283.PubMedCrossRefGoogle Scholar
  28. 28.
    Grossman, W. J., J. W. Verbsky, W. Barchet, M. Colonna, J. P. Atkinson, and T. J. Ley. 2004. Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity 21:589–601.PubMedCrossRefGoogle Scholar
  29. 29.
    Grossman, W. J., J. W. Verbsky, B. L. Tollefsen, C. Kemper, J. P. Atkinson, and T. J. Ley. 2004. Differential expression of granzymes A and B in human cytotoxic lymphocyte subsets and T regulatory cells. Blood 104:2840–2848.PubMedCrossRefGoogle Scholar
  30. 30.
    Cottrez, F., and H. Groux. 2001. Regulation of TGF-beta response during T cell activation is modulated by IL-10. J Immunol 167:773–778.PubMedGoogle Scholar
  31. 31.
    Kemper, C., A. C. Chan, J. M. Green, K. A. Brett, K. M. Murphy, and J. P. Atkinson. 2003. Activation of human CD4+ cells with CD3 and CD46 induces a T-regulatory cell 1 phenotype. Nature 421:388–392.PubMedCrossRefGoogle Scholar
  32. 32.
    Steinman, R. M., D. Hawiger, and M. C. Nussenzweig. 2003. Tolerogenic dendritic cells. Annu Rev Immunol 21:685–711.PubMedCrossRefGoogle Scholar
  33. 33.
    Jonuleit, H., E. Schmitt, G. Schuler, J. Knop, and A. H. Enk. 2000. Induction of interleukin 10-producing, nonproliferating CD4(+) T cells with regulatory properties by repetitive stimulation with allogeneic immature human dendritic cells. J Exp Med 192: 1213–1222.PubMedCrossRefGoogle Scholar
  34. 34.
    Kuwana, M., J. Kaburaki, T. M. Wright, Y. Kawakami, and Y. Ikeda. 2001. Induction of antigen-specific human CD4(+) T cell anergy by peripheral blood DC2 precursors. Eur J Immunol 31:2547–2557.PubMedCrossRefGoogle Scholar
  35. 35.
    Zuany-Amorim, C., E. Sawicka, C. Manlius, A. Le Moine, L. R. Brunet, D. M. Kemeny, G. Bowen, G. Rook, and C. Walker. 2002. Suppression of airway eosinophilia by killed Mycobacterium vaccae-induced allergen-specific regulatory T-cells. Nat Med 8: 625–629.PubMedCrossRefGoogle Scholar
  36. 36.
    McGuirk, P., C. McCann, and K. H. Mills. 2002. Pathogen-specific T regulatory 1 cells induced in the respiratory tract by a bacterial molecule that stimulates interleukin 10 production by dendritic cells: a novel strategy for evasion of protective T helper type 1 responses by Bordetella pertussis. J Exp Med 195:221–231.PubMedCrossRefGoogle Scholar
  37. 37.
    Lavelle, E. C., E. McNeela, M. E. Armstrong, O. Leavy, S. C. Higgins, and K. H. Mills. 2003. Cholera toxin promotes the induction of regulatory T cells specific for bystander antigens by modulating dendritic cell activation. J Immunol 171:2384–2392.PubMedGoogle Scholar
  38. 38.
    Battaglia, M., A. Stabilini, E. Draghici, S. Gregori, C. Mocchetti, E. Bonifacio, and M. G. Roncarolo. 2006. Rapamycin and interleukin-10 treatment induces T regulatory type 1 cells that mediate antigen-specific transplantation tolerance. Diabetes 55:40–49.PubMedCrossRefGoogle Scholar
  39. 39.
    Battaglia, M., A. Stabilini, E. Draghici, B. Migliavacca, S. Gregori, E. Bonifacio, and M. G. Roncarolo. 2006. Induction of Tolerance in Type 1 Diabetes via Both CD4+CD25+ T Regulatory Cells and T Regulatory Type 1 Cells. Diabetes 55:1571–1580.PubMedCrossRefGoogle Scholar
  40. 40.
    Asiedu, C. K., K. J. Goodwin, G. Balgansuren, S. M. Jenkins, S. Le Bas-Bernardet, U. Jargal, D. M. Neville, Jr., and J. M. Thomas. 2005. Elevated T regulatory cells in long-term stable transplant tolerance in rhesus macaques induced by anti-CD3 immunotoxin and deoxyspergualin. J Immunol 175:8060–8068.PubMedGoogle Scholar
  41. 41.
    Herold, K. C., J. B. Burton, F. Francois, E. Poumian-Ruiz, M. Glandt, and J. A. Bluestone. 2003. Activation of human T cells by FcR nonbinding anti-CD3 mAb, hOKT3gamma1(Ala-Ala). J Clin Invest 111:409–418.PubMedGoogle Scholar
  42. 42.
