Advertisement

DCs in Immune Tolerance in Steady-State Conditions

  • Tomohiro Fukaya
  • Hideaki Takagi
  • Honami Taya
  • Katsuaki Sato
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 677)

Abstract

Dendritic cells (DCs) are antigen-presenting cells (APCs) characterized by a unique capacity to stimulate naïve T cells and initiate primary immune responses. Recent studies suggest that DCs are also involved in the induction of immunological tolerance in peripheral tissues under steady-state conditions by maintaining the homeostasis of self-reactive CD4+Foxp3+naturally occurring thymic-derived regulatory T cells (nTregs) and de novo generation of antigen-specific CD4+Foxp3+inducible regulatory T cells (iTregs). We demonstrate here the impact of CD11+DCs on the antigen-specific differentiation of CD4+Foxp3+iTregs from CD4+Foxp3T cells under steady-state and inflammatory conditions. CD11c+DCs promoted the transforming growth factor (TGF)-β1-mediated conversion of CD4+Foxp3T cells into CD4+Foxp3+iTregs in vitro, while stimulation of CD11c+DCs with CpG oligodeoxynucleotide (ODN) abrogated this conversion. Furthermore, antigen-specific generation of CD4+Foxp3+iTregs required the function of CD11+DCs under steady-state conditions, whereas such conversion was severely abolished under inflammatory conditions. Thus, these results suggest the crucial role of DCs in the antigen-specific de novo conversion of CD4+Foxp3T cells into CD4+Foxp3+iTregs under steady-state conditions, thereby leading to the establishment of peripheral immune tolerance.

Key words

Dendritic cells Tolerance Regulatory T cells Steady-state conditions Inflammatory conditions 

Notes

Acknowledgements

The author would like to thank Yumiko Sato, Kaori Sato, Kawori Eizumi, and Naomi Uchimura for excellent technical assistance. This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, and Culture of Japan (c) 17790334 and 19590505 (K.S.).

References

  1. 1.
    Sato, K. and Fujita, S. (2007) Dendritic cells-nature and classification. Allergol. Int. 56, 183–191.PubMedCrossRefGoogle Scholar
  2. 2.
    Mucida, D., Park, Y., Kim, G., Turovskaya, O., Scott, I., Kronenberg, M., et al. (2007) Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317, 256–260.PubMedCrossRefGoogle Scholar
  3. 3.
    Kretschmer, K., Apostolou, I., Hawiger, D., Khazaie, K., Nussenzweig, M. C., and von Boehmer, H. (2005) Inducing and expanding regulatory T cell populations by foreign antigen. Nat. Immunol. 6, 1219–1227.PubMedCrossRefGoogle Scholar
  4. 4.
    Birnberg, T., Bar-On, L., Sapoznikov, A., Caton, M. L., Cervantes-Barragán, L., Makia, D., et al. (2008) Lack of conventional dendritic cells is compatible with normal development and T cell homeostasis, but causes myeloid proliferative syndrome. Immunity 29, 986–997.PubMedCrossRefGoogle Scholar
  5. 5.
    Ohnmacht, C., Pullner, A., King, S. B., Drexler, I., Meier, S., Brocker, T., et al. (2009) Constitutive ablation of dendritic cells breaks self-tolerance of CD4 T cells and results in spontaneous fatal autoimmunity. J. Exp. Med. 206, 549–559.PubMedCrossRefGoogle Scholar
  6. 6.
    Hori, S., Nomura, T., and Sakaguchi, S. (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057–1061.PubMedCrossRefGoogle Scholar
  7. 7.
    Curotto de Lafaille, M. A. and Lafaille, J. J. (2009) Natural and adaptive Foxp3+ regulatory T cells: More of the same or a division of labor? Immunity 30, 626–635.PubMedCrossRefGoogle Scholar
  8. 8.
    Zhou, L., Chong, M. M., and Littman, D. R. (2009) Plasticity of CD4+ T cell lineage differentiation. Immunity 30, 646–655.PubMedCrossRefGoogle Scholar
  9. 9.
    Fujita, S., Sato, Y., Sato, K., Eizumi, K., Fukaya, T., Kubo, M., et al. (2007) Regulatory dendritic cells protect against cutaneous chronic graft-versus-host disease mediated through CD4+CD25+Foxp3+T cells. Blood 110, 3793–3803.PubMedCrossRefGoogle Scholar
  10. 10.
    Sato, K., Eizumi, K., Fukaya, T., Fujita, S., Sato, Y., Takagi, H., et al. (2009) Naturally occurring regulatory dendritic cells regulate murine cutaneous chronic graft-versus-host disease. Blood 113, 4780–4789.PubMedCrossRefGoogle Scholar
  11. 11.
    Jung, S., Unutmaz, D., Wong, P., Sano, G., De Los Santos, K., Sparwasser, T., et al. (2002) In vivo depletion of CD11c+ dendritic cells abrogates priming of CD8+ T cells by exogenous cell-associated antigens. Immunity 17, 211–220.PubMedCrossRefGoogle Scholar
  12. 12.
    Sadhu, C., Ting, H.J., Lipsky, B., Hensley, K., Garcia-Martinez, L.F., Simon, S.I., et al. (2007) CD11c/CD18: novel ligands and a role in delayed-type hypersensitivity. J. Leukoc. Biol. 81, 1395–1403.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press 2010

Authors and Affiliations

  • Tomohiro Fukaya
    • 1
  • Hideaki Takagi
    • 1
  • Honami Taya
    • 1
  • Katsuaki Sato
    • 1
  1. 1.Laboratory for Dendritic Cell ImmunobiologyRIKEN Research Center for Allergy and ImmunologyKanagawaJapan

Personalised recommendations