Skip to main content

Advertisement

Log in

IL-9 Contributes to Immunosuppression Mediated by Regulatory T Cells and Mast Cells in B-Cell Non-Hodgkin’s Lymphoma

  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

Abstract

It has been known that regulatory T (Treg) cells and mast cells (MCs) are involved in tumor immunity regulation, but the exact roles and mechanisms of Treg cells and MCs in B-cell non-Hodgkin’s lymphoma (NHL) are incompletely defined. In the present study, we found that the number of Foxp3+ Treg cells and CD117+ MCs increased in B-cell NHL patients. Concomitantly, a high level of interleukin (IL)-9 was observed in the sera from B-cell NHL patients. Neutralizing IL-9 significantly inhibited tumor growth in the lymphoma model of murine, and this process was associated with down-regulation of Treg cells and MCs. Furthermore, IL-9 was also demonstrated to induce expression of MC-related genes and proliferation of MCs from the bone marrow stem cells. Collectively, our results indicate that Treg cell and MCs are involved in immunosuppression in B-cell NHL, and IL-9 is a key mediator of Treg cells and MCs in that process. These findings provide novel insight for the pathogenesis and possible therapeutic strategy of B-cell NHL.

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

Access this article

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

Instant access to the full article PDF.

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

Similar content being viewed by others

References

  1. Lippman SM, Spier CM, Miller TP, et al. Tumor-infiltrating T-lymphocytes in B-cell diffuse large cell lymphoma related to disease course. Mod Pathol. 1990;3(3):361–7.

    PubMed  CAS  Google Scholar 

  2. de Jong D. Molecular pathogenesis of follicular lymphoma: a cross talk of genetic and immunologic factors. J Clin Oncol. 2005;23(26):6358–63.

    Article  PubMed  Google Scholar 

  3. Drach J, Seidl S, Kaufmann H. Treatment of mantle cell lymphoma: targeting the microenvironment. Expert Rev Anticancer Ther. 2005;5(3):477–85.

    Article  PubMed  CAS  Google Scholar 

  4. Ansell SM, Stenson M, Habermann TM, et al. CD4+ T-cell immune response to large B-cell non-Hodgkin’s lymphoma predicts patient outcome. J Clin Oncol. 2001;19(3):720–6.

    PubMed  CAS  Google Scholar 

  5. Lawrence T. Inflammation and cancer: a failure of resolution? Trends Pharmacol Sci. 2007;28(4):162–5.

    Article  PubMed  CAS  Google Scholar 

  6. Balkwill F, Charles KA, Mantovani A. Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell. 2005;7(3):211–7.

    Article  PubMed  CAS  Google Scholar 

  7. Zou W, Regulatory T. Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol. 2006;6(4):295–307.

    Article  PubMed  CAS  Google Scholar 

  8. Ullrich SE, Nghiem DX, Khaskina P. Suppression of an established immune response by UVA—a critical role for mast cells. Photochem Photobiol. 2007;83(5):1095–100.

    Article  PubMed  CAS  Google Scholar 

  9. Woo EY, Chu CS, Goletz TJ, et al. Regulatory CD4(+)CD25(+) T cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer. Cancer Res. 2001;61(12):4766–72.

    PubMed  CAS  Google Scholar 

  10. Liyanage UK, Moore TT, Joo HG, et al. Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol. 2002;169(5):2756–61.

    PubMed  CAS  Google Scholar 

  11. Curiel TJ, Coukos G, Zou L, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med. 2004;10(9):942–9.

    Article  PubMed  CAS  Google Scholar 

  12. Viguier M, Lemaitre F, Verola O, et al. Foxp3 expressing CD4+CD25(high) regulatory T cells are overrepresented in human metastatic melanoma lymph nodes and inhibit the function of infiltrating T cells. J Immunol. 2004;173(2):1444–53.

    PubMed  CAS  Google Scholar 

  13. Dudley ME, Wunderlich JR, Robbins PF, et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science. 2002;298(5594):850–4.

