Skip to main content
SpringerLink
Log in

Effects of Regulatory T Cell–Dendritic Cell Interactions on Adaptive Immune Responses

  • Chapter
  • First Online:
Cancer Immunotherapy Meets Oncology

  • 1884 Accesses

Abstract

The limited efficacy of chemo- or radiotherapy against neoplasias necessitates the development of complementary therapeutic strategies. Tumor immunotherapy represents a promising approach as it harnesses the potential of the host immune system to recognize and eradicate transformed cells. So far, T cell-based immunotherapy still suffers from a striking discrepancy between the induction of tumor-specific immune responses in experimental settings and therapeutic immunity in clinically relevant conditions. However, therapeutic approaches targeting immune regulatory mechanisms have lately shown encouraging results and have initiated long-lasting tumor control in patients. Therefore, a deeper understanding of these mechanisms and their role in tumor development and growth is desirable. The therapeutic manipulation of immune regulatory mechanisms represents a complementary and synergistic approach to antigen-specific vaccination strategies.

All authors contributed equally to this work and are listed in alphabetical order

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

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 139.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Blank C, Mackensen A (2007) Contribution of the PD-L1/PD-1 pathway to T-cell exhaustion: an update on implications for chronic infections and tumor evasion. Cancer Immunol Immunother CII 56(5):739–745. doi:10.1007/s00262-006-0272-1

    Article  Google Scholar 

  • Boissonnas A, Scholer-Dahirel A, Simon-Blancal V, Pace L, Valet F, Kissenpfennig A et al (2010) Foxp3+ T cells induce perforin-dependent dendritic cell death in tumor-draining lymph nodes. Immunity 32(2):266–278. doi:10.1016/j.immuni.2009.11.015

    Article  PubMed  CAS  Google Scholar 

  • Bopp T, Becker C, Klein M, Klein-Hessling S, Palmetshofer A, Serfling E et al (2007) Cyclic adenosine monophosphate is a key component of regulatory T cell-mediated suppression. J Exp Med 204(6):1303–1310. doi:10.1084/jem.20062129

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P et al (2004) Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10(9):942–949. doi:10.1038/nm1093

    Article  PubMed  CAS  Google Scholar 

  • Derré L, Rivals J-P, Jandus C, Pastor S, Rimoldi D, Romero P et al (2010) BTLA mediates inhibition of human tumor-specific CD8+ T cells that can be partially reversed by vaccination. J Clin Invest 120(1):157–167. doi:10.1172/JCI40070

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Eigler A, Siegmund B, Emmerich U, Baumann KH, Hartmann G, Endres S (1998) Anti-inflammatory activities of cAMP-elevating agents: enhancement of IL-10 synthesis and concurrent suppression of TNF production. J Leukoc Biol 63(1):101–107

    PubMed  CAS  Google Scholar 

  • Ercolini AM, Ladle BH, Manning EA, Pfannenstiel LW, Armstrong TD, Machiels J-PH et al (2005) Recruitment of latent pools of high-avidity CD8(+) T cells to the antitumor immune response. J Exp Med 201(10):1591–1602. doi:10.1084/jem.20042167

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Fallarino F, Grohmann U, Hwang KW, Orabona C, Vacca C, Bianchi R et al (2003) Modulation of tryptophan catabolism by regulatory T cells. Nat Immunol 4(12):1206–1212. doi:10.1038/ni1003

    Article  PubMed  Google Scholar 

  • Fassbender M, Gerlitzki B, Ullrich N, Lupp C, Klein M, Radsak MP et al (2010) Cyclic adenosine monophosphate and IL-10 coordinately contribute to nTreg cell-mediated suppression of dendritic cell activation. Cell Immunol 265(2):91–96. doi:10.1016/j.cellimm.2010.07.007

    Article  PubMed  CAS  Google Scholar 

  • Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H et al (2000) Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 192(7):1027–1034

