T cell killing by tolerogenic dendritic cells protects mice from allergy
Ulrike Luckey, … , Martin Metz, Kerstin Steinbrink
Ulrike Luckey, … , Martin Metz, Kerstin Steinbrink
Published September 1, 2011
Citation Information: J Clin Invest. 2011;121(10):3860-3871. https://doi.org/10.1172/JCI45963.
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Research Article Immunology

T cell killing by tolerogenic dendritic cells protects mice from allergy

Abstract

It is well established that allergy development can be prevented by repeated low-dose exposure to contact allergens. Exactly which immune mechanisms are responsible for this so-called low zone tolerance (LZT) is not clear, although CD8+ suppressor T cells are known to have a role. Here, we show that TNF released by tolerogenic CD11+CD8+ DCs located in skin-draining lymph nodes is required and sufficient for development of tolerance to contact allergens in mice. DC-derived TNF protected mice from contact allergy by inducing apoptosis in allergen-specific effector CD8+ T cells via TNF receptor 2 but did not contribute to the generation and function of the regulatory T cells associated with LZT. The TNF-mediated killing mechanism was induced in an allergen-specific manner. Activation of tolerogenic DCs by LZT CD8+ suppressor T cells and enhanced TNF receptor 2 expression on contact allergen–