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Increased Th22 cells are independently associated with Th17 cells in type 1 diabetes

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Abstract

Type 1 diabetes (T1D) is perceived as an autoimmune disease caused by T cell-mediated destruction of the insulin-producing pancreatic β cells. However, the number of inflammatory T cells in blood, as well as the relative importance of each cell type is unclear. Forty-two patients with T1D and 30 controls were enrolled. Circulating primary CD4+ or CD8+ T cells were quantified with 5-color flow cytometry. Serum IL-22 and IL-17 levels were examined by ELISA. Serum autoantibodies were measured by radio-binding assays, using 35S-labeled glutamic acid decarboxylase-65 (GAD65), protein tyrosine phosphatase-2 (IA-2), and zinc transporter 8 (ZnT8). Th17–Th22 and Tc1–Tc17 were significantly elevated in patients with T1D compared to control subjects, while there were no significant differences in Th1 cells. The levels of these T cells in different stages of T1D were investigated. Th22 cells showed a positive correlation with Th17 cells in T1D patients. However, we did not find any correlation between IL-17 and IL-22 in sera. Autoantibodies were not significantly different between patients with early T1D and those who have had it for a longer duration. This study indicates that Th22 may contribute to the pathogenesis of T1D. Blockade of Th22 cells might be of clinical profit in T1D patients.

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References

  1. J.A. Bluestone, K. Herold, G. Eisenbarth, Genetics, pathogenesis and clinical interventions in type 1 diabetes. Nature 464(7293), 1293–1300 (2010)

    Article  CAS  PubMed  Google Scholar 

  2. J.A. Emamaullee, J. Davis, S. Merani, C. Toso, J.F. Elliott, A. Thiesen, A.M. Shapiro, Inhibition of Th17 cells regulates autoimmune diabetes in NOD mice. Diabetes 58(6), 1302–1311 (2009)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. R. Jain, D.M. Tartar, R.K. Gregg, R.D. Divekar, J.J. Bell, H.H. Lee, P. Yu, J.S. Ellis, C.M. Hoeman, C.L. Franklin, H. Zaghouani, Innocuous IFNgamma induced by adjuvant-free antigen restores normoglycemia in NOD mice through inhibition of IL-17 production. J. Exp. Med. 205(1), 207–218 (2008)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. J. Honkanen, J.K. Nieminen, R. Gao, K. Luopajarvi, H.M. Salo, J. Ilonen, M. Knip, T. Otonkoski, O. Vaarala, IL-17 immunity in human type 1 diabetes. J Immunol 185(3), 1959–1967 (2010)

    Article  CAS  PubMed  Google Scholar 

  5. P. Miossec, T. Korn, V.K. Kuchroo, Interleukin-17 and type 17 helper T cells. N. Engl. J. Med. 361(9), 888–898 (2009)

    Article  CAS  PubMed  Google Scholar 

  6. S. Arif, F. Moore, K. Marks, T. Bouckenooghe, C.M. Dayan, R. Planas, M. Vives-Pi, J. Powrie, T. Tree, P. Marchetti, G.C. Huang, E.N. Gurzov, R. Pujol-Borrell, D.L. Eizirik, M. Peakman, Peripheral and islet interleukin-17 pathway activation characterizes human autoimmune diabetes and promotes cytokine-mediated beta-cell death. Diabetes 60(8), 2112–2119 (2011)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. M. Ryba-Stanislawowska, M. Skrzypkowska, M. Mysliwiec, J. Mysliwska, Loss of the balance between CD4(+)Foxp3(+) regulatory T cells and CD4(+)IL17A(+) Th17 cells in patients with type 1 diabetes. Hum. Immunol. 74(6), 701–707 (2013)

    Article  CAS  PubMed  Google Scholar 

  8. S. Trifari, C.D. Kaplan, E.H. Tran, N.K. Crellin, H. Spits, Identification of a human helper T cell population that has abundant production of interleukin 22 and is distinct from T(H)-17, T(H)1 and T(H)2 cells. Nat. Immunol. 10(8), 864–871 (2009)

