, Volume 39, Issue 3, pp 1205–1215 | Cite as

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

  • Leilei Zhou
  • Tianyi Cao
  • Yufeng Wang
  • Hui Yao
  • Guanhuan Du
  • Guangjie Chen
  • Xiaoyin Niu
  • Guoyao TangEmail author


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.


oral lichen planus regulatory T cells FOXP3 TGF-β IL-10 IL-17A 



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).


  1. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 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.CrossRefPubMedGoogle Scholar
  3. 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.CrossRefPubMedGoogle Scholar
  4. 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.CrossRefPubMedGoogle Scholar
  5. 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.CrossRefGoogle Scholar
  6. 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.CrossRefPubMedGoogle Scholar
  7. 7.
    Huang, F., and Y.G. Chen. 2012. Regulation of TGF-beta receptor activity. Cell Bioscience 2: 9.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Corthay, A. 2009. How do regulatory T cells work? Scandinavian Journal of Immunology 70: 326–336.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 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.PubMedPubMedCentralGoogle Scholar
  11. 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.CrossRefPubMedGoogle Scholar
  12. 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.PubMedGoogle Scholar
  13. 13.
    Pandiyan, P., and J. Zhu. 2015. Origin and functions of pro-inflammatory cytokine producing Foxp3+ regulatory T cells. Cytokine 76: 13–24.CrossRefPubMedGoogle Scholar
  14. 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.CrossRefPubMedGoogle Scholar
  15. 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.CrossRefPubMedGoogle Scholar
  16. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 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.CrossRefPubMedGoogle Scholar
  19. 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.CrossRefPubMedGoogle Scholar
  20. 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.CrossRefPubMedGoogle Scholar
  21. 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.CrossRefPubMedGoogle Scholar
  22. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 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.CrossRefGoogle Scholar
  26. 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.CrossRefPubMedGoogle Scholar
  27. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 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.CrossRefGoogle Scholar
  29. 29.
    Vignali, D.A., L.W. Collison, and C.J. Workman. 2008. How regulatory T cells work. Nature Reviews. Immunology 8: 523–532.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 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.CrossRefGoogle Scholar
  31. 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.CrossRefGoogle Scholar
  32. 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.CrossRefPubMedGoogle Scholar
  33. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 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.CrossRefPubMedGoogle Scholar
  37. 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. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 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.CrossRefPubMedGoogle Scholar
  42. 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.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Leilei Zhou
    • 1
  • Tianyi Cao
    • 1
  • Yufeng Wang
    • 1
  • Hui Yao
    • 1
  • Guanhuan Du
    • 1
  • Guangjie Chen
    • 2
  • Xiaoyin Niu
    • 2
  • Guoyao Tang
    • 1
    Email author
  1. 1.Shanghai Key Laboratory of Stomatology, Department of Oral Mucosal Diseases, Ninth People’ s HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
  2. 2.Department of Immunology, Institutes of Medical Sciences, Shanghai Institute of ImmunologyShanghai JiaoTong University School of MedicineShanghaiChina

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