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Galgani M, De Rosa V, De Simone S, Leonardi A, D’Oro U, Napolitani G et al (2004) Cyclic AMP modulates the functional plasticity of immature dendritic cells by inhibiting Src-like kinases through protein kinase A-mediated signaling. J Biol Chem 279(31):32507–32514. doi:10.1074/jbc.M403355200

    Article  PubMed  CAS  Google Scholar 

  • Gutcher I, Donkor MK, Ma Q, Rudensky AY, Flavell RA, Li MO (2011) Autocrine transforming growth factor-β1 promotes in vivo Th17 cell differentiation. Immunity 34(3):396–408. doi:10.1016/j.immuni.2011.03.005

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Hammad H, Kool M, Soullié T, Narumiya S, Trottein F, Hoogsteden HC, Lambrecht BN (2007) Activation of the D prostanoid 1 receptor suppresses asthma by modulation of lung dendritic cell function and induction of regulatory T cells. J Exp Med 204(2):357–367. doi:10.1084/jem.20061196

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Josefowicz SZ, Lu L-F, Rudensky AY (2012) Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol 30:531–564. doi:10.1146/annurev.immunol.25.022106.141623

    Article  PubMed  CAS  Google Scholar 

  • Kammer GM (1988) The adenylate cyclase-cAMP-protein kinase A pathway and regulation of the immune response. Immunol Today 9(7–8):222–229. doi:10.1016/0167-5699(88)91220-0

    Article  PubMed  CAS  Google Scholar 

  • Kuball J, Schmitz FW, Voss R-H, Ferreira EA, Engel R, Guillaume P et al (2005) Cooperation of human tumor-reactive CD4+ and CD8+ T cells after redirection of their specificity by a high-affinity p53A2.1-specific TCR. Immunity 22(1):117–129. doi:10.1016/j.immuni.2004.12.005

    Article  PubMed  CAS  Google Scholar 

  • Lahl K, Loddenkemper C, Drouin C, Freyer J, Arnason J, Eberl G et al (2007) Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease. J Exp Med 204(1):57–63. doi:10.1084/jem.20061852

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Laouar Y, Town T, Jeng D, Tran E, Wan Y, Kuchroo VK, Flavell RA (2008) TGF-beta signaling in dendritic cells is a prerequisite for the control of autoimmune encephalomyelitis. Proc Natl Acad Sci U S A 105(31):10865–10870. doi:10.1073/pnas.0805058105

    Article  PubMed Central  PubMed  Google Scholar 

  • Li MO, Flavell RA (2008) TGF-beta: a master of all T cell trades. Cell 134(3):392–404. doi:10.1016/j.cell.2008.07.025

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Li MO, Wan YY, Flavell RA (2007) T cell-produced transforming growth factor-beta1 controls T cell tolerance and regulates Th1- and Th17-cell differentiation. Immunity 26(5):579–591. doi:10.1016/j.immuni.2007.03.014

    Article  PubMed  CAS  Google Scholar 

  • Liang B, Workman C, Lee J, Chew C, Dale BM, Colonna L et al (2008) Regulatory T cells inhibit dendritic cells by lymphocyte activation gene-3 engagement of MHC class II. J Immunol 180(9):5916–5926

    Article  PubMed  CAS  Google Scholar 

  • 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(5):629–644

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Onishi Y, Fehervari Z, Yamaguchi T, Sakaguchi S (2008) Foxp3+ natural regulatory T cells preferentially form aggregates on dendritic cells in vitro and actively inhibit their maturation. Proc Natl Acad Sci U S A 105(29):10113–10118. doi:10.1073/pnas.0711106105

    Article  PubMed Central  PubMed  Google Scholar 

  • Onizuka S, Tawara I, Shimizu J, Sakaguchi S, Fujita T, Nakayama E (1999) Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor alpha) monoclonal antibody. Cancer Res 59(13):3128–3133

    PubMed  CAS  Google Scholar 

  • Probst HC, McCoy K, Okazaki T, Honjo T, van den Broek M (2005) Resting dendritic cells induce peripheral CD8+ T cell tolerance through PD-1 and CTLA-4. Nat Immunol 6(3):280–286. doi:10.1038/ni1165

    Article  PubMed  CAS  Google Scholar 

  • Qureshi OS, Zheng Y, Nakamura K, Attridge K, Manzotti C, Schmidt EM et al (2011) Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science 332(6029):600–603. doi:10.1126/science.1202947

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Ramalingam R, Larmonier CB, Thurston RD, Midura-Kiela MT, Zheng SG, Ghishan FK, Kiela PR (2012) Dendritic cell-specific disruption of TGF-β receptor II leads to altered regulatory T cell phenotype and spontaneous multiorgan autoimmunity. J Immunol 189(8):3878–3893. doi:10.4049/jimmunol.1201029

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Ring S, Karakhanova S, Johnson T, Enk AH, Mahnke K (2010) Gap junctions between regulatory T cells and dendritic cells prevent sensitization of CD8(+) T cells. J Allergy Clin Immunol 125(1):237–246.e1–7. doi:10.1016/j.jaci.2009.10.025

    Article  PubMed  CAS  Google Scholar 

  • Schildknecht A, Brauer S, Brenner C, Lahl K, Schild H, Sparwasser T et al (2010) FoxP3+ regulatory T cells essentially contribute to peripheral CD8+ T-cell tolerance induced by steady-state dendritic cells. Proc Natl Acad Sci U S A 107(1):199–203. doi:10.1073/pnas.0910620107

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Stanislawski T, Voss RH, Lotz C, Sadovnikova E, Willemsen RA, Kuball J et al (2001) Circumventing tolerance to a human MDM2-derived tumor antigen by TCR gene transfer. Nat Immunol 2(10):962–970. doi:10.1038/ni1001-962

    Article  PubMed  CAS  Google Scholar 

  • Steinberg MW, Turovskaya O, Shaikh RB, Kim G, McCole DF, Pfeffer K et al (2008) A crucial role for HVEM and BTLA in preventing intestinal inflammation. J Exp Med 205(6):1463–1476. doi:10.1084/jem.20071160

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Stoltze L, Schirle M, Schwarz G, Schröter C, Thompson MW, Hersh LB et al (2000) Two new proteases in the MHC class I processing pathway. Nat Immunol 1(5):413–418. doi:10.1038/80852

    Article  PubMed  CAS  Google Scholar 

  • Sutmuller RP, van Duivenvoorde LM, van Elsas A, Schumacher TN, Wildenberg ME, Allison JP 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(6):823–832

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Tadokoro CE, Shakhar G, Shen S, Ding Y, Lino AC, Maraver A et al (2006) Regulatory T cells inhibit stable contacts between CD4+ T cells and dendritic cells in vivo. J Exp Med 203(3):505–511. doi:10.1084/jem.20050783

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Tang Q, Adams JY, Tooley AJ, Bi M, Fife BT, Serra P et al (2006) Visualizing regulatory T cell control of autoimmune responses in nonobese diabetic mice. Nat Immunol 7(1):83–92. doi:10.1038/ni1289

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Tenzer S, Wee E, Burgevin A, Stewart-Jones G, Friis L, Lamberth K et al (2009) Antigen processing influences HIV-specific cytotoxic T lymphocyte immunodominance. Nat Immunol 10(6):636–646. doi:10.1038/ni.1728

    Article  PubMed  CAS  Google Scholar 

  • 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(2):287–296

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Walker LSK, Sansom DM (2011) The emerging role of CTLA4 as a cell-extrinsic regulator of T cell responses. Nat Rev Immunol 11(12):852–863. doi:10.1038/nri3108

