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Tumor Biology

, Volume 34, Issue 2, pp 929–940 | Cite as

Downregulation of IL-17-producing T cells is associated with regulatory T cell expansion and disease progression in chronic lymphocytic leukemia

  • Farhad Jadidi-Niaragh
  • Ghasem Ghalamfarsa
  • Ali Memarian
  • Hossein Asgarian-Omran
  • Seyed Mohsen Razavi
  • Abdolfattah Sarrafnejad
  • Fazel Shokri
Research Article

Abstract

Little is known about the immunobiology of interleukin-17 (IL-17)-producing T cells and regulatory T cells (Treg) in chronic lymphocytic leukemia (CLL). In this study, the frequencies of Th17, Tc17, and CD39+ Treg cells were enumerated in peripheral T cells isolated from 40 CLL patients and 15 normal subjects by flow cytometry. Our results showed a lower frequency of Th17 and Tc17 cells in progressive (0.99 ± 0.12 % of total CD3+CD4+ cells; 0.44 ± 0.09 % of total CD8+ cells) compared to indolent patients (1.57 ± 0.24 %, p = 0.042; 0.82 ± 0.2 %, p = 0.09) and normal subjects (1.78 ± 0.2 %, p = 0.003; 0.71 ± 0.09 %, p = 0.04). Decrease in IL-17-producing T cells was associated with CD39+ Treg cells expansion. Variation of IL-17-producing cells and Treg cells in indolent and progressive patients was neither associated to the expression levels of Th1- and Th2-specific transcription factors T-bet and GATA-3 nor to the frequencies of IFN-γ and IL-4-producing CD4+ T cells in a selected number of samples. Additionally, suppressive potential of CD4+ Treg was similar in CLL patients and normal subjects. Our data indicate that progression of CLL is associated with downregulation of IL-17-producing T cells and expansion of Treg cells, implying contribution of these subsets of T cells in the progression of CLL.

Keywords

Th17 Tc17 Regulatory T cell Chronic lymphocytic leukemia Interleukin 17 

Notes

Acknowledgments

We would like to thank Mehdi Yousefi, Tahereh Shahrestani, and Bita Ansaripour for their excellent technical support. This study was supported in part by a grant from Tehran University of Medical Sciences (grant number 9879).

Conflicts of interest

None.

Supplementary material

13277_2012_628_MOESM1_ESM.doc (117 kb)
Table S1 (DOC 117 kb)