    Article  PubMed  CAS  Google Scholar 

  14. Beyer M, Kochanek M, Darabi K, 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(6):2018–25.

    Article  PubMed  CAS  Google Scholar 

  15. Rech AJ, Vonderheide RH. Clinical use of anti-CD25 antibody daclizumab to enhance immune responses to tumor antigen vaccination by targeting regulatory T cells. Ann N Y Acad Sci. 2009;1174:99–106.

    Article  PubMed  CAS  Google Scholar 

  16. Ansell SM, Hurvitz SA, Koenig PA, et al. Phase I study of ipilimumab, an anti-CTLA-4 monoclonal antibody, in patients with relapsed and refractory B-cell non-Hodgkin lymphoma. Clin Cancer Res. 2009;15(20):6446–53.

    Article  PubMed  CAS  Google Scholar 

  17. Cao Y, Zhao J, Yang Z et al. CD4+FOXP3+ regulatory T cell depletion by low-dose cyclophosphamide prevents recurrence in patients with large condylomata acuminata after laser therapy. Clin Immunol. 2010;136(1):21–9.

    Google Scholar 

  18. Galli SJ, Kalesnikoff J, Grimbaldeston MA, et al. Mast cells as “tunable” effector and immunoregulatory cells: recent advances. Annu Rev Immunol. 2005;23:749–86.

    Article  PubMed  CAS  Google Scholar 

  19. Galli SJ, Nakae S, Tsai M. Mast cells in the development of adaptive immune responses. Nat Immunol. 2005;6(2):135–42.

    Article  PubMed  CAS  Google Scholar 

  20. Galinsky DS, Nechushtan H. Mast cells and cancer—no longer just basic science. Crit Rev Oncol Hematol. 2008;68(2):115–30.

    Article  PubMed  Google Scholar 

  21. Taskinen M, Karjalainen-Lindsberg ML, Leppa S. Prognostic influence of tumor-infiltrating mast cells in patients with follicular lymphoma treated with rituximab and CHOP. Blood. 2008;111(9):4664–7.

    Article  PubMed  CAS  Google Scholar 

  22. Huang B, Lei Z, Zhang GM, et al. SCF-mediated mast cell infiltration and activation exacerbate the inflammation and immunosuppression in tumor microenvironment. Blood. 2008;112(4):1269–79.

    Article  PubMed  CAS  Google Scholar 

  23. Yang Z, Zhang B, Li D et al. Mast cells mobilize myeloid-derived suppressor cells and Treg cells in tumor microenvironment via IL-17 pathway in murine hepatocarcinoma model. PLoS One. 2010;5(1):e8922.

    Google Scholar 

  24. Townsend JM, Fallon GP, Matthews JD, et al. IL-9-deficient mice establish fundamental roles for IL-9 in pulmonary mastocytosis and goblet cell hyperplasia but not T cell development. Immunity. 2000;13(4):573–83.

    Article  PubMed  CAS  Google Scholar 

  25. Hauber HP, Bergeron C, Hamid Q. IL-9 in allergic inflammation. Int Arch Allergy Immunol. 2004;134(1):79–87.

    Article  PubMed  CAS  Google Scholar 

  26. Lu LF, Lind EF, Gondek DC, et al. Mast cells are essential intermediaries in regulatory T-cell tolerance. Nature. 2006;442(7106):997–1002.

    Article  PubMed  CAS  Google Scholar 

  27. Eller K, Wolf D, Huber JM, et al. IL-9 production by regulatory T cells recruits mast cells that are essential for regulatory T cell-induced immune suppression. J Immunol. 2011;186(1):83–91.

    Article  PubMed  CAS  Google Scholar 

  28. Houot R, Levy R. T-cell modulation combined with intratumoral CpG cures lymphoma in a mouse model without the need for chemotherapy. Blood. 2009;113(15):3546–52.