    Article  CAS  PubMed  Google Scholar 

  9. M. Veldhoen, K. Hirota, A.M. Westendorf, J. Buer, L. Dumoutier, J.C. Renauld, B. Stockinger, The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453(7191), 106–109 (2008)

    Article  CAS  PubMed  Google Scholar 

  10. L. Zhang, Y.G. Li, Y.H. Li, L. Qi, X.G. Liu, C.Z. Yuan, N.W. Hu, D.X. Ma, Z.F. Li, Q. Yang, W. Li, J.M. Li, Increased frequencies of Th22 cells as well as Th17 cells in the peripheral blood of patients with ankylosing spondylitis and rheumatoid arthritis. PLoS One 7(4), e31000 (2012)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. S. Kagami, H.L. Rizzo, J.J. Lee, Y. Koguchi, A. Blauvelt, Circulating Th17, Th22, and Th1 cells are increased in psoriasis. J. Invest. Dermatol. 130(5), 1373–1383 (2010)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. T. Liu, L. Peng, P. Yu, Y. Zhao, Y. Shi, X. Mao, W. Chen, P. Cheng, T. Wang, N. Chen, J. Zhang, X. Liu, N. Li, G. Guo, W. Tong, Y. Zhuang, Q. Zou, Increased circulating Th22 and Th17 cells are associated with tumor progression and patient survival in human gastric cancer. J. Clin. Immunol. 32(6), 1332–1339 (2012)

    Article  CAS  PubMed  Google Scholar 

  13. M.E. Truchetet, N.C. Brembilla, E. Montanari, Y. Allanore, C. Chizzolini, Increased frequency of circulating Th22 in addition to Th17 and Th2 lymphocytes in systemic sclerosis: association with interstitial lung disease. Arthritis Res. Ther. 13(5), R166 (2011)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. T. Kondo, H. Takata, F. Matsuki, M. Takiguchi, Cutting edge: Phenotypic characterization and differentiation of human CD8+ T cells producing IL-17. J. Immunol. 182(4), 1794–1798 (2009)

    Article  CAS  PubMed  Google Scholar 

  15. M. Huber, S. Heink, H. Grothe, A. Guralnik, K. Reinhard, K. Elflein, T. Hunig, H.W. Mittrucker, A. Brustle, T. Kamradt, M. Lohoff, A Th17-like developmental process leads to CD8(+) Tc17 cells with reduced cytotoxic activity. Eur. J. Immunol. 39(7), 1716–1725 (2009)

    Article  CAS  PubMed  Google Scholar 

  16. A.M. Intlekofer, A. Banerjee, N. Takemoto, S.M. Gordon, C.S. Dejong, H. Shin, C.A. Hunter, E.J. Wherry, T. Lindsten, S.L. Reiner, Anomalous type 17 response to viral infection by CD8+ T cells lacking T-bet and eomesodermin. Science 321(5887), 408–411 (2008)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. D.M. Kuang, C. Peng, Q. Zhao, Y. Wu, L.Y. Zhu, J. Wang, X.Y. Yin, L. Li, L. Zheng, Tumor-activated monocytes promote expansion of IL-17-producing CD8 + T cells in hepatocellular carcinoma patients. J. Immunol. 185(3), 1544–1549 (2010)

    Article  CAS  PubMed  Google Scholar 

  18. J.S. Tzartos, M.A. Friese, M.J. Craner, J. Palace, J. Newcombe, M.M. Esiri, L. Fugger, Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis. Am. J. Pathol. 172(1), 146–155 (2008)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. P.C. Res, G. Piskin, O.J. de Boer, C.M. van der Loos, P. Teeling, J.D. Bos, M.B. Teunissen, Overrepresentation of IL-17A and IL-22 producing CD8 T cells in lesional skin suggests their involvement in the pathogenesis of psoriasis. PLoS One 5(11), e14108 (2010)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. A. Saxena, S. Desbois, N. Carrie, M. Lawand, L.T. Mars, R.S. Liblau, Tc17 CD8+ T cells potentiate Th1-mediated autoimmune diabetes in a mouse model. J. Immunol. 189(6), 3140–3149 (2012)