References

  1. 1.
    Chiorazzi N, Rai KR, Ferrarini M. Chronic lymphocytic leukemia. N Engl J Med. 2005;352:804–15.PubMedCrossRefGoogle Scholar
  2. 2.
    Hojjat-Farsangi M, Jeddi-Tehrani M, Razavi SM, Sharifian RA, Mellstedt H, Shokri F, et al. Immunoglobulin heavy chain variable region gene usage and mutational status of the leukemic B cells in Iranian patients with chronic lymphocytic leukemia. Cancer Sci. 2009;100:2346–53.PubMedCrossRefGoogle Scholar
  3. 3.
    Tamura K, Sawada H, Izumi Y, Fukuda T, Utsunomiya A, Ikeda S, et al. Chronic lymphocytic leukemia (CLL) is rare, but the proportion of T–CLL is high in Japan. European Journal of Haematology. 2001;67:152–7.PubMedCrossRefGoogle Scholar
  4. 4.
    Ravandi F, O'Brien S. Immune defects in patients with chronic lymphocytic leukemia. Cancer Immunol Immunother. 2006;55:197–209.PubMedCrossRefGoogle Scholar
  5. 5.
    Kröber A, Seiler T, Benner A, Bullinger L, Brückle E, Lichter P, et al. Vh mutation status, cd38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia. Blood. 2002;100:1410.PubMedGoogle Scholar
  6. 6.
    Kharfan-Dabaja MA, Chavez JC, Khorfan KA, Pinilla-Ibarz J. Clinical and therapeutic implications of the mutational status of IGVH in patients with chronic lymphocytic leukemia. Cancer. 2008;113:897–906.PubMedCrossRefGoogle Scholar
  7. 7.
    Kay N, O'Brien S, Pettitt A, Stilgenbauer S. The role of prognostic factors in assessing ‘high-risk’subgroups of patients with chronic lymphocytic leukemia. Leukemia. 2007;21:1885–91.PubMedCrossRefGoogle Scholar
  8. 8.
    Orchard JA, Ibbotson RE, Davis Z, Wiestner A, Rosenwald A, Thomas PW, et al. Zap-70 expression and prognosis in chronic lymphocytic leukaemia. Lancet. 2004;363:105–11.PubMedCrossRefGoogle Scholar
  9. 9.
    Jadidi-Niaragh F, Mirshafiey A. Th17 cell, the new player of neuroinflammatory process in multiple sclerosis. Scand J Immunol. 2011;74:1–13.PubMedCrossRefGoogle Scholar
  10. 10.
    Zou W, Restifo NP. T(h)17 cells in tumour immunity and immunotherapy. Nat Rev Immunol. 2010;10:248–56.PubMedCrossRefGoogle Scholar
  11. 11.
    Alexandrakis MG, Pappa CA, Miyakis S, Sfiridaki A, Kafousi M, Alegakis A, et al. Serum interleukin-17 and its relationship to angiogenic factors in multiple myeloma. Eur J Intern Med. 2006;17:412–6.PubMedCrossRefGoogle Scholar
  12. 12.
    Dhodapkar KM, Barbuto S, Matthews P, Kukreja A, Mazumder A, Vesole D, et al. Dendritic cells mediate the induction of polyfunctional human IL17-producing cells (th17-1 cells) enriched in the bone marrow of patients with myeloma. Blood. 2008;112:2878–85.PubMedCrossRefGoogle Scholar
  13. 13.
    Wu C, Wang S, Wang F, Chen Q, Peng S, Zhang Y, et al. Increased frequencies of T helper type 17 cells in the peripheral blood of patients with acute myeloid leukaemia. Clin Exp Immunol. 2009;158:199–204.PubMedCrossRefGoogle Scholar
  14. 14.
    Yang ZZ, Novak AJ, Ziesmer SC, Witzig TE, Ansell SM. Malignant b cells skew the balance of regulatory T cells and th17 cells in b-cell non-Hodgkin's lymphoma. Cancer Res. 2009;69:5522–30.PubMedCrossRefGoogle Scholar
  15. 15.
    Kondo T, Takata H, Matsuki F, Takiguchi M. Cutting edge: Phenotypic characterization and differentiation of human cd8+ T cells producing IL-17. J Immunol. 2009;182:1794–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Huber M, Heink S, Grothe H, Guralnik A, Reinhard K, Elflein K, et al. A Th17-like developmental process leads to cd8(+) Tc17 cells with reduced cytotoxic activity. Eur J Immunol. 2009;39:1716–25.PubMedCrossRefGoogle Scholar
  17. 17.
    Garcia-Hernandez Mde L, Hamada H, Reome JB, Misra SK, Tighe MP, Dutton RW. Adoptive transfer of tumor-specific Tc17 effector T cells controls the growth of b16 melanoma in mice. J Immunol. 2010;184:4215–27.PubMedCrossRefGoogle Scholar
  18. 18.
    Hinrichs CS, Kaiser A, Paulos CM, Cassard L, Sanchez-Perez L, Heemskerk B, et al. Type 17 cd8+ T cells display enhanced antitumor immunity. Blood. 2009;114:596–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Kuang DM, Peng C, Zhao Q, Wu Y, Zhu LY, Wang J, et al. Tumor-activated monocytes promote expansion of IL-17-producing cd8+ T cells in hepatocellular carcinoma patients. J Immunol. 2010;185:1544–9.PubMedCrossRefGoogle Scholar
