Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Antigen-specific regulatory T cells develop via the ICOS–ICOS-ligand pathway and inhibit allergen-induced airway hyperreactivity

Nature Medicine volume 8, pages 1024–1032 (2002)Cite this article

This article has been updated

Abstract

Asthma is caused by T-helper cell 2 (Th2)-driven immune responses, but the immunological mechanisms that protect against asthma development are poorly understood. T-cell tolerance, induced by respiratory exposure to allergen, can inhibit the development of airway hyperreactivity (AHR), a cardinal feature of asthma, and we show here that regulatory T (TR) cells can mediate this protective effect. Mature pulmonary dendritic cells in the bronchial lymph nodes of mice exposed to respiratory allergen induced the development of TR cells, in a process that required T-cell costimulation via the inducible costimulator (ICOS)–ICOS-ligand pathway. The TR cells produced IL-10, and had potent inhibitory activity; when adoptively transferred into sensitized mice,* TR cells blocked the development of AHR. Both the development and the inhibitory function of regulatory cells were dependent on the presence of IL-10 and on ICOS–ICOS-ligand interactions. These studies demonstrate that TR cells and the ICOS–ICOS-ligand signaling pathway are critically involved in respiratory tolerance and in downregulating pulmonary inflammation in asthma.

*There was an error in the AOP version of this article. The sentence in the abstract that read The TR cells produced IL-10, and had potent inhibitory activity; when adoptively transferred into sensitized mouse TR cells, blocked the development of AHR was worded incorrectly. The following sentence is correct: The TR cells produced IL-10, and had potent inhibitory activity; when adoptively transferred into sensitized mice, TR cells blocked the development of AHR. This has been corrected in the HTML and the PDF. We regret this error.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: T-cell lines produce IL-10 when generated with IL-10-secreting DCs.
Figure 2: Development of IL-10-producing T cells in mice exposed to i.n. OVA.
Figure 3: TR cells regulate airway inflammation.
Figure 4: Effector function of regulatory T cells is dependent on IL-10 and ICOS.
Figure 5: ICOS costimulation is required for intranasal tolerance.
Figure 6: ICOS-L expression on DCs is required for i.n. tolerance.

Similar content being viewed by others

Change history

  • 26 August 2002

    This was incorrect in AOP version but corrected in print. Changed one word in the abstract and moved a comma, as per the note.

Notes

  1. NOTE: There was an error in the AOP version of this article. The sentence in the abstract that read The TR cells produced IL-10, and had potent inhibitory activity; when adoptively transferred into sensitized mouse TR cells, blocked the development of AHR was worded incorrectly. The following sentence is correct: The TR cells produced IL-10, and had potent inhibitory activity; when adoptively transferred into sensitized mice, TR cells blocked the development of AHR. This has been corrected in the HTML and the PDF. We regret this error.

References

  1. Forecasted state-specific estimates of self-reported asthma prevalence—United States, 1998. MMWR Morb. Mortal. Wkly Rep. 47, 1022–1025 (1998).

  2. Holgate, S.T. The epidemic of allergy and asthma. Nature 402, b2–4 (1999).

    Article  CAS  PubMed  Google Scholar 

  3. Umetsu, D.T. & DeKruyff, R.H. Th1 and Th2 CD4+ cells in human allergic diseases. J. Aller. Clin. Immunol. 100, 1–6 (1997).

    Article  CAS  Google Scholar 

  4. Wills-Karp, M. Immunologic basis of antigen-induced airway hyperresponsiveness. Annu. Rev. Immunol. 17, 255–281 (1999).

    Article  CAS  PubMed  Google Scholar 

  5. Walter, D.M. et al. Critical role for IL-13 in the development of allergen-induced airway hyperreactivity. J. Immunol. 167, 4668–4675 (2001).

    Article  CAS  PubMed  Google Scholar 

  6. Mosmann, T.R. & Coffman, R.L. Th1 and Th2 cells: Different patterns of lymphokine secretion lead to different functional properties. Ann. Rev. Immunol. 7, 145–173 (1989).

    Article  CAS  Google Scholar 

  7. Romagnani, S. Lymphokine production by human T cells in disease states. Ann. Rev. Immunol. 12, 227–257 (1994).

    Article  CAS  Google Scholar 

  8. Corrigan, C.J. & Kay, A.B. CD4 T-lymphocyte activation in acute severe asthma. Relationship to disease severity and atopic status. Am. Rev. Respir. Dis. 141, 970–977 (1990).