    Article  PubMed  CAS  Google Scholar 

  • Walunas TL, Bakker CY, Bluestone JA (1996) CTLA-4 ligation blocks CD28-dependent T cell activation. J Exp Med 183(6):2541–2550

    Article  PubMed  CAS  Google Scholar 

  • Warger T, Osterloh P, Rechtsteiner G, Fassbender M, Heib V, Schmid B et al (2006) Synergistic activation of dendritic cells by combined Toll-like receptor ligation induces superior CTL responses in vivo. Blood 108(2):544–550. doi:10.1182/blood-2005-10-4015

    Article  PubMed  CAS  Google Scholar 

  • Watanabe N, Gavrieli M, Sedy JR, Yang J, Fallarino F, Loftin SK et al (2003) BTLA is a lymphocyte inhibitory receptor with similarities to CTLA-4 and PD-1. Nat Immunol 4(7):670–679. doi:10.1038/ni944

    Article  PubMed  CAS  Google Scholar 

  • Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z et al (2008) CTLA-4 control over Foxp3+ regulatory T cell function. Science 322(5899):271–275. doi:10.1126/science.1160062

    Article  PubMed  CAS  Google Scholar 

  • Yang Y, Huang C-T, Huang X, Pardoll DM (2004) Persistent Toll-like receptor signals are required for reversal of regulatory T cell-mediated CD8 tolerance. Nat Immunol 5(5):508–515. doi:10.1038/ni1059

    Article  PubMed  CAS  Google Scholar 

  • Yu P, Lee Y, Liu W, Krausz T, Chong A, Schreiber H, Fu Y-X (2005) Intratumor depletion of CD4+ cells unmasks tumor immunogenicity leading to the rejection of late-stage tumors. J Exp Med 201(5):779–791. doi:10.1084/jem.20041684

    Article  PubMed Central  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The work discussed in this review was supported by the Deutsche Forschungsgemeinschaft and by the Forschungszentrum Immunologie of the government of Rhineland-Palatinate.

Author information

Authors and Affiliations

  1. Institute for Immunology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131, Mainz, Germany

    Tobias Bopp, Hans Christian Probst, Edgar Schmitt, Michael Stassen, Hansjörg Schild & Stefan Tenzer

  2. Research Center for Immunology (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, 55131, Mainz, Germany

    Tobias Bopp, Hans Christian Probst, Markus Radsak, Edgar Schmitt, Michael Stassen, Hansjörg Schild & Stefan Tenzer

  3. III-Medical Clinic, University Medical Center of the Johannes Gutenberg-University Mainz, 55131, Mainz, Germany

    Markus Radsak

Authors
  1. Tobias Bopp
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hans Christian Probst
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Markus Radsak
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Edgar Schmitt
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Michael Stassen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hansjörg Schild
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Stefan Tenzer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hansjörg Schild .

Editor information

Editors and Affiliations

  1. Immunotherapy Development Center (IDC), TRON-Translational Oncology University Medical Center, Johannes Gutenberg University, Mainz, Germany

    Cedrik Michael Britten

  2. Department of Immunotherapy Development Center, TRON-Translational Oncology University Medical Center, Johannes Gutenberg-University, Mainz, Germany

    Sebastian Kreiter

  3. Department of Immunotherapy Development Center, TRON-Translational Oncology University Medical Center, Johannes Gutenberg University, Mainz, Germany

    Mustafa Diken

  4. Department of Immunology, University of Tübingen, Tübingen, Germany

    Hans-Georg Rammensee

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Bopp, T. et al. (2014). Effects of Regulatory T Cell–Dendritic Cell Interactions on Adaptive Immune Responses. In: Britten, C., Kreiter, S., Diken, M., Rammensee, HG. (eds) Cancer Immunotherapy Meets Oncology. Springer, Cham. https://doi.org/10.1007/978-3-319-05104-8_3

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-05104-8_3

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-05103-1

  • Online ISBN: 978-3-319-05104-8

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation