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Tumor-derived CD4+CD25+ regulatory T cell suppression of dendritic cell function involves TGF-β and IL-10

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Abstract

CD4+CD25+ regulatory T cells have been characterized as a critical population of immunosuppressive cells. They play a crucial role in cancer progression by inhibiting the effector function of CD4+ or CD8+ T lymphocytes. However, whether regulatory T lymphocytes that expand during tumor progression can modulate dendritic cell function is unclear. To address this issue, we have evaluated the inhibitory potential of CD4+CD25+ regulatory T cells from mice bearing a BCR–ABL+ leukemia on bone marrow-derived dendritic cells. We present data demonstrating that CD4+CD25+FoxP3+ regulatory T cells from tumor-bearing animals impede dendritic cell function by down-regulating the activation of the transcription factor NF-κB. The expression of the co-stimulatory molecules CD80, CD86 and CD40, the production of TNF-α, IL-12, and CCL5/RANTES by the suppressed DC is strongly down-regulated. The suppression mechanism requires TGF-β and IL-10 and is associated with induction of the Smad signaling pathway and activation of the STAT3 transcription factor.

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References

  1. Sakaguchi S (2005) Naturally arising Foxp3-expressing CD25(+)CD4(+) regulatory T cells in immunological tolerance to self and non-self. Nat Immunol 6:345–352

    Article  PubMed  CAS  Google Scholar 

  2. Shevach EM (2002) CD4+ CD25+ suppressor T cells: more questions than answers. Nat Rev Immunol 2:389–400

    PubMed  CAS  Google Scholar 

  3. Asano M, Toda M, Sakaguchi N et al (1996) Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation. J Exp Med 184:387–396

    Article  PubMed  CAS  Google Scholar 

  4. Sakaguchi S, Sakaguchi N, Asano M et al (1995) Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 155:1151–1164

    PubMed  CAS  Google Scholar 

  5. Belkaid Y, Piccirillo CA, Mendez S et al (2002) CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity. Nature 420:502–507

    Article  PubMed  CAS  Google Scholar 

  6. Cobbold SP, Nolan KF, Graca L et al (2003) Regulatory T cells and dendritic cells in transplantation tolerance: molecular markers and mechanisms. Immunol Rev 196:109–124

    Article  PubMed  CAS  Google Scholar 

  7. Shimizu J, Yamazaki S, Sakaguchi S (1999) Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. J Immunol 163:5211–5218

    PubMed  CAS  Google Scholar 

  8. Sakaguchi S (2000) Regulatory T cells: key controllers of immunologic self-tolerance. Cell 101:455–458

    Article  PubMed  CAS  Google Scholar 

  9. Antony PA, Piccirillo CA, Akpinarli A et al (2005) CD8+ T cell immunity against a tumor/self-antigen is augmented by CD4+ T helper cells and hindered by naturally occurring T regulatory cells. J Immunol 174:2591–2601

    PubMed  CAS  Google Scholar 

  10. Woo EY, Yeh H, Chu CS et al (2002) Cutting edge: regulatory T cells from lung cancer patients directly inhibit autologous T cell proliferation. J Immunol 168:4272–4276

    PubMed  CAS  Google Scholar 

  11. Liyanage UK, Moore TT, Joo HG et al (2002) Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol 169:2756–2761

    PubMed  CAS  Google Scholar 

  12. Ormandy LA, Hillemann T, Wedemeyer H et al (2005) Increased populations of regulatory T cells in peripheral blood of patients with hepatocellular carcinoma. Cancer Res 65:2457–2464

    Article  PubMed  CAS  Google Scholar 

  13. Liu JY, Zhang XS, Ding Y et al (2005) The changes of CD4+CD25+/CD4+ proportion in spleen of tumor-bearing BALB/c mice. J Transl Med 3:5

    Article  PubMed  Google Scholar 

  14. Ghiringhelli F, Larmonier N, Schmitt E et al (2004) CD4+CD25+ regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative. Eur J Immunol 34:336–344

    Article  PubMed  CAS  Google Scholar 

  15. Sutmuller RP, van Duivenvoorde LM, van Elsas A et al (2001) Synergism of cytotoxic T lymphocyte-associated antigen 4 blockade and depletion of CD25(+) regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses. J Exp Med 194:823–832

    Article  PubMed  CAS  Google Scholar 

  16. Yu P, Lee Y, Liu W et al (2005) Intratumor depletion of CD4+ cells unmasks tumor immunogenicity leading to the rejection of late-stage tumors. J Exp Med 201:779–791