    Article  CAS  PubMed  Google Scholar 

  9. Hansen, G., Berry, G., DeKruyff, R.H. & Umetsu, D.T. Allergen-specific Th1 cells fail to counterbalance Th2 cell-induced airway hyperreactivity but cause severe airway inflammation. J. Clin. Invest. 103, 175–183 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Hansen, G. et al. CD4(+) T helper cells engineered to produce latent TGF-β1 reverse allergen-induced airway hyperreactivity and inflammation. J. Clin. Invest. 105, 61–70 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Akbari, O., DeKruyff, R.H. & Umetsu, D.T. Pulmonary dendritic cells producing IL-10 mediate tolerance induced by respiratory exposure to antigen. Nature Immunol. 2, 725–731 (2001).

    Article  CAS  Google Scholar 

  12. Tsitoura, D.C., DeKruyff, R.H., Lamb, J.R. & Umetsu, D.T. Intranasal exposure to protein antigen induces immunological tolerance mediated by functionally disabled CD4+ T cells. J. Immunol. 163, 2592–2600 (1999).

    CAS  PubMed  Google Scholar 

  13. McAdam, A.J. et al. Mouse inducible costimulatory molecule (ICOS) expression is enhanced by CD28 costimulation and regulates differentiation of CD4(+) T cells. J. Immunol. 165, 5035–5040 (2000).

    Article  CAS  PubMed  Google Scholar 

  14. Hutloff, A. et al. ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28. Nature 397, 263–266 (1999).

    Article  CAS  PubMed  Google Scholar 

  15. Yoshinaga, S.K. et al. T-cell co-stimulation through B7RP-1 and ICOS. Nature 402, 827–832 (1999).

    Article  CAS  PubMed  Google Scholar 

  16. Groux, H. et al. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389, 737–742 (1997).

    Article  CAS  PubMed  Google Scholar 

  17. Roncarolo, M.G., Levings, M.K. & Traversari, C. Differentiation of T regulatory cells by immature dendritic cells. J. Exp. Med. 193, F5–F9 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. McAdam, A.J. et al. ICOS is critical for CD40-mediated antibody class switching. Nature 409, 102–105 (2001).

    Article  CAS  PubMed  Google Scholar 

  19. Gonzalo, J.A. et al. ICOS is critical for T helper cell-mediated lung mucosal inflammatory responses. Nature Immunol. 2, 597–604 (2001).

    Article  CAS  Google Scholar 

  20. Oro, A.S., Guarino, T.J., Driver, R., Steinman, L. & Umetsu, D.T. Regulation of disease susceptibility: Decreased prevalence of IgE- mediated allergic disease in patients with multiple sclerosis. J. Allergy Clin. Immunol. 97, 1402–1408 (1996).

    Article  CAS  PubMed  Google Scholar 

  21. Shirakawa, T., Enomoto, T., Shimazu, S. & Hopkin, J.M. The inverse association between tuberculin responses and atopic disorder. Science 275, 77–79 (1997).

    Article  CAS  PubMed  Google Scholar 

  22. Secrist, H., Chelen, C.J., Wen, Y., Marshall, J.D. & Umetsu, D.T. Allergen immunotherapy decreases interleukin 4 production in CD4+ T cells from allergic individuals. J. Exp. Med. 178, 2123–2130 (1993).

    Article  CAS  PubMed  Google Scholar 

  23. Varney, V.A. et al. Influence of grass pollen immunotherapy on cellular infiltration and cytokine mRNA expression during allergen-induced late-phase cutaneous responses. J. Clin. Invest. 92, 644–651 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kim, T.S. et al. An OVA-IL-12 fusion protein is more effective than OVA plus rIL-12 in inducing a Th1-dominated immune response and inhibiting antigen-specific IgE production. J. Immunol. 158, 4137–4144 (1997).

    CAS  PubMed  Google Scholar 

  25. Yeung, V.P., Gieni, R.S., Umetsu, D.T. & DeKruyff, R.H. Heat-killed Listeria monocytogenes as an adjuvant converts established murine Th2-dominated immune responses into Th1-dominated responses. J. Immunol. 161, 4146–4152 (1998).

    CAS  PubMed  Google Scholar 

  26. Raz, E. et al. Preferential induction of a Th1 immune response and inhibition of specific IgE antibody formation by plasmid DNA immunization. Proc. Natl. Acad. Sci. USA 93, 5141–5145 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Hsu, C.H. et al. Immunoprophylaxis of allergen-induced immunoglobulin E synthesis and airway hyperresponsiveness in vivo by genetic immunization. Nature Med. 2, 540–544 (1996).