    Chatenoud, L. 2003. CD3-specific antibody-induced active tolerance: from bench to bedside. Nat Rev Immunol 3:123–132.PubMedCrossRefGoogle Scholar
  43. 43.
    Herold, K. C., W. Hagopian, J. A. Auger, E. Poumian-Ruiz, L. Taylor, D. Donaldson, S. E. Gitelman, D. M. Harlan, D. Xu, R. A. Zivin, and J. A. Bluestone. 2002. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med 346: 1692–1698.PubMedCrossRefGoogle Scholar
  44. 44.
    Veldman, C., A. Hohne, D. Dieckmann, G. Schuler, and M. Hertl. 2004. Type I regulatory T cells specific for desmoglein 3 are more frequently detected in healthy individuals than in patients with pemphigus vulgaris. J Immunol 172:6468–6475.PubMedGoogle Scholar
  45. 45.
    Arif, S., T. I. Tree, T. P. Astill, J. M. Tremble, A. J. Bishop, C. M. Dayan, B. O. Roep, and M. Peakman. 2004. Autoreactive T cell responses show proinflammatory polarization in diabetes but a regulatory phenotype in health. J Clin Invest 113:451–463.PubMedGoogle Scholar
  46. 46.
    Yudoh, K., H. Matsuno, F. Nakazawa, T. Yonezawa, and T. Kimura. 2000. Reduced expression of the regulatory CD4+ T cell subset is related to Th1/Th2 balance and disease severity in rheumatoid arthritis. Arthritis Rheum 43:617–627.PubMedCrossRefGoogle Scholar
  47. 47.
    Hall, A. M., F. J. Ward, M. A. Vickers, L. M. Stott, S. J. Urbaniak, and R. N. Barker. 2002. Interleukin-10-mediated regulatory T-cell responses to epitopes on a human red blood cell autoantigen. Blood 100:4529–4536.PubMedCrossRefGoogle Scholar
  48. 48.
    Mowat, A. M. 2003. Anatomical basis of tolerance and immunity to intestinal antigens. Nat Rev Immunol 3:331–341.PubMedCrossRefGoogle Scholar
  49. 49.
    Troncone, R., C. Gianfrani, G. Mazzarella, L. Greco, J. Guardiola, S. Auricchio, and P. De Berardinis. 1998. Majority of gliadin-specific T-cell clones from celiac small intestinal mucosa produce interferon-gamma and interleukin-4. Dig Dis Sci 43:156–161.PubMedCrossRefGoogle Scholar
  50. 50.
    Salvati, V. M., G. Mazzarella, C. Gianfrani, M. K. Levings, R. Stefanile, B. De Giulio, G. Iaquinto, N. Giardullo, S. Auricchio, M. G. Roncarolo, and R. Troncone. 2005. Recombinant human interleukin 10 suppresses gliadin dependent T cell activation in ex vivo cultured coeliac intestinal mucosa. Gut 54:46–53.PubMedCrossRefGoogle Scholar
  51. 51.
    Gianfrani, C., M. K. Levings, C. Sartirana, G. Mazzarella, G. Barba, D. Zanzi, A. Camarca, G. Iaquinto, N. Giardullo, S. Auricchio, R. Troncone, and M. G. Roncarolo. 2006. Gliadin-specific type 1 regulatory T cells from the intestinal mucosa of treated celiac patients inhibit pathogenic T cells. J Immunol 177:4178–4186.PubMedGoogle Scholar
  52. 52.
    Umetsu, D. T., and R. H. DeKruyff. 2006. The regulation of allergy and asthma. Immunol Rev 212:238–255.PubMedCrossRefGoogle Scholar
  53. 53.
    Cavani, A., F. Nasorri, C. Prezzi, S. Sebastiani, C. Albanesi, and G. Girolomoni. 2000. Human CD4+ T lymphocytes with remarkable regulatory functions on dendritic cells and nickel-specific Th1 immune responses. J Invest Dermatol 114:295–302.PubMedCrossRefGoogle Scholar
  54. 54.
    Saloga, J., I. Bellinghausen, and J. Knop. 1999. Do Tr1 cells play a role in immunotherapy? Int Arch Allergy Immunol 118:210–211.PubMedCrossRefGoogle Scholar
  55. 55.
    Reefer, A. J., R. M. Carneiro, N. J. Custis, T. A. Platts-Mills, S. S. Sung, J. Hammer, and J. A. Woodfolk. 2004. A role for IL-10-mediated HLA-DR7-restricted T cell-dependent events in development of the modified Th2 response to cat allergen. J Immunol 172: 2763–2772.PubMedGoogle Scholar
  56. 56.
