Crosstalk of regulatory T cells and tolerogenic dendritic cells prevents contact allergy in subjects with low zone tolerance

J Allergy Clin Immunol. 2012 Sep;130(3):781-797.e11. doi: 10.1016/j.jaci.2012.06.022.


Background: Allergic contact dermatitis is one of the most common occupational diseases. A main protective mechanism in those who do not develop allergic contact dermatitis is tolerance induction by repeated exposure to low doses of contact allergen, which is termed low zone tolerance (LZT). The mechanisms that determine the tolerance induction in subjects with LZT are still elusive.

Objective: We performed analysis of the role of CD4(+)CD25(+) forkhead box protein 3 (FOXP3)-positive regulatory T (Treg) cells and dendritic cells (DCs) in mice with LZT.

Methods: Mechanisms of tolerance induction were analyzed in a murine model of LZT by using FOXP3 and IL-10 reporter mice, as well as mice that allow the selective depletion of Treg cells or DCs.

Results: Depletion of CD4(+)CD25(+)FOXP3(+) Treg cells during tolerance induction completely abolishes the development of LZT, resulting in a pronounced contact hypersensitivity response. Adoptive transfer experiments, depletion studies, and use of cell type-specific deficient mice revealed that IL-10 production is critical for the suppressor function of Treg cells in mice with LZT and that tolerogenic CD8(+)CD11c(+) DCs located in the skin-draining lymph nodes are essential for LZT. In the absence of Treg cells, DCs did not develop tolerogenic functions, indicating that activated IL-10(+) Treg cells might imprint the tolerogenic DC phenotype. Cell communication analysis revealed that the education of tolerogenic DCs might involve a direct interaction with Treg cells mediated by gap junctions. Subsequently, induction of tolerogenic CD11c(+) DCs leads to the generation of hapten-specific CD8(+) Treg cells, which protect against contact hypersensitivity.

Conclusions: Our data demonstrate critical interactions between CD4(+)CD25(+)FOXP3(+) Treg cells and tolerogenic CD8(+)CD11c(+) DCs during the induction of LZT.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD11c Antigen / analysis
  • Cell Communication*
  • Dendritic Cells / physiology*
  • Dermatitis, Allergic Contact / immunology
  • Dermatitis, Allergic Contact / prevention & control*
  • Forkhead Transcription Factors / analysis
  • Immune Tolerance*
  • Interleukin-10 / physiology
  • Interleukin-2 Receptor alpha Subunit / physiology
  • Lymphocyte Activation
  • Mice
  • Mice, Transgenic
  • Receptors, CCR7 / analysis
  • T-Lymphocytes, Regulatory / physiology*


  • CD11c Antigen
  • Ccr7 protein, mouse
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Il2ra protein, mouse
  • Interleukin-2 Receptor alpha Subunit
  • Receptors, CCR7
  • Interleukin-10