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

详细信息    查看全文

• 作者：Ulrike Luckey ; Talkea Schmidt ; Nikolai Pfender ; Maike Romer ; Nadine Lorenz ; Stefan F. Martin ; Tobias Bopp ; Edgar Schmitt ; Alexey Nikolaev ; Nir Yogev ; Ari Waisman ; Thilo Jakob ; Kerstin Steinbrink
• 关键词：Tolerance ; low zone tolerance ; contact hypersensitivity ; regulatory T cells ; dendritic cells ; hapten ; IL-10 ; contact allergen ; allergic contact dermatitis
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2012
• 出版时间：September, 2012
• 年：2012
• 卷：130
• 期：3
• 页码：781-797.e11
• 全文大小：3721 K

文摘

| Figures/TablesFigures/Tables | ReferencesReferences

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.