    Article  CAS  PubMed  Google Scholar 

  28. Gavett, S.H. et al. Interleukin 12 inhibits antigen-induced airway hyperresponsiveness, inflammation, and Th2 cytokine expression in mice. J. Exp. Med. 182, 1527–1536 (1995).

    Article  CAS  PubMed  Google Scholar 

  29. Randolph, D.A., Carruthers, C.J., Szabo, S.J., Murphy, K.M. & Chaplin, D.D. Modulation of airway inflammation by passive transfer of allergen-specific Th1 and Th2 cells in a mouse model of asthma. J. Immunol. 162, 2375–2383 (1999).

    CAS  PubMed  Google Scholar 

  30. Coffman, R.L. & Mosmann, T.R. CD4+ T-cell subsets: Regulation of differentiation and function. Res. Immunol. 142, 7–9 (1991).

    Article  CAS  PubMed  Google Scholar 

  31. Ding, L., Linsley, P.S., Huang, L.Y., Germain, R.N. & Shevach, E.M. IL-10 inhibits macrophage costimulatory activity by selectively inhibiting the up-regulation of B7 expression. J. Immunol. 151, 1224–1234 (1993).

    CAS  PubMed  Google Scholar 

  32. Makela, M.J. et al. IL-10 is necessary for the expression of airway hyperresponsiveness but not pulmonary inflammation after allergic sensitization. Proc. Natl. Acad. Sci. USA 97, 6007–6012 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Levings, M.K. & Roncarolo, M.G. T-regulatory 1 cells: A novel subset of CD4 T cells with immunoregulatory properties. J. Allergy Clin. Immunol. 106, S109–112 (2000).

    Article  CAS  PubMed  Google Scholar 

  34. Akdis, C.A., Blesken, T., Akdis, M., Wuthrich, B. & Blaser, K. Role of interleukin 10 in specific immunotherapy. J. Clin. Invest. 102, 98–106 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Jonuleit, H. et al. Identification and functional characterization of human CD4(+)CD25(+) T cells with regulatory properties isolated from peripheral blood. J. Exp. Med. 193, 1285–1294 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Barrat, F.J. et al. 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 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Huang, F.P. et al. A discrete subpopulation of dendritic cells transports apoptotic intestinal epithelial cells to T cell areas of mesenteric lymph nodes. J. Exp. Med. 191, 435–444 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Sauter, B. et al. Consequences of cell death: Exposure to necrotic tumor cells, but not primary tissue cells or apoptotic cells, induces the maturation of immunostimulatory dendritic cells. J. Exp. Med. 191, 423–434 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Nakajima, A. et al. Requirement of CD28-CD86 co-stimulation in the interaction between antigen-primed T helper type 2 and B cells. Int. Immunol. 9, 637–644 (1997).

    Article  CAS  PubMed  Google Scholar 

  40. Chen, Y., Kuchroo, V.K., Inobe, J., Hafler, D.A. & Weiner, H.L. Regulatory T cell clones induced by oral tolerance: Suppression of autoimmune encephalomyelitis. Science 265, 1237–1240 (1994).

    Article  CAS  PubMed  Google Scholar 

  41. Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M. & Toda, M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor α-chains (CD25). J. Immunol. 160, 1151–1164 (1995).

    Google Scholar 

  42. Thornton, A. & Shevach, E.M. CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J. Exp. Med. 188, 287–296 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. McGuirk, P., McCann, C. & Mills, K.H. 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 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Tivol, E. et al. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3, 541–547 (1995).

    Article  CAS  PubMed  Google Scholar 

  45. Mages, H.W. et al. Molecular cloning and characterization of murine ICOS and identification of B7h as ICOS ligand. Eur. J. Immunol. 30, 1040–1047 (2000).

    Article  CAS  PubMed  Google Scholar 

  46. Swallow, M.M., Wallin, J.J. & Sha, W.C. B7h, a novel costimulatory homolog of B7.1 and B7.2, is induced by TNFα. Immunity 11, 423–432 (1999).

    Article  CAS  PubMed  Google Scholar 

  47. Ling, V. et al. Cutting edge: Identification of GL50, a novel B7-like protein that functionally binds to ICOS receptor. J. Immunol 164, 1653–1637 (2000).

    Article  CAS  PubMed  Google Scholar 

  48. Coyle, A.J. et al. The CD28-related molecule ICOS is required for effective T cell- dependent immune responses. Immunity 13, 95–105 (2000).