  20. 20.
    Beyer M, Kochanek M, Darabi K, Popov A, Jensen M, Endl E, et al. Reduced frequencies and suppressive function of cd4+cd25hi regulatory T cells in patients with chronic lymphocytic leukemia after therapy with fludarabine. Blood. 2005;106:2018–25.PubMedCrossRefGoogle Scholar
  21. 21.
    D'Arena G, Laurenti L, Minervini MM, Deaglio S, Bonello L, De Martino L, et al. Regulatory T-cell number is increased in chronic lymphocytic leukemia patients and correlates with progressive disease. Leuk Res. 2011;35:363–8.PubMedCrossRefGoogle Scholar
  22. 22.
    Giannopoulos K, Schmitt M, Kowal M, Wlasiuk P, Bojarska-Junak A, Chen J, et al. Characterization of regulatory T cells in patients with b-cell chronic lymphocytic leukemia. Oncol Rep. 2008;20:677–82.PubMedGoogle Scholar
  23. 23.
    Giannopoulos K, Schmitt M, Wlasiuk P, Chen J, Bojarska-Junak A, Kowal M, et al. The high frequency of T regulatory cells in patients with b-cell chronic lymphocytic leukemia is diminished through treatment with thalidomide. Leukemia. 2008;22:222–4.PubMedCrossRefGoogle Scholar
  24. 24.
    Jadidi-Niaragh F, Jeddi-Tehrani M, Ansaripour B, Razavi SM, Sharifian RA, Shokri F: Reduced frequency of NKT-like cells in patients with progressive chronic lymphocytic leukemia. Med Oncol. 2012;29(5):3561–9.Google Scholar
  25. 25.
    Li MO, Wan YY, Flavell RA. T cell-produced transforming growth factor-beta1 controls T cell tolerance and regulates Th1- and Th17-cell differentiation. Immunity. 2007;26:579–91.PubMedCrossRefGoogle Scholar
  26. 26.
    Fletcher JM, Lonergan R, Costelloe L, Kinsella K, Moran B, O'Farrelly C, et al. Cd39+Foxp3+ regulatory T cells suppress pathogenic Th17 cells and are impaired in multiple sclerosis. J Immunol. 2009;183:7602–10.PubMedCrossRefGoogle Scholar
  27. 27.
    Clayton A, Al-Taei S, Webber J, Mason MD, Tabi Z. Cancer exosomes express cd39 and cd73, which suppress T cells through adenosine production. J Immunol. 2011;187:676–83.PubMedCrossRefGoogle Scholar
  28. 28.
    Ye ZJ, Zhou Q, Zhang JC, Li X, Wu C, Qin SM, et al. Cd39+ regulatory T cells suppress generation and differentiation of Th17 cells in human malignant pleural effusion via a lap-dependent mechanism. Respir Res. 2011;12:77–87.PubMedCrossRefGoogle Scholar
  29. 29.
    Jaffe ES. The 2008 who classification of lymphomas: implications for clinical practice and translational research. Hematology Am Soc Hematol Educ Program 2009:523-531.Google Scholar
  30. 30.
    Cheson BD, Bennett JM, Grever M, Kay N, Keating MJ, O'Brien S, et al. National cancer institute-sponsored working group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood. 1996;87:4990–7.PubMedGoogle Scholar
  31. 31.
    Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the international workshop on chronic lymphocytic leukemia updating the national cancer institute–working group 1996 guidelines. Blood. 2008;111:5446–56.PubMedCrossRefGoogle Scholar
  32. 32.
    Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS. Clinical staging of chronic lymphocytic leukemia. Blood. 1975;46:219–34.PubMedGoogle Scholar
  33. 33.
    Gharagozlou S, Kardar GA, Rabbani H, Shokri F. Molecular analysis of the heavy chain variable region genes of human hybridoma clones specific for coagulation factor viii. Thromb Haemost. 2005;94:1131–7.PubMedGoogle Scholar
  34. 34.
    Dickinson AM, George S, Proctor SJ. T cell subpopulations in CLL: methods of T cell enrichment artificially alter proportions of okt4 and okt8 positive cells. Clin Exp Immunol. 1983;54:525–31.PubMedGoogle Scholar
  35. 35.
    Memarian A, Hojjat-Farsangi M, Asgarian-Omran H, Younesi V, Jeddi-Tehrani M, Sharifian RA, et al. Variation in WNT genes expression in different subtypes of chronic lymphocytic leukemia. Leukemia & Lymphoma. 2009;50:2061–70.CrossRefGoogle Scholar
  36. 36.
