Skip to main content

Advertisement

SpringerLink
Log in

Immune tolerance induced by intravenous transfer of immature dendritic cells via up-regulating numbers of suppressive IL-10+ IFN-γ+-producing CD4+ T cells

  • Published:
Immunologic Research Aims and scope Submit manuscript

Abstract

Dendritic cells (DCs) regulate immunity and immune tolerance in vivo. However, the mechanisms of DC-mediated tolerance have not been fully elucidated. Here, we demonstrate that intravenous (i.v.) transfer of bone marrow-derived DCs pulsed with myelin oligodendrocyte glycoprotein (MOG) peptide blocks the development of experimental autoimmune encephalomyelitis in C57BL/6J mice. i.v. transfer of MOG-pulsed DCs leads to the down-regulation of the production of IL-17A and IFN-γ and up-regulation of IL-10 secretion. The development of regulatory T cells (Tregs) is facilitated via up-regulation of FoxP3 expression and production of IL-10. The number of suppressive CD4+IL-10+IFN-γ+ T cells is also improved. The expression of OX40, CD154, and CD28 is down-regulated, but the expression of CD152, CD80, PD-1, ICOS, and BTLA is up-regulated on CD4+ T cells after i.v. transfer of immature DCs. The expression of CCR4, CCR5, and CCR7 on CD4+ T cells is also improved. Our results suggest that immature DCs may induce tolerance via facilitating the development of CD4+FoxP3+ Tregs and suppressive CD4+IL-10+IFN-γ+ T cells in vivo.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

APC:

Antigen-presenting cell

BTLA:

B- and T-lymphocyte attenuator

CTLA-4:

Cytotoxic T-lymphocyte antigen-4

DC:

Dendritic cell

EAE:

Experimental autoimmune encephalomyelitis

FCS:

Fetal calf serum

GM-CSF:

Granulocyte–macrophage colony-stimulating factor

ICOS:

Inducible co-stimulator

i.v:

Intravenous

MOG:

Myelin oligodendrocyte glycoprotein

MS:

Multiple sclerosis

PD-1:

Programmed death-1

TCR:

T-cell receptor

Tregs:

Regulatory T cells

2-ME:

2-Mercaptoethanol

References

  1. Melief CJ. Cancer immunotherapy by dendritic cells. Immunity. 2008;29:372–83.

    Article  PubMed  CAS  Google Scholar 

  2. Nikolic T, Welzen-Coppens JM, Leenen PJ, Drexhage HA, Versnel MA. Plasmacytoid dendritic cells in autoimmune diabetes—potential tools for immunotherapy. Immunobiology. 2009;214:791–9.

    Article  PubMed  CAS  Google Scholar 

  3. Keir ME, Sharpe AH. The B7/CD28 costimulatory family in autoimmunity. Immunol Rev. 2005;204:128–43.

    Article  PubMed  CAS  Google Scholar 

  4. Miossec P. IL-17 and Th17 cells in human inflammatory diseases. Microbes Infect. 2009;11:625–30.

    Article  PubMed  CAS  Google Scholar 

  5. Correale J, Farez M, Gilmore W. Vaccines for multiple sclerosis: progress to date. CNS Drugs. 2008;22:175–98.

    Article  PubMed  CAS  Google Scholar 

  6. Li H, Zhang GX, Chen Y, Xu H, Fitzgerald DC, Zhao Z, Rostami A. CD11c+ CD11b+ dendritic cells play an important role in intravenous tolerance and the suppression of experimental autoimmune encephalomyelitis. J Immunol. 2008;181:2483–93.

    PubMed  CAS  Google Scholar 

  7. Lee I, Wang L, Wells AD, Dorf ME, Ozkaynak E, Hancock WW. Recruitment of Foxp3+ T regulatory cells mediating allograft tolerance depends on the CCR4 chemokine receptor. J Exp Med. 2005;201:1037–44.