    Article  PubMed  CAS  Google Scholar 

  17. Prasad SJ, Farrand KJ, Matthews SA et al (2005) Dendritic cells loaded with stressed tumor cells elicit long-lasting protective tumor immunity in mice depleted of CD4+CD25+ regulatory T cells. J Immunol 174:90–98

    PubMed  CAS  Google Scholar 

  18. Fontenot JD, Rudensky AY (2005) A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3. Nat Immunol 6:331–337

    Article  PubMed  CAS  Google Scholar 

  19. Fontenot JD, Gavin MA, Rudensky AY (2003) Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 4:330–336

    Article  PubMed  CAS  Google Scholar 

  20. Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299:1057–1061

    Article  PubMed  CAS  Google Scholar 

  21. Fontenot JD, Rasmussen JP, Williams LM et al (2005) Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 22:329–341

    Article  PubMed  CAS  Google Scholar 

  22. Nakamura K, Kitani A, Fuss I et al (2004) TGF-beta 1 plays an important role in the mechanism of CD4+CD25+ regulatory T cell activity in both humans and mice. J Immunol 172:834–842

    PubMed  CAS  Google Scholar 

  23. Nakamura K, Kitani A, Strober W (2001) Cell contact-dependent immunosuppression by CD4(+)CD25(+) regulatory T cells is mediated by cell surface-bound transforming growth factor beta. J Exp Med 194:629–644

    Article  PubMed  CAS  Google Scholar 

  24. Piccirillo CA, Letterio JJ, Thornton AM et al (2002) CD4(+)CD25(+) regulatory T cells can mediate suppressor function in the absence of transforming growth factor beta1 production and responsiveness. J Exp Med 196:237–246

    Article  PubMed  CAS  Google Scholar 

  25. Misra N, Bayry J, Lacroix-Desmazes S et al (2004) Cutting edge: human CD4+CD25+ T cells restrain the maturation and antigen-presenting function of dendritic cells. J Immunol 172:4676–4680

    PubMed  CAS  Google Scholar 

  26. Sato K, Tateishi S, Kubo K et al (2005) Downregulation of IL-12 and a novel negative feedback system mediated by CD25(+)CD4(+) T cells. Biochem Biophys Res Commun 330:226–232

    Article  PubMed  CAS  Google Scholar 

  27. Cederbom L, Hall H, Ivars F (2000) CD4+CD25+ regulatory T cells down-regulate co-stimulatory molecules on antigen-presenting cells. Eur J Immunol 30:1538–1543

    Article  PubMed  CAS  Google Scholar 

  28. Serra P, Amrani A, Yamanouchi J et al (2003) CD40 ligation releases immature dendritic cells from the control of regulatory CD4+CD25+ T cells. Immunity 19:877–889

    Article  PubMed  CAS  Google Scholar 

  29. Chen W, Qin H, Reese VA et al (1998) CTLs specific for bcr–abl joining region segment peptides fail to lyse leukemia cells expressing p210 bcr–abl protein. J Immunother 21:257–268

    Article  PubMed  CAS  Google Scholar 

  30. McLaughlin J, Chianese E, Witte ON (1987) In vitro transformation of immature hematopoietic cells by the P210 BCR/ABL oncogene product of the Philadelphia chromosome. Proc Natl Acad Sci USA 84:6558–6562

    Article  PubMed  CAS  Google Scholar 

  31. He L, Feng H, Raymond A et al (2001) Dendritic-cell-peptide immunization provides immunoprotection against bcr–abl-positive leukemia in mice. Cancer Immunol Immunother 50:31–40

    Article  PubMed  CAS  Google Scholar 

  32. Feng H, Zeng Y, Whitesell L et al (2001) Stressed apoptotic tumor cells express heat shock proteins and elicit tumor-specific immunity. Blood 97:3505–3512

    Article  PubMed  CAS  Google Scholar 

  33. Nishikawa H, Jager E, Ritter G et al (2005) CD4+ CD25+ regulatory T cells control the induction of antigen-specific CD4+ helper T cell responses in cancer patients. Blood 106:1008–1011

    Article  PubMed  CAS  Google Scholar 

  34. Somasundaram R, Jacob L, Swoboda R et al (2002) Inhibition of cytolytic T lymphocyte proliferation by autologous CD4+/CD25+ regulatory T cells in a colorectal carcinoma patient is mediated by transforming growth factor-beta. Cancer Res 62:5267–5272

    PubMed  CAS  Google Scholar 

  35. Onishi H, Kuroki H, Matsumoto K et al (2004) Monocyte-derived dendritic cells that capture dead tumor cells secrete IL-12 and TNF-alpha through IL-12/TNF-alpha/NF-kappaB autocrine loop. Cancer Immunol Immunother 53:1093–1100