    Article  CAS  PubMed  Google Scholar 

  21. L. Yu, K. Herold, H. Krause-Steinrauf, P.L. McGee, B. Bundy, A. Pugliese, J. Krischer, G.S. Eisenbarth, Rituximab selectively suppresses specific islet antibodies. Diabetes 60(10), 2560–2565 (2011)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. T. Duhen, R. Geiger, D. Jarrossay, A. Lanzavecchia, F. Sallusto, Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells. Nat. Immunol. 10(8), 857–863 (2009)

    Article  CAS  PubMed  Google Scholar 

  23. N. Zhang, H.F. Pan, D.Q. Ye, Th22 in inflammatory and autoimmune disease: prospects for therapeutic intervention. Mol. Cell. Biochem. 353(1–2), 41–46 (2011)

    Article  CAS  PubMed  Google Scholar 

  24. H. Chen, F. Wen, X. Zhang, S.B. Su, Expression of T-helper-associated cytokines in patients with type 2 diabetes mellitus with retinopathy. Molecular vision 18, 219–226 (2012)

    CAS  PubMed Central  PubMed  Google Scholar 

  25. X.Y. Yang, H.Y. Wang, X.Y. Zhao, L.J. Wang, Q.H. Lv, Q.Q. Wang, Th22, but not Th17 Might be a Good Index to Predict the Tissue Involvement of Systemic Lupus Erythematosus. J. Clin. Immunol. 33(4), 767–774 (2013)

    Article  CAS  PubMed  Google Scholar 

  26. S. Tsai, A. Shameli, P. Santamaria, CD8 + T cells in type 1 diabetes. Adv. Immunol. 100, 79–124 (2008)

    Article  CAS  PubMed  Google Scholar 

  27. M. Huber, S. Heink, A. Pagenstecher, K. Reinhard, J. Ritter, A. Visekruna, A. Guralnik, N. Bollig, K. Jeltsch, C. Heinemann, E. Wittmann, T. Buch, O. Prazeres da Costa, A. Brustle, D. Brenner, T.W. Mak, H.W. Mittrucker, B. Tackenberg, T. Kamradt, M. Lohoff, IL-17A secretion by CD8+ T cells supports Th17-mediated autoimmune encephalomyelitis. J. Clin. Investig. 123(1), 247–260 (2013)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. C. Ortega, A.S. Fernandez, J.M. Carrillo, P. Romero, I.J. Molina, J.C. Moreno, M. Santamaria, IL-17-producing CD8+ T lymphocytes from psoriasis skin plaques are cytotoxic effector cells that secrete Th17-related cytokines. J. Leukoc. Biol. 86(2), 435–443 (2009)

    Article  CAS  PubMed  Google Scholar 

  29. H. Hamada, L. Garcia-Hernandez Mde, J.B. Reome, S.K. Misra, T.M. Strutt, K.K. McKinstry, A.M. Cooper, S.L. Swain, R.W. Dutton, Tc17, a unique subset of CD8 T cells that can protect against lethal influenza challenge. J. Immunol. 182(6), 3469–3481 (2009)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. C.S. Hinrichs, A. Kaiser, C.M. Paulos, L. Cassard, L. Sanchez-Perez, B. Heemskerk, C. Wrzesinski, Z.A. Borman, P. Muranski, N.P. Restifo, Type 17 CD8 + T cells display enhanced antitumor immunity. Blood 114(3), 596–599 (2009)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. S. Eyerich, K. Eyerich, A. Cavani, C. Schmidt-Weber, IL-17 and IL-22: siblings, not twins. Trends Immunol. 31(9), 354–361 (2010)

    Article  CAS  PubMed  Google Scholar 

  32. E. Volpe, N. Servant, R. Zollinger, S.I. Bogiatzi, P. Hupe, E. Barillot, V. Soumelis, A critical function for transforming growth factor-beta, interleukin 23 and proinflammatory cytokines in driving and modulating human T(H)-17 responses. Nat. Immunol. 9(6), 650–657 (2008)