    Article  CAS  PubMed  Google Scholar 

  49. Dong, C. et al. ICOS co-stimulatory receptor is essential for T-cell activation and function. Nature 409, 97–101 (2001).

    Article  CAS  PubMed  Google Scholar 

  50. Marrack, P., Shimonkevitz, R., Hannum, C., Haskins, K. & Kappler, J. The major histocompatibility complex-restricted antigen receptor on T cells. IV. An antiidiotypic antibody predicts both antigen and I- specificity. J. Exp. Med. 158, 1635–1646 (1983).

    Article  CAS  PubMed  Google Scholar 

  51. Maloney, D.G., Kaminski, M.S., Burowski, D., Haimovich, J. & Levy, R. Monoclonal anti-idiotype antibodies against the murine B cell lymphoma 38C13: Characterization and use as probes for the biology of the tumor in vivo and in vitro. Hybridoma 4, 191–209 (1985).

    Article  CAS  PubMed  Google Scholar 

  52. Lyons, A.B. & Parish, C.R. Determination of lymphocyte division by flow cytometry. J. Immunol. Methods 171, 131–137 (1994).

    Article  CAS  PubMed  Google Scholar 

  53. Hansen, G., Yeung, V.P., Berry, G., Umetsu, D.T. & DeKruyff, R.H. Vaccination with heat-killed Listeria as adjuvant reverses established allergen-induced airway hyperreactivity and inflammation: Role of CD8+ T cells and IL-18. J. Immunol. 164, 223–230 (2000).

    Article  CAS  PubMed  Google Scholar 

  54. Scheicher, C., Mehlig, M., Zecher, R. & Reske, K. Dendritic cells from mouse bone marrow: In vitro differentiation using low doses of recombinant granulocyte-macrophage colony-stimulating factor. J. Immunol. Meth. 154, 253–264 (1992).

    Article  CAS  Google Scholar 

  55. Inaba, K. et al. Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor. J. Exp. Med. 176, 1693–1702 (1992).

    Article  CAS  PubMed  Google Scholar 

  56. Stockinger, B. & Hausmann, B. Functional recognition of in vivo processed self antigen. Int. Immunol. 6, 247–254 (1994).

    Article  CAS  PubMed  Google Scholar 

  57. Kearney, E.R., Pape, K.A., Loh, D.Y. & Jenkins, M.K. Visualization of peptide-specific T cell immunity and peripheral tolerance induction in vivo. Immunity 1, 327–239 (1994).

    Article  CAS  PubMed  Google Scholar 

  58. Assenmacher, M., Schmitz, J. & Radbruch, A. Flow cytometric determination of cytokines in activated murine T helper lymphocytes: Expression of interleukin-10 in interferon-γ and in interleukin-4-expressing cells. Eur. J. Immunol. 24, 1097–1101 (1994).

    Article  CAS  PubMed  Google Scholar 

  59. Sander, B., Andersson, J. & Andersson, U. Assessment of cytokines by immunofluorescence and the paraformaldehyde- saponin procedure. Immunol. Rev. 119, 65–93 (1991).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by the NIH Public Health Service (RO1HL62348, AI24571, AI26322, CA84500, AI39671, and AI38310), and a fellowship from the California Lung Association.

Author information

Authors and Affiliations

  1. Division of Immunology and Allergy, Department of Pediatrics, School of Medicine, Stanford University, Stanford, California, USA

    Omid Akbari, Everett H. Meyer, Rosemarie H. DeKruyff & Dale T. Umetsu

  2. Department of Pathology, School of Medicine, Stanford University, Stanford, California, USA

    Gerald Berry

  3. Department of Adult Oncology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA

    Gordon J. Freeman & Edward A. Greenfield

  4. Immunology Research Division, Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA

    Tammy T. Chang & Arlene H. Sharpe

Authors
  1. Omid Akbari
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gordon J. Freeman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Everett H. Meyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Edward A. Greenfield
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tammy T. Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Arlene H. Sharpe
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gerald Berry
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Rosemarie H. DeKruyff
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Dale T. Umetsu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dale T. Umetsu.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Akbari, O., Freeman, G., Meyer, E. et al. Antigen-specific regulatory T cells develop via the ICOS–ICOS-ligand pathway and inhibit allergen-induced airway hyperreactivity. Nat Med 8, 1024–1032 (2002). https://doi.org/10.1038/nm745

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm745

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing