Skip to main content

Advertisement

SpringerLink
Log in

Frequently Increased but Functionally Impaired CD4+CD25+ Regulatory T Cells in Patients with Oral Lichen Planus

  • ORIGINAL ARTICLE
  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

Oral lichen planus (OLP) is a T cell-mediated chronic inflammatory mucosal disease, and CD4+CD25+ regulatory T cells (Tregs) are considered involved in the pathogenesis of OLP. In this study, to investigate whether there are intrinsic factors that might cause functional changes in Tregs in this disease, we evaluated the frequency of Tregs in peripheral blood and oral lesions and the expression levels of function-related transcription factors, forkhead/winged-helix transcription factor box P3 (FOXP3), transforming growth factor β (TGF-β), interleukin 10 (IL-10), and TGF-β receptors (TβRI and TβRII) mRNAs in Tregs of patients with oral lichen planus (OLP). We also investigated the frequency of pro-inflammatory cytokines (IFN-γ and IL-17A) producing Foxp3+ regulatory cells. Increased proportions of Tregs were found in OLP patients. The expression of FOXP3 on mRNA and protein level was elevated in the Tregs of OLP. The expression of TGF-β was lower both on the mRNA and serum level, whereas the expression of IL-10 showed no significant difference between the OLP patients and normal controls. The percentages of CD4+FOXP3+IL-17+ T cells were significantly higher than that of normal controls, whereas the percentages of CD4+FOXP3+IFN-γ+ T cells did not differ significantly. Furthermore, impaired suppressive function of CD4+CD25+ T cells was demonstrated in OLP patients by in vitro proliferation assay. These data indicate that Tregs in OLP are frequently expanded but functionally deficient. This could explain, at least in part, why the increased Tregs in OLP fail to control the pathogenesis and development of this autoimmune disease.

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

Similar content being viewed by others

References

  1. Pereira, J.S., B.V. Monteiro, C.F. Nonaka, E.J. Silveira, and M.C. Miguel. 2012. FoxP3(+) T regulatory cells in oral lichen planus and its correlation with the distinct clinical appearance of the lesions. International Journal of Experimental Pathology 93: 287–294.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Sousa, F.A., T.C. Paradella, A.A. Brandao, and L.E. Rosa. 2009. Oral lichen planus versus epithelial dysplasia: difficulties in diagnosis. Brazilian Journal of Otorhinolaryngology 75: 716–720.

    Article  PubMed  Google Scholar 

  3. Tao, X.A., J. Xia, X.B. Chen, H. Wang, Y.H. Dai, N.L. Rhodus, and B. Cheng. 2010. FOXP3 T regulatory cells in lesions of oral lichen planus correlated with disease activity. Oral Diseases 16: 76–82.

    Article  PubMed  Google Scholar 

  4. Shen, Z., X. Gao, L. Ma, Z. Zhou, X. Shen, and W. Liu. 2014. Expression of Foxp3 and interleukin-17 in lichen planus lesions with emphasis on difference in oral and cutaneous variants. Archives of Dermatological Research 306: 441–446.

    Article  CAS  PubMed  Google Scholar 

  5. Li, Z., D. Li, A. Tsun, and B. Li. 2015. FOXP3(+) regulatory T cells and their functional regulation. Cellular & Molecular Immunology 12: 558–565.

    Article  Google Scholar 

  6. Menetrier-Caux, C., T. Curiel, J. Faget, M. Manuel, C. Caux, and W. Zou. 2012. Targeting regulatory T cells. Targeted Oncology 7: 15–28.