    Weaver CT, Hatton RD. Interplay between the Th17 and Treg cell lineages: a (co-)evolutionary perspective. Nat Rev Immunol. 2009;9:883–9.PubMedCrossRefGoogle Scholar
  37. 37.
    Jadidi-Niaragh F, Mirshafiey A: The deviated balance between regulatory T cell and th17 in autoimmunity. Immunopharmacol Immunotoxicol. 2012;34(5):727–39.Google Scholar
  38. 38.
    Chaudhry A, Rudra D, Treuting P, Samstein RM, Liang Y, Kas A, et al. Cd4+ regulatory T cells control Th17 responses in a Stat3-dependent manner. Science. 2009;326:986–91.PubMedCrossRefGoogle Scholar
  39. 39.
    Zhang Y, Ma D, Tian Y, Wang X, Qiao Y, Cui B. The imbalance of th17/Treg in patients with uterine cervical cancer. Clin Chim Acta. 2011;412:894–900.PubMedCrossRefGoogle Scholar
  40. 40.
    Yang XO, Nurieva R, Martinez GJ, Kang HS, Chung Y, Pappu BP, et al. Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity. 2008;29:44–56.PubMedCrossRefGoogle Scholar
  41. 41.
    Martin-Orozco N, Muranski P, Chung Y, Yang XO, Yamazaki T, Lu S, et al. T helper 17 cells promote cytotoxic T cell activation in tumor immunity. Immunity. 2009;31:787–98.PubMedCrossRefGoogle Scholar
  42. 42.
    Ankathatti Munegowda M, Deng Y, Mulligan SJ, Xiang J. Th17 and Th17-stimulated Cd8 T cells play a distinct role in Th17-induced preventive and therapeutic antitumor immunity. Cancer Immunol Immunother. 2011;60:1473–84.PubMedCrossRefGoogle Scholar
  43. 43.
    Sfanos KS, Bruno TC, Maris CH, Xu L, Thoburn CJ, DeMarzo AM, et al. Phenotypic analysis of prostate-infiltrating lymphocytes reveals Th17 and Treg skewing. Clin Cancer Res. 2008;14:3254–61.PubMedCrossRefGoogle Scholar
  44. 44.
    Gnerlich JL, Mitchem JB, Weir JS, Sankpal NV, Kashiwagi H, Belt BA, et al. Induction of Th17 cells in the tumor microenvironment improves survival in a murine model of pancreatic cancer. J Immunol. 2010;185:4063–71.PubMedCrossRefGoogle Scholar
  45. 45.
    Kryczek I, Banerjee M, Cheng P, Vatan L, Szeliga W, Wei S, et al. Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments. Blood. 2009;114:1141–9.PubMedCrossRefGoogle Scholar
  46. 46.
    Horlock C, Stott B, Dyson PJ, Morishita M, Coombes RC, Savage P, et al. The effects of trastuzumab on the Cd4+Cd25+Foxp3+ and Cd4+IL17a+ T-cell axis in patients with breast cancer. Br J Cancer. 2009;100:1061–7.PubMedCrossRefGoogle Scholar
  47. 47.
    Prabhala RH, Pelluru D, Fulciniti M, Prabhala HK, Nanjappa P, Song W, et al. Elevated Il-17 produced by Th17 cells promotes myeloma cell growth and inhibits immune function in multiple myeloma. Blood. 2010;115:5385–92.PubMedCrossRefGoogle Scholar
  48. 48.
    Giannopoulos K, Wlasiuk P, Dmoszynska A, Rolinski J, Schmitt M. Peptide vaccination induces profound changes in the immune system in patients with B-cell chronic lymphocytic leukemia. Folia Histochem Cytobiol. 2011;49:161–7.PubMedGoogle Scholar
  49. 49.
    Idler I, Giannopoulos K, Zenz T, Bhattacharya N, Nothing M, Dohner H, et al. Lenalidomide treatment of chronic lymphocytic leukaemia patients reduces regulatory T cells and induces Th17 T helper cells. Br J Haematol. 2010;148:948–50.PubMedCrossRefGoogle Scholar
  50. 50.
    Bouley J, Deriano L, Delic J, Merle-Beral H. New molecular markers in resistant B-CLL. Leuk Lymphoma. 2006;47:791–801.PubMedCrossRefGoogle Scholar
  51. 51.
    Thunberg U, Johnson A, Roos G, Thorn I, Tobin G, Sallstrom J, et al. Cd38 expression is a poor predictor for VH gene mutational status and prognosis in chronic lymphocytic leukemia. Blood. 2001;97:1892–4.PubMedCrossRefGoogle Scholar
  52. 52.
    Kryczek I, Wei S, Zou L, Altuwaijri S, Szeliga W, Kolls J, et al. Cutting edge: Th17 and regulatory T cell dynamics and the regulation by IL-2 in the tumor microenvironment. J Immunol. 2007;178:6730–3.PubMedGoogle Scholar
  53. 53.
    Tajima M, Wakita D, Satoh T, Kitamura H, Nishimura T. IL-17/IFN-gamma double producing Cd8(+) T (Tc17/IFN-gamma) cells: a novel cytotoxic T-cell subset converted from Tc17 cells by IL-12. International Immunology. 2011;23:751–9.PubMedCrossRefGoogle Scholar
  54. 54.