    Article  CAS  PubMed  Google Scholar 

  33. Y. Zheng, D.M. Danilenko, P. Valdez, I. Kasman, J. Eastham-Anderson, J. Wu, W. Ouyang, Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature 445(7128), 648–651 (2007)

    Article  CAS  PubMed  Google Scholar 

  34. F. Abbasi, P. Amiri, F.A. Sayahpour, S. Pirmoradi, M. Abolhalaj, B. Larijani, J.T. Bazzaz, M.M. Amoli, TGF-beta and IL-23 gene expression in unstimulated PBMCs of patients with diabetes. Endocrine 41(3), 430–434 (2012)

    Article  CAS  PubMed  Google Scholar 

  35. P.R. Mangan, L.E. Harrington, D.B. O’Quinn, W.S. Helms, D.C. Bullard, C.O. Elson, R.D. Hatton, S.M. Wahl, T.R. Schoeb, C.T. Weaver, Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 441(7090), 231–234 (2006)

    Article  CAS  PubMed  Google Scholar 

  36. M. Ryba-Stanislawowska, M. Skrzypkowska, J. Mysliwska, M. Mysliwiec, The serum IL-6 profile and Treg/Th17 peripheral cell populations in patients with type 1 diabetes. Mediators Inflamm. 2013, 205284 (2013)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. P.J. Bingley, Clinical applications of diabetes antibody testing. J. Clin. Endocrinol. Metab. 95(1), 25–33 (2010)

    Article  CAS  PubMed  Google Scholar 

  38. P. Achenbach, K. Koczwara, A. Knopff, H. Naserke, A.G. Ziegler, E. Bonifacio, Mature high-affinity immune responses to (pro) insulin anticipate the autoimmune cascade that leads to type 1 diabetes. J. Clin. Invest. 114(4), 589–597 (2004)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. P. Vardi, A.G. Ziegler, J.H. Mathews, S. Dib, R.J. Keller, A.T. Ricker, J.I. Wolfsdorf, R.D. Herskowitz, A. Rabizadeh, G.S. Eisenbarth et al., Concentration of insulin autoantibodies at onset of type I diabetes. Inverse log-linear correlation with age. Diabetes Care 11(9), 736–739 (1988)

    CAS  PubMed  Google Scholar 

  40. S.A. Arslanian, D.J. Becker, B. Rabin, R. Atchison, M. Eberhardt, D. Cavender, J. Dorman, A.L. Drash, Correlates of insulin antibodies in newly diagnosed children with insulin-dependent diabetes before insulin therapy. Diabetes 34(9), 926–930 (1985)

    Article  CAS  PubMed  Google Scholar 

  41. J.M. Wenzlau, M. Walter, T.J. Gardner, L.M. Frisch, L. Yu, G.S. Eisenbarth, A.G. Ziegler, H.W. Davidson, J.C. Hutton, Kinetics of the post-onset decline in zinc transporter 8 autoantibodies in type 1 diabetic human subjects. J. Clin. Endocrinol. Metab. 95(10), 4712–4719 (2010)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. P. Achenbach, E. Bonifacio, A.J. Williams, A.G. Ziegler, E.A. Gale, P.J. Bingley, Autoantibodies to IA-2beta improve diabetes risk assessment in high-risk relatives. Diabetologia 51(3), 488–492 (2008)

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The study was supported by Grants from the National Natural Science Foundation of China (number 30971405, 81270897) and a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

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The authors report no conflicts of interest.

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  1. Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China

    Xinyu Xu, Shuai Zheng, Fan Yang, Yun Shi, Yong Gu, Heng Chen, Mei Zhang & Tao Yang

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Correspondence to Tao Yang.

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Xu, X., Zheng, S., Yang, F. et al. Increased Th22 cells are independently associated with Th17 cells in type 1 diabetes. Endocrine 46, 90–98 (2014). https://doi.org/10.1007/s12020-013-0030-z

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