    Article  PubMed  Google Scholar 

  7. Huang, F., and Y.G. Chen. 2012. Regulation of TGF-beta receptor activity. Cell Bioscience 2: 9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Corthay, A. 2009. How do regulatory T cells work? Scandinavian Journal of Immunology 70: 326–336.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Liu, W., A.L. Putnam, Z. Xu-Yu, G.L. Szot, M.R. Lee, S. Zhu, P.A. Gottlieb, P. Kapranov, T.R. Gingeras, B. Fazekas de St Groth, et al. 2006. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. Journal of Experimental Medicine 203: 1701–1711.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Drennan, S., N.D. Stafford, J. Greenman, and V.L. Green. 2013. Increased frequency and suppressive activity of CD127(low/-) regulatory T cells in the peripheral circulation of patients with head and neck squamous cell carcinoma are associated with advanced stage and nodal involvement. Immunology 140: 335–343.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Hu, Y., C. Dong, M. Chen, Y. Chen, A. Gu, Y. Xia, H. Sun, Z. Li, and Y. Wang. 2015. Effects of monobutyl phthalate on steroidogenesis through steroidogenic acute regulatory protein regulated by transcription factors in mouse Leydig tumor cells. Journal of Endocrinological Investigation 38: 875–884.

    Article  CAS  PubMed  Google Scholar 

  12. Lei, L., L. Zhan, W. Tan, S. Chen, Y. Li, and M. Reynolds. 2014. Foxp3 gene expression in oral lichen planus: a clinicopathological study. Molecular Medicine Reports 9: 928–934.

    CAS  PubMed  Google Scholar 

  13. Pandiyan, P., and J. Zhu. 2015. Origin and functions of pro-inflammatory cytokine producing Foxp3+ regulatory T cells. Cytokine 76: 13–24.

    Article  CAS  PubMed  Google Scholar 

  14. Tao, X., Y. Huang, R. Li, R. Qing, L. Ma, N.L. Rhodus, and B. Cheng. 2007. Assessment of local angiogenesis and vascular endothelial growth factor in the patients with atrophic-erosive and reticular oral lichen planus. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics 103: 661–669.

    Article  PubMed  Google Scholar 

  15. Barath, S., P. Soltesz, E. Kiss, M. Aleksza, M. Zeher, G. Szegedi, and S. Sipka. 2007. The severity of systemic lupus erythematosus negatively correlates with the increasing number of CD4 + CD25(high)FoxP3+ regulatory T cells during repeated plasmapheresis treatments of patients. Autoimmunity 40: 521–528.

    Article  CAS  PubMed  Google Scholar 

  16. Yamazaki, S., T. Iyoda, K. Tarbell, K. Olson, K. Velinzon, K. Inaba, and R.M. Steinman. 2003. Direct expansion of functional CD25+ CD4+ regulatory T cells by antigen-processing dendritic cells. Journal of Experimental Medicine 198: 235–247.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Walker, L.S., A. Chodos, M. Eggena, H. Dooms, and A.K. Abbas. 2003. Antigen-dependent proliferation of CD4+ CD25+ regulatory T cells in vivo. Journal of Experimental Medicine 198: 249–258.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Fontenot, J.D., M.A. Gavin, and A.Y. Rudensky. 2003. Foxp3 programs the development and function of CD4 + CD25+ regulatory T cells. Nature Immunology 4: 330–336.

    Article  CAS  PubMed  Google Scholar 

  19. Brunkow, M.E., E.W. Jeffery, K.A. Hjerrild, B. Paeper, L.B. Clark, S.A. Yasayko, J.E. Wilkinson, D. Galas, S.F. Ziegler, and F. Ramsdell. 2001. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nature Genetics 27: 68–73.

    Article  CAS  PubMed  Google Scholar 

  20. Bennett, C.L., J. Christie, F. Ramsdell, M.E. Brunkow, P.J. Ferguson, L. Whitesell, T.E. Kelly, F.T. Saulsbury, P.F. Chance, and H.D. Ochs. 2001. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nature Genetics 27: 20–21.

    Article  CAS  PubMed  Google Scholar 

  21. Miyara, M., Y. Yoshioka, A. Kitoh, T. Shima, K. Wing, A. Niwa, C. Parizot, C. Taflin, T. Heike, D. Valeyre, et al. 2009. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 30: 899–911.

    Article  CAS  PubMed  Google Scholar 

  22. Alunno, A., E. Bartoloni, G. Nocentini, O. Bistoni, S. Ronchetti, M.G. Petrillo, C. Riccardi, and R. Gerli. 2010. Role of regulatory T cells in rheumatoid arthritis: facts and hypothesis. Auto Immun Highlights 1: 45–51.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Buckner, J.H. 2010. Mechanisms of impaired regulation by CD4(+)CD25(+)FOXP3(+) regulatory T cells in human autoimmune diseases. Nature Reviews Immunology 10: 849–859.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Lawson, J.M., J. Tremble, C. Dayan, H. Beyan, R.D. Leslie, M. Peakman, and T.I. Tree. 2008. Increased resistance to CD4 + CD25hi regulatory T cell-mediated suppression in patients with type 1 diabetes. Clinical and Experimental Immunology 154: 353–359.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Venken, K., N. Hellings, T. Broekmans, K. Hensen, J.L. Rummens, and P. Stinissen. 2008. Natural naive CD4 + CD25 + CD127low regulatory T cell (Treg) development and function are disturbed in multiple sclerosis patients: recovery of memory Treg homeostasis during disease progression. Journal of Immunology 180: 6411–6420.

    Article  CAS  Google Scholar 

  26. Bonelli, M., A. Savitskaya, K. von Dalwigk, C.W. Steiner, D. Aletaha, J.S. Smolen, and C. Scheinecker. 2008. Quantitative and qualitative deficiencies of regulatory T cells in patients with systemic lupus erythematosus (SLE). International Immunology 20: 861–868.

    Article  CAS  PubMed  Google Scholar 

  27. Yuan, Q., S.K. Bromley, T.K. Means, K.J. Jones, F. Hayashi, A.K. Bhan, and A.D. Luster. 2007. CCR4-dependent regulatory T cell function in inflammatory bowel disease. Journal of Experimental Medicine 204: 1327–1334.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Sugiyama, H., R. Gyulai, E. Toichi, E. Garaczi, S. Shimada, S.R. Stevens, T.S. McCormick, and K.D. Cooper. 2005. Dysfunctional blood and target tissue CD4 + CD25high regulatory T cells in psoriasis: mechanism underlying unrestrained pathogenic effector T cell proliferation. Journal of Immunology 174: 164–173.

    Article  CAS  Google Scholar 

  29. Vignali, D.A., L.W. Collison, and C.J. Workman. 2008. How regulatory T cells work. Nature Reviews. Immunology 8: 523–532.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Joetham, A., K. Takeda, C. Taube, N. Miyahara, S. Matsubara, T. Koya, Y.H. Rha, A. Dakhama, and E.W. Gelfand. 2007. Naturally occurring lung CD4(+)CD25(+) T cell regulation of airway allergic responses depends on IL-10 induction of TGF-beta. Journal of Immunology 178: 1433–1442.

    Article  CAS  Google Scholar 

  31. Kursar, M., M. Koch, H.W. Mittrucker, G. Nouailles, K. Bonhagen, T. Kamradt, and S.H. Kaufmann. 2007. Cutting edge: regulatory T cells prevent efficient clearance of mycobacterium tuberculosis. Journal of Immunology 178: 2661–2665.

    Article  CAS  Google Scholar 

  32. Li, M.O., Y.Y. Wan, and R.A. Flavell. 2007. T cell-produced transforming growth factor-beta1 controls T cell tolerance and regulates Th1- and Th17-cell differentiation. Immunity 26: 579–591.