    Article  PubMed  CAS  Google Scholar 

  29. Naito S, von Eschenbach AC, Giavazzi R, et al. Growth and metastasis of tumor cells isolated from a human renal cell carcinoma implanted into different organs of nude mice. Cancer Res. 1986;46(8):4109–15.

    PubMed  CAS  Google Scholar 

  30. Feng L, Sun X, Csizmadia E et al. Vascular CD39/ENTPD1 directly promotes tumor cell growth by scavenging extracellular adenosine triphosphate. Neoplasia. 2010;13(3):206–16.

    Google Scholar 

  31. Liu Y, Li N, You L, et al. HSP70 is associated with endothelial activation in placental vascular diseases. Mol Med. 2008;14(9–10):561–6.

    PubMed  CAS  Google Scholar 

  32. Pillai V, Ortega SB, Wang CK, et al. Transient regulatory T-cells: a state attained by all activated human T-cells. Clin Immunol. 2007;123(1):18–29.

    Article  PubMed  CAS  Google Scholar 

  33. Zhang X, Li M, Lian D, et al. Generation of therapeutic dendritic cells and regulatory T cells for preventing allogeneic cardiac graft rejection. Clin Immunol. 2008;127(3):313–21.

    Article  PubMed  CAS  Google Scholar 

  34. Gri G, Piconese S, Frossi B, et al. CD4+CD25+ regulatory T cells suppress mast cell degranulation and allergic responses through OX40–OX40L interaction. Immunity. 2008;29(5):771–81.

    Article  PubMed  CAS  Google Scholar 

  35. Qiao H, Andrade MV, Lisboa FA, et al. FcepsilonR1 and toll-like receptors mediate synergistic signals to markedly augment production of inflammatory cytokines in murine mast cells. Blood. 2006;107(2):610–8.

    Article  PubMed  CAS  Google Scholar 

  36. Stassen M, Hultner L, Schmitt E. Classical and alternative pathways of mast cell activation. Crit Rev Immunol. 2002;22(2):115–40.

    PubMed  CAS  Google Scholar 

  37. Wu B, Huang C, Kato-Maeda M, et al. IL-9 is associated with an impaired Th1 immune response in patients with tuberculosis. Clin Immunol. 2008;126(2):202–10.

    Article  PubMed  CAS  Google Scholar 

  38. Renauld JC, Kermouni A, Vink A, et al. Interleukin-9 and its receptor: involvement in mast cell differentiation and T cell oncogenesis. J Leukoc Biol. 1995;57(3):353–60.

    PubMed  CAS  Google Scholar 

  39. Elyaman W, Bradshaw EM, Uyttenhove C, et al. IL-9 induces differentiation of TH17 cells and enhances function of FoxP3+ natural regulatory T cells. Proc Natl Acad Sci USA. 2009;106(31):12885–90.

    Article  PubMed  CAS  Google Scholar 

  40. Hu ZQ, Zhao WH, Shimamura T. Regulation of mast cell development by inflammatory factors. Curr Med Chem. 2007;14(28):3044–50.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work is supported by grants from the Natural Science Foundation of Shandong Province, China (No. Y2007C053; ZR2009CM059) and the Scientific & Technological Project of Shandong Province, China (No. 2007GG10002008; 2010GSF10250). We thank the staff of the Department of Hematology, Department of Pathology, and Department of General Surgery in Shandong Provincial Hospital for helping with patients’ identification and tissue collection. We thank the technicians of the Research Center of Shandong Provincial Hospital for their assistance in research conducting.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Xin Wang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Feng, LL., Gao, JM., Li, PP. et al. IL-9 Contributes to Immunosuppression Mediated by Regulatory T Cells and Mast Cells in B-Cell Non-Hodgkin’s Lymphoma. J Clin Immunol 31, 1084–1094 (2011). https://doi.org/10.1007/s10875-011-9584-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10875-011-9584-9

Keywords

Navigation