    Hamai A, Pignon P, Raimbaud I, Duperrier-Amouriaux K, Senellart H, Hiret S, et al. Human T(h)17 immune cells specific for the tumor antigen mage-a3 convert to IFN-gamma-secreting cells as they differentiate into effector T cells in vivo. Cancer Research. 2012;72:1059–63.PubMedCrossRefGoogle Scholar
  55. 55.
    Haabeth OAW, Lorvik KB, Hammarström C, Donaldson IM, Haraldsen G, Bogen B. Corthay A: inflammation driven by tumour-specific Th1 cells protects against B-cell cancer. Nature communications. 2011;2:240.PubMedCrossRefGoogle Scholar
  56. 56.
    Podhorecka M, Dmoszynska A, Rolinski J, Wasik E. T type 1/type 2 subsets balance in B-cell chronic lymphocytic leukemia—the three-color flow cytometry analysis. Leuk Res. 2002;26:657–60.PubMedCrossRefGoogle Scholar
  57. 57.
    Hill SJ, Peters SH, Ayliffe MJ, Merceica J, Bansal AS. Reduced IL-4 and interferon-gamma (IFN-gamma) expression by Cd4 T cells in patients with chronic lymphocytic leukaemia. Clin Exp Immunol. 1999;117:8–11.PubMedCrossRefGoogle Scholar
  58. 58.
    Gallego A, Vargas JA, Castejon R, Citores MJ, Romero Y, Millan I, et al. Production of intracellular IL-2, TNF-alpha, and IFN-gamma by T cells in B-CLL. Cytometry B Clin Cytom. 2003;56:23–9.PubMedCrossRefGoogle Scholar
  59. 59.
    Pourgheysari B, Bruton R, Parry H, Billingham L, Fegan C, Murray J, et al. The number of cytomegalovirus-specific Cd4+ T cells is markedly expanded in patients with B-cell chronic lymphocytic leukemia and determines the total Cd4+ T-cell repertoire. Blood. 2010;116:2968–74.PubMedCrossRefGoogle Scholar
  60. 60.
    Walton JA, Lydyard PM, Nathwani A, Emery V, Akbar A, Glennie MJ, et al. Patients with B cell chronic lymphocytic leukaemia have an expanded population of Cd4 perforin expressing T cells enriched for human cytomegalovirus specificity and an effector-memory phenotype. Br J Haematol. 2010;148:274–84.PubMedCrossRefGoogle Scholar
  61. 61.
    Lindqvist CA, Christiansson LH, Thorn I, Mangsbo S, Paul-Wetterberg G, Sundstrom C, et al. Both Cd4+ Foxp3+ and Cd4+ Foxp3- T cells from patients with B-cell malignancy express cytolytic markers and kill autologous leukaemic B cells in vitro. Immunology. 2011;133:296–306.PubMedCrossRefGoogle Scholar
  62. 62.
    Weiss L, Melchardt T, Egle A, Grabmer C, Greil R, Tinhofer I. Regulatory T cells predict the time to initial treatment in early stage chronic lymphocytic leukemia. Cancer. 2011;117:2163–9.PubMedCrossRefGoogle Scholar
  63. 63.
    Pulte D, Furman RR, Broekman MJ, Drosopoulos JHF, Ballard HS, Olson KE, et al. Cd39 expression on T lymphocytes correlates with severity of disease in patients with chronic lymphocytic leukemia. Clinical Lymphoma Myeloma & Leukemia. 2011;11:367–72.CrossRefGoogle Scholar
  64. 64.
    Lotz M, Ranheim E, Kipps TJ. Transforming growth factor beta as endogenous growth inhibitor of chronic lymphocytic leukemia B cells. The Journal of experimental medicine. 1994;179:999–1004.PubMedCrossRefGoogle Scholar
  65. 65.
    Carter NARE, Mauri C. IL-10 produced by B cells is crucial for the suppression of Th17/ Th1 responses, induction of Tr1 cells and reduction of collagen-induced arthritis. Arthritis research and therapy. 2012;14:R32.PubMedCrossRefGoogle Scholar
  66. 66.
    Huber S, Gagliani N, Esplugues E, O'Connor Jr W, Huber FJ, Chaudhry A, et al. Th17 cells express interleukin-10 receptor and are controlled by Foxp3 and Foxp3+ regulatory Cd4+ T cells in an interleukin-10-dependent manner. Immunity. 2011;34:554–65.PubMedCrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2012

Authors and Affiliations

  • Farhad Jadidi-Niaragh
    • 1
  • Ghasem Ghalamfarsa
    • 1
  • Ali Memarian
    • 2
  • Hossein Asgarian-Omran
    • 1
  • Seyed Mohsen Razavi
    • 3
  • Abdolfattah Sarrafnejad
    • 1
  • Fazel Shokri
    • 1
  1. 1.Department of Immunology, School of Public HealthTehran University of Medical SciencesTehranIran
  2. 2.Department of Immunology, School of MedicineTehran University of Medical SciencesTehranIran
  3. 3.Clinic of Hematology and Oncology, Firozgar Hospital, Faculty of MedicineTehran University of Medical SciencesTehranIran

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