    Article  CAS  PubMed  Google Scholar 

  33. Fahlen, L., S. Read, L. Gorelik, S.D. Hurst, R.L. Coffman, R.A. Flavell, and F. Powrie. 2005. T cells that cannot respond to TGF-beta escape control by CD4(+)CD25(+) regulatory T cells. Journal of Experimental Medicine 201: 737–746.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Chen, M.L., M.J. Pittet, L. Gorelik, R.A. Flavell, R. Weissleder, H. von Boehmer, and K. Khazaie. 2005. Regulatory T cells suppress tumor-specific CD8 T cell cytotoxicity through TGF-beta signals in vivo. Proceedings of the National Academy of Sciences of the United States of America 102: 419–424.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Marie, J.C., J.J. Letterio, M. Gavin, and A.Y. Rudensky. 2005. TGF-beta1 maintains suppressor function and Foxp3 expression in CD4 + CD25+ regulatory T cells. Journal of Experimental Medicine 201: 1061–1067.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Rubtsov, Y.P., J.P. Rasmussen, E.Y. Chi, J. Fontenot, L. Castelli, X. Ye, P. Treuting, L. Siewe, A. Roers, W.R. Henderson Jr., et al. 2008. Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity 28: 546–558.

    Article  CAS  PubMed  Google Scholar 

  37. Taghavi Zenouz, A., F. Pouralibaba, Z. Babaloo, M. Mehdipour, and Z. Jamali. 2012. Evaluation of serum TNF-alpha and TGF-beta in patients with oral lichen planus. Journal of Dental Research Dental Clinical Dental Prospects 6: 143–147.

    Google Scholar 

  38. Wan, Y.Y., and R.A. Flavell. 2008. TGF-beta and regulatory T cell in immunity and autoimmunity. Journal of Clinical Immunology 28: 647–659.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Beriou, G., C.M. Costantino, C.W. Ashley, L. Yang, V.K. Kuchroo, C. Baecher-Allan, and D.A. Hafler. 2009. IL-17-producing human peripheral regulatory T cells retain suppressive function. Blood 113: 4240–4249.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Hovhannisyan, Z., J. Treatman, D.R. Littman, and L. Mayer. 2011. Characterization of interleukin-17-producing regulatory T cells in inflamed intestinal mucosa from patients with inflammatory bowel diseases. Gastroenterology 140: 957–965.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Duarte, J.H., S. Zelenay, M.L. Bergman, A.C. Martins, and J. Demengeot. 2009. Natural Treg cells spontaneously differentiate into pathogenic helper cells in lymphopenic conditions. European Journal of Immunology 39: 948–955.

    Article  CAS  PubMed  Google Scholar 

  42. Bovenschen, H.J., P.C. van de Kerkhof, P.E. van Erp, R. Woestenenk, I. Joosten, and H.J. Koenen. 2011. Foxp3+ regulatory T cells of psoriasis patients easily differentiate into IL-17A-producing cells and are found in lesional skin. Journal of Investigative Dermatology 131: 1853–1860.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by research grants National Construction Project of Clinical Key Specialized Department ([2013] 544) and National Science Foundation of China (Grant No. 81170967 and Grant No. 81570975).

Author information

Authors and Affiliations

  1. Shanghai Key Laboratory of Stomatology, Department of Oral Mucosal Diseases, Ninth People’ s Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai, 200011, China

    Leilei Zhou, Tianyi Cao, Yufeng Wang, Hui Yao, Guanhuan Du & Guoyao Tang

  2. Department of Immunology, Institutes of Medical Sciences, Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine, Shanghai, China

    Guangjie Chen & Xiaoyin Niu

Authors
  1. Leilei Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tianyi Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yufeng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hui Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Guanhuan Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Guangjie Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xiaoyin Niu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Guoyao Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Guoyao Tang.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhou, L., Cao, T., Wang, Y. et al. Frequently Increased but Functionally Impaired CD4+CD25+ Regulatory T Cells in Patients with Oral Lichen Planus. Inflammation 39, 1205–1215 (2016). https://doi.org/10.1007/s10753-016-0356-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-016-0356-9

KEY WORDS

Search

Navigation