    Article  PubMed  CAS  Google Scholar 

  8. Dobaczewski M, Xia Y, Bujak M, Gonzalez-Quesada C, Frangogiannis NG. CCR5 signaling suppresses inflammation and reduces adverse remodeling of the infarcted heart, mediating recruitment of regulatory T cells. Am J Pathol. 2010;176:2177–87.

    Article  PubMed  CAS  Google Scholar 

  9. Xu L, Xu W, Qiu S, Xiong S. Enrichment of CCR6+ Foxp3+ regulatory T cells in the tumor mass correlates with impaired CD8+ T cell function and poor prognosis of breast cancer. Clin Immunol. 2010;135:466–75.

    Article  PubMed  CAS  Google Scholar 

  10. Eller K, Weber T, Pruenster M, Wolf AM, Mayer G, Rosenkranz AR, Rot A. CCR7 deficiency exacerbates injury in acute nephritis due to aberrant localization of regulatory T cells. J Am Soc Nephrol. 2010;21:42–52.

    Article  PubMed  CAS  Google Scholar 

  11. Ueha S, Yoneyama H, Hontsu S, Kurachi M, Kitabatake M, Abe J, Yoshie O, Shibayama S, Sugiyama T, Matsushima K. CCR7 mediates the migration of Foxp3+ regulatory T cells to the paracortical areas of peripheral lymph nodes through high endothelial venules. J Leukoc Biol. 2007;82:1230–8.

    Article  PubMed  CAS  Google Scholar 

  12. Schneider MA, Meingassner JG, Lipp M, Moore HD, Rot A. CCR7 is required for the in vivo function of CD4+ CD25+ regulatory T cells. J Exp Med. 2007;204:735–45.

    Article  PubMed  CAS  Google Scholar 

  13. Lutz MB, Kukutsch N, Ogilvie AL, Rossner S, Koch F, Romani N, Schuler G. An advanced culture method for generating large quantities of highly pure dendritic cells from mouse bone marrow. J Immunol Methods. 1999;223:77–92.

    Article  PubMed  CAS  Google Scholar 

  14. Zhang GX, Kishi M, Xu H, Rostami A. Mature bone marrow-derived dendritic cells polarize Th2 response and suppress experimental autoimmune encephalomyelitis. Mult Scler. 2002;8:463–8.

    Article  PubMed  CAS  Google Scholar 

  15. Morel PA, Turner MS. Dendritic cells and the maintenance of self-tolerance. Immunol Res. 2011;50:124–9.

    Article  PubMed  CAS  Google Scholar 

  16. Carreno LJ, Gonzalez PA, Bueno SM, Riedel CA, Kalergis AM. Modulation of the dendritic cell-T-cell synapse to promote pathogen immunity and prevent autoimmunity. Immunotherapy. 2011;3:6–11.

    Article  PubMed  Google Scholar 

  17. Murphy AC, Lalor SJ, Lynch MA, Mills KH. Infiltration of Th1 and Th17 cells and activation of microglia in the CNS during the course of experimental autoimmune encephalomyelitis. Brain Behav Immun. 2011;24:641–51.

    Article  Google Scholar 

  18. Selvaraj RK, Geiger TL. Mitigation of experimental allergic encephalomyelitis by TGF-beta induced Foxp3+ regulatory T lymphocytes through the induction of anergy and infectious tolerance. J Immunol. 2008;180:2830–8.

    PubMed  CAS  Google Scholar 

  19. Gerosa F, Nisii C, Righetti S, Micciolo R, Marchesini M, Cazzadori A, Trinchieri G. CD4(+) T cell clones producing both interferon-gamma and interleukin-10 predominate in bronchoalveolar lavages of active pulmonary tuberculosis patients. Clin Immunol. 1999;92:224–34.

    Article  PubMed  CAS  Google Scholar 

  20. Chen J, Liu XS. Development and function of IL-10 IFN-gamma-secreting CD4(+) T cells. J Leukoc Biol. 2009;86:1305–10.

    Article  PubMed  CAS  Google Scholar 

  21. Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol. 2008;8:467–77.

    Article  PubMed  CAS  Google Scholar 

  22. Weinberg AD, Wegmann KW, Funatake C, Whitham RH. Blocking OX-40/OX-40 ligand interaction in vitro and in vivo leads to decreased T cell function and amelioration of experimental allergic encephalomyelitis. J Immunol. 1999;162:1818–26.

    PubMed  CAS  Google Scholar 

  23. Girvin AM, Dal Canto MC, Miller SD. CD40/CD40L interaction is essential for the induction of EAE in the absence of CD28-mediated co-stimulation. J Autoimmun. 2002;18:83–94.

    Article  PubMed  Google Scholar 

  24. Girvin AM, Dal Canto MC, Rhee L, Salomon B, Sharpe A, Bluestone JA, Miller SD. A critical role for B7/CD28 costimulation in experimental autoimmune encephalomyelitis: a comparative study using costimulatory molecule-deficient mice and monoclonal antibody blockade. J Immunol. 2000;164:136–43.

    PubMed  CAS  Google Scholar 

  25. Podojil JR, Kohm AP, Miller SD. CD4+ T cell expressed CD80 regulates central nervous system effector function and survival during experimental autoimmune encephalomyelitis. J Immunol. 2006;177:2948–58.

    PubMed  CAS  Google Scholar 

  26. Ratts RB, Arredondo LR, Bittner P, Perrin PJ, Lovett-Racke AE, Racke MK. The role of CTLA-4 in tolerance induction and ttigen administration cell differentiation in experimental autoimmune encephalomyelitis: i.v. antigen administration. Int Immunol. 1999;11:1889–96.

    Article  PubMed  CAS  Google Scholar 

  27. Carter LL, Leach MW, Azoitei ML, Cui J, Pelker JW, Jussif J, Benoit S, Ireland G, Luxenberg D, Askew GR, Milarski KL, Groves C, Brown T, Carito BA, Percival K, Carreno BM, Collins M, Marusic S. PD-1/PD-L1, but not PD-1/PD-L2, interactions regulate the severity of experimental autoimmune encephalomyelitis. J Neuroimmunol. 2007;182:124–34.

    Article  PubMed  CAS  Google Scholar 

  28. Watanabe N, Gavrieli M, Sedy JR, Yang J, Fallarino F, Loftin SK, Hurchla MA, Zimmerman N, Sim J, Zang X, Murphy TL, Russell JH, Allison JP, Murphy KM. BTLA is a lymphocyte inhibitory receptor with similarities to CTLA-4 and PD-1. Nat Immunol. 2003;4:670–9.

    Article  PubMed  CAS  Google Scholar 

  29. Galicia G, Kasran A, Uyttenhove C, De Swert K, Van Snick J, Ceuppens JL. ICOS deficiency results in exacerbated IL-17 mediated experimental autoimmune encephalomyelitis. J Clin Immunol. 2009;29:426–33.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by the NIH and the National Multiple Sclerosis Society. We thank Katherine Regan for editorial assistance.

Author information

Authors and Affiliations

  1. Department of Neurology, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA, 19107, USA

    Fang Zhou, Bogoljub Ciric, Guang-Xian Zhang & Abdolmohamad Rostami

Authors
  1. Fang Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bogoljub Ciric
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Guang-Xian Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Abdolmohamad Rostami
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Guang-Xian Zhang or Abdolmohamad Rostami.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhou, F., Ciric, B., Zhang, GX. et al. Immune tolerance induced by intravenous transfer of immature dendritic cells via up-regulating numbers of suppressive IL-10+ IFN-γ+-producing CD4+ T cells. Immunol Res 56, 1–8 (2013). https://doi.org/10.1007/s12026-012-8382-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12026-012-8382-7

Keywords

Search

Navigation