Skip to main content
SpringerLink
Log in

Roles of CD4+CD25+ T cells in the development of experimental murine allergic conjunctivitis

  • Laboratory Investigation
  • Published:
Graefe's Archive for Clinical and Experimental Ophthalmology Aims and scope Submit manuscript

Abstract

Background

CD25+ regulatory T (T reg) cells play a suppressive role in experimental autoimmune uveoretinitis as well as experimental airway inflammation but their involvement in the development of allergic conjunctivitis (AC) remains unclear. We therefore investigated whether T reg cells play a role in the development of experimental AC (EC).

Methods

BALB/c and C57BL/6 mice were actively immunized with ragweed (RW). The mice were treated with an anti-CD25 Ab (PC61) or control normal rat IgG (nrIgG) either 2 days prior to active immunization or during the induction phase (days 0, 2, 4, 6 and 8). Ten days after active immunization, the mice were challenged with RW-containing drops. Twenty-four hours after the challenge, the conjunctivas were harvested for histological analysis of eosinophil infiltration, and the spleens were harvested for cell culture for splenocyte transfer. Cultured splenocytes were transferred into syngeneic mice, and 4 days after the transfer, the recipient mice were challenged with RW. Twenty-four hours after the challenge, conjunctivas were collected for histological analysis.

Results

Pretreatment with PC61 did not affect EC in either strain of mice; however, treatment with PC61 during the induction phase significantly suppressed EC in C57BL/6 mice. In contrast, transfer of RW-primed splenocytes from mice treated with PC61 induced EC that was significantly more severe regardless of strain and treatment protocol.

Conclusions

The finding that T reg cells play a suppressive role in the development of EC in splenocyte transfer experiments suggests that modulation of T reg cells may be a possible therapy for AC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Akdis M, Blaser K, Akdis CA (2005) T regulatory cells in allergy: novel concepts in the pathogenesis, prevention, and treatment of allergic diseases. J Allergy Clin Immunol 116:961–968

    Article  PubMed  CAS  Google Scholar 

  2. Baecher-Allan C, Brown JA, Freeman GJ, Hafler DA (2001) CD4+CD25high regulatory cells in human peripheral blood. J Immunol 167:1245–1253

    PubMed  CAS  Google Scholar 

  3. Bielory L (2002) Update on ocular allergy treatment. Expert Opin Pharmacother 3:541–553

    Article  PubMed  Google Scholar 

  4. Bonini S, Coassin M, Aronni S, Lambiase A (2004) Vernal keratoconjunctivitis. Eye 18:345–351

    Article  PubMed  CAS  Google Scholar 

  5. Coombes JL, Robinson NJ, Maloy KJ, Uhlig HH, Powrie F (2005) Regulatory T cells and intestinal homeostasis. Immunol Rev 204:184–194

    Article  PubMed  CAS  Google Scholar 

  6. Fukushima A, Fukata K, Ozaki A, Takata M, Kuroda N, Enzan H, Ueno H (2002) Exertion of the suppressive effects of IFN-gamma on experimental immune mediated blepharoconjunctivitis in Brown Norway rats during the induction phase but not the effector phase. Br J Ophthalmol 86:1166–1171

    Article  PubMed  CAS  Google Scholar 

  7. Fukushima A, Ozaki A, Fukata K, Ishida W, Ueno H (2003) Ag-specific recognition, activation, and effector function of T cells in the conjunctiva with experimental immune-mediated blepharoconjunctivitis. Invest Ophthalmol Vis Sci 44:4366–4374

    Article  PubMed  Google Scholar 

  8. Fukushima A, Ozaki A, Jian Z, Ishida W, Fukata K, Ueno H, Liu FT (2005) Dissection of antigen-specific humoral and cellular immune responses for the development of experimental immune-mediated blepharoconjunctivitis in C57BL/6 mice. Curr Eye Res 30:241–248

    Article  PubMed  CAS  Google Scholar 

  9. Fukushima A, Yamaguchi T, Ishida W, Fukata K, Mittler RS, Yagita H, Ueno H (2005) Engagement of 4-1BB inhibits the development of experimental allergic conjunctivitis in mice. J Immunol 175:4897–4903

    PubMed  CAS  Google Scholar 

  10. Fukushima A, Yamaguchi T, Ishida W, Fukata K, Yagita H, Ueno H (2005) The interaction between ICOS and B7RP-1 is not required for the development of experimental murine allergic conjunctivitis. Biochem Biophys Res Commun 338:1726–1731

    Article  PubMed  CAS  Google Scholar 

  11. Fukushima A, Yamaguchi T, Ishida W, Fukata K, Yagita H, Ueno H (2006) Roles of OX40 in the development of murine experimental allergic conjunctivitis: exacerbation and attenuation by stimulation and blocking of OX40. Invest Ophthalmol Vis Sci 47:657–663

    Article  PubMed  Google Scholar 

  12. Fukushima A, Yamaguchi T, Ishida W, Fukata K, Taniguchi T, Liu FT, Ueno H (2006) Genetic background determines susceptibility to experimental immune-mediated blepharoconjunctivitis: comparison of Balb/c and C57BL/6 mice. Exp Eye Res 82:210–218

    Article  PubMed  CAS  Google Scholar 

  13. Hadeiba H, Locksley RM (2003) Lung CD25 CD4 regulatory T cells suppress type 2 immune responses but not bronchial hyperreactivity. J Immunol 170:5502–5510

    PubMed  CAS  Google Scholar 

  14. Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299:1057–1061

    Article  PubMed  CAS  Google Scholar 

  15. Jaffar Z, Sivakuru T, Roberts K (2004) CD4+CD25+ T cells regulate airway eosinophilic inflammation by modulating the Th2 cell phenotype. J Immunol 172:3842–3849

    PubMed  CAS  Google Scholar 

  16. Kearley J, Barker JE, Robinson DS, Lloyd CM (2005) Resolution of airway inflammation and hyperreactivity after in vivo transfer of CD4+CD25+ regulatory T cells is interleukin 10 dependent. J Exp Med 202:1539–1547

    Article  PubMed  CAS  Google Scholar 

  17. Kumar RK, Herbert C, Webb DC, Li L, Foster PS (2004) Effects of anticytokine therapy in a mouse model of chronic asthma. Am J Respir Crit Care Med 170:1043–1048

    Article  PubMed  Google Scholar 

  18. Levings MK, Roncarolo MG (2005) Phenotypic and functional differences between human CD4+CD25+ and type 1 regulatory T cells. Curr Top Microbiol Immunol 293:303–326

    Article  PubMed  CAS  Google Scholar 

  19. Lewkowich IP, Herman NS, Schleifer KW, Dance MP, Chen BL, Dienger KM, Sproles AA, Shah JS, Kohl J, Belkaid Y, Wills-Karp M (2005) CD4+CD25+ T cells protect against experimentally induced asthma and alter pulmonary dendritic cell phenotype and function. J Exp Med 202:1549–1561

    Article  PubMed  CAS  Google Scholar 

  20. Lowenthal JW, Corthesy P, Tougne C, Lees R, MacDonald HR, Malek T, Robb RJ, Shevach EM (1983) Identification and initial characterization of a rat monoclonal antibody reactive with the murine interleukin 2 receptor-ligand complex. Proc Natl Acad Sci USA 80:5694–5698

    Article  Google Scholar 

  21. Magone MT, Whitcup SM, Fukushima A, Chan CC, Silver PB, Rizzo LV (2000) The role of IL-12 in the induction of late-phase cellular infiltration in a murine model of allergic conjunctivitis. J Allergy Clin Immunol 105:299–308

    Article  PubMed  CAS  Google Scholar 

  22. Nabholz M (1985) High and low affinity IL 2 receptors: analysis by IL 2 dissociation rate and reactivity with monoclonal anti-receptor antibody PC61. J Immunol 135:3988–3994

    PubMed  Google Scholar 

  23. Ozaki A, Seki Y, Fukushima A, Kubo M (2005) The control of allergic conjunctivitis by suppressor of cytokine signaling (SOCS)3 and SOCS5 in a murine model. J Immunol 175:5489–5497

    PubMed  CAS  Google Scholar 

  24. Piccirillo CA, Shevach EM (2004) Naturally-occurring CD4+CD25+ immunoregulatory T cells: central players in the arena of peripheral tolerance. Semin Immunol 16:81–88

    Article  PubMed  CAS  Google Scholar 

  25. Podack ER, Kupfer A (1991) T-cell effector functions: mechanisms for delivery of cytotoxicity and help. Annu Rev Cell Biol 7:479–504

    Article  PubMed  CAS  Google Scholar 

  26. Sakaguchi S, Sakaguchi N, Shimizu J, Yamazaki S, Sakihama T, Itoh M, Kuniyasu Y, Nomura T, Toda M, Takahashi T (2001) Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol Rev 182:18–32

    Article  PubMed  CAS  Google Scholar 

  27. Sakaguchi S, Sakaguchi N (2005) Regulatory T cells in immunologic self-tolerance and autoimmune disease. Int Rev Immunol 24:211–226

    Article  PubMed  CAS  Google Scholar 

  28. Shevach EM (2002) CD4+ CD25+ suppressor T cells: more questions than answers. Nat Rev Immunol 2:389–400

    PubMed  CAS  Google Scholar 

  29. Suto A, Nakajima H, Kagami SI, Suzuki K, Saito Y, Iwamoto I (2001) Role of CD4(+) CD25(+) regulatory T cells in T helper 2 cell-mediated allergic inflammation in the airways. Am J Respir Crit Care Med 164:680–687

    PubMed  CAS  Google Scholar 

  30. Takeuchi M, Keino H, Kezuka T, Usui M, Taguchi O (2004) Immune responses to retinal self-antigens in CD25(+)CD4(+) regulatory T-cell-depleted mice. Invest Ophthalmol Vis Sci 45:1879–1886

    Article  PubMed  Google Scholar 

  31. Wiley RE, Goncharova S, Shea T, Johnson JR, Coyle AJ, Jordana M (2003) Evaluation of inducible costimulator/B7-related protein-1 as a therapeutic target in a murine model of allergic airway inflammation. Am J Respir Cell Mol Biol 28:722–730

    Article  PubMed  CAS  Google Scholar 

  32. Yoshida O, Yoshida H, Iwamoto H, Nishino K, Fukushima A, Ueno H (1999) Genetic background determines the nature of immune responses and experimental immune-mediated blepharoconjunctivitis (EC). Curr Eye Res 18:117–124

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Ophthalmology, Kochi Medical School, Kohasu, Oko-cho, Nankoku-city, 783-8505, Japan

    Atsuki Fukushima, Tomoko Yamaguchi, Tamaki Sumi & Hisayuki Ueno

  2. Department of Biomolecular Recognition and Ophthalmology, Yamaguchi University School of Medicine, Ube, Yamaguchi, Japan

    Ken Fukuda, Naoki Kumagai & Teruo Nishida

  3. Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan

    Masaru Takeuchi

  4. Division of Molecular Pathology, Aichi Cancer Center Research Institute, Nagoya, Japan

    Osamu Taguchi

Authors
  1. Atsuki Fukushima
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tomoko Yamaguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tamaki Sumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ken Fukuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Naoki Kumagai
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Teruo Nishida
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Masaru Takeuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Osamu Taguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hisayuki Ueno
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Atsuki Fukushima.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fukushima, A., Yamaguchi, T., Sumi, T. et al. Roles of CD4+CD25+ T cells in the development of experimental murine allergic conjunctivitis. Graefe's Arch Clin Exp Ophthalmol 245, 705–714 (2007). https://doi.org/10.1007/s00417-006-0404-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00417-006-0404-5

Keywords

Search

Navigation