    Akdis, M. 2006. Healthy immune response to allergens: T regulatory cells and more. Curr Opin Immunol 18:738–744.PubMedCrossRefGoogle Scholar
  57. 57.
    Weston, L., A. Geczy, and H. Briscoe. 2005. Production od IL-10 by alloreactive sibling donor cells and its influence on teh development of acute GvHD. Bone Marrow Transplant 37:207–212.Google Scholar
  58. 58.
    Holler, E., M. G. Roncarolo, R. Hintermeier-Knabe, G. Eissner, B. Ertl, U. Schulz, H. Knabe, H. J. Kolb, R. Andreesen, and W. Wilmanns. 2000. Prognostic significance of increased IL-10 production in patients prior to allogeneic bone marrow transplantation. Bone Marrow Transplant 25:237–241.PubMedCrossRefGoogle Scholar
  59. 59.
    Baker, K. S., M. G. Roncarolo, C. Peters, M. Bigler, T. DeFor, and B. R. Blazar. 1999. High spontaneous IL-10 production in unrelated bone marrow transplant recipients is associated with fewer transplant-related complications and early deaths. Bone Marrow Transplant 23:1123–1129.PubMedCrossRefGoogle Scholar
  60. 60.
    VanBuskirk, A. M., W. J. Burlingham, E. Jankowska-Gan, T. Chin, S. Kusaka, F. Geissler, R. P. Pelletier, and C. G. Orosz. 2000. Human allograft acceptance is associated with immune regulation. J Clin Invest 106:145–155.PubMedCrossRefGoogle Scholar
  61. 61.
    Satoguina, J., M. Mempel, J. Larbi, M. Badusche, C. Loliger, O. Adjei, G. Gachelin, B. Fleischer, and A. Hoerauf. 2002. Antigen-specific T regulatory-1 cells are associated with immunosuppression in a chronic helminth infection (onchocerciasis). Microbes Infect 4: 1291–1300.PubMedCrossRefGoogle Scholar
  62. 62.
    Kullberg, M. C., A. G. Rothfuchs, D. Jankovic, P. Caspar, T. A. Wynn, P. L. Gorelick, A. W. Cheever, and A. Sher. 2001. Helicobacter hepaticus-induced colitis in interleukin-10-deficient mice: cytokine requirements for the induction and maintenance of intestinal inflammation. Infect Immun 69:4232–4241.PubMedCrossRefGoogle Scholar
  63. 63.
    Fiore, F., B. Nuschak, S. Peola, S. Mariani, M. Muraro, M. Foglietta, M. Coscia, B. Bruno, M. Boccadoro, and M. Massaia. 2005. Exposure to myeloma cell lysates affects the immune competence of dendritic cells and favors the induction of Tr1-like regulatory T cells. Eur J Immunol 35:1155–1163.PubMedCrossRefGoogle Scholar
  64. 64.
    Akasaki, Y., G. Liu, N. H. Chung, M. Ehtesham, K. L. Black, and J. S. Yu. 2004. Induction of a CD4+ T regulatory type 1 response by cyclooxygenase-2-overexpressing glioma. J Immunol 173:4352–4359.PubMedGoogle Scholar
  65. 65.
    Marshall, N. A., L. E. Christie, L. R. Munro, D. J. Culligan, P. W. Johnston, R. N. Barker, and M. A. Vickers. 2004. Immunosuppressive regulatory T cells are abundant in the reactive lymphocytes of Hodgkin lymphoma. Blood 103:1755–1762.PubMedCrossRefGoogle Scholar
  66. 66.
    Wei, S., I. Kryczek, L. Zou, B. Daniel, P. Cheng, P. Mottram, T. Curiel, A. Lange, and W. Zou. 2005. Plasmacytoid dendritic cells induce CD8+ regulatory T cells in human ovarian carcinoma. Cancer Res 65:5020–5026.PubMedCrossRefGoogle Scholar
  67. 67.
    Bejarano, M. T., R. de Waal Malefyt, J. S. Abrams, M. Bigler, R. Bacchetta, J. E. de Vries, and M. G. Roncarolo. 1992. Interleukin 10 inhibits allogeneic proliferative and cytotoxic T cell responses generated in primary mixed lymphocyte cultures. Int Immunol 4:1389–1397.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Manuela Battaglia
  • Silvia Gregori
    • 1
  • Rosa Bacchetta
  • Maria Grazia Roncarolo
    • 1
  1. 1.Immunology of Diabetes UnitSan Raffaele Telethon Institute for Gene Therapy (HSR-TIGET); San Raffaele Scientific InstituteItaly

Personalised recommendations