    Article  PubMed  CAS  Google Scholar 

  36. Sakaguchi S (2004) Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 22:531–562

    Article  PubMed  CAS  Google Scholar 

  37. Thornton AM, Shevach EM (1998) CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J Exp Med 188:287–296

    Article  PubMed  CAS  Google Scholar 

  38. Chen W, Wahl SM (2003) TGF-beta: the missing link in CD4+CD25+ regulatory T cell-mediated immunosuppression. Cytokine Growth Factor Rev 14:85–89

    Article  PubMed  CAS  Google Scholar 

  39. Moore KW, de Waal Malefyt R, Coffman RL et al (2001) Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 19:683–765

    Article  PubMed  CAS  Google Scholar 

  40. Williams LM, Ricchetti G, Sarma U et al (2004) Interleukin-10 suppression of myeloid cell activation—a continuing puzzle. Immunology 113:281–292

    Article  PubMed  CAS  Google Scholar 

  41. Hoentjen F, Sartor RB, Ozaki M et al (2005) STAT3 regulates NF-kappaB recruitment to the IL-12p40 promoter in dendritic cells. Blood 105:689–696

    Article  PubMed  CAS  Google Scholar 

  42. Taams LS, van Amelsfort JM, Tiemessen MM et al (2005) Modulation of monocyte/macrophage function by human CD4+CD25+ regulatory T cells. Hum Immunol 66:222–230

    Article  PubMed  CAS  Google Scholar 

  43. Almand B, Clark JI, Nikitina E et al (2001) Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer. J Immunol 166:678–689

    PubMed  CAS  Google Scholar 

  44. Almand B, Resser JR, Lindman B et al (2000) Clinical significance of defective dendritic cell differentiation in cancer. Clin Cancer Res 6:1755–1766

    PubMed  CAS  Google Scholar 

  45. Chaux P, Favre N, Martin M et al (1997) Tumor-infiltrating dendritic cells are defective in their antigen-presenting function and inducible B7 expression in rats. Int J Cancer 72:619–624

    Article  PubMed  CAS  Google Scholar 

  46. Gabrilovich D (2004) Mechanisms and functional significance of tumour-induced dendritic-cell defects. Nat Rev Immunol 4:941–952

    Article  PubMed  CAS  Google Scholar 

  47. Monti P, Leone BE, Zerbi A et al (2004) Tumor-derived MUC1 mucins interact with differentiating monocytes and induce IL-10 high IL-12 low regulatory dendritic cell. J Immunol 172:7341–7349

    PubMed  CAS  Google Scholar 

  48. Steinbrink K, Jonuleit H, Muller G et al (1999) Interleukin-10-treated human dendritic cells induce a melanoma-antigen-specific anergy in CD8(+) T cells resulting in a failure to lyse tumor cells. Blood 93:1634–1642

    PubMed  CAS  Google Scholar 

  49. Kuwana M (2002) Induction of anergic and regulatory T cells by plasmacytoid dendritic cells and other dendritic cell subsets. Hum Immunol 63:1156–1163

    Article  PubMed  CAS  Google Scholar 

  50. Verginis P, Li HS, Carayanniotis G (2005) Tolerogenic semimature dendritic cells suppress experimental autoimmune thyroiditis by activation of thyroglobulin-specific CD4+CD25+ T Cells. J Immunol 174:7433–7439

    PubMed  CAS  Google Scholar 

  51. Mahnke K, Qian Y, Knop J et al (2003) Induction of CD4+/CD25+ regulatory T cells by targeting of antigens to immature dendritic cells. Blood 101:4862–4869

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors wish to thank Pawel Kiela for his helpful comments and Jennifer Uno for her help with real-time PCR. This work was supported in part by the NIH grant R01 CA104926 and the Tee Up for Tots Fund.

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Authors and Affiliations

  1. Department of Pediatrics, Steele Children’s Research Center, University of Arizona, 1501 N. Campbell Ave., P.O. Box 245073, Tucson, AZ, 85724-5073, USA

    Nicolas Larmonier, Marilyn Marron, Yi Zeng, Jessica Cantrell, Angela Romanoski, Marjan Sepassi, Sylvia Thompson, Xinchun Chen, Samita Andreansky & Emmanuel Katsanis

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  1. Nicolas Larmonier
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Correspondence to Emmanuel Katsanis.

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Larmonier, N., Marron, M., Zeng, Y. et al. Tumor-derived CD4+CD25+ regulatory T cell suppression of dendritic cell function involves TGF-β and IL-10. Cancer Immunol Immunother 56, 48–59 (2007). https://doi.org/10.1007/s00262-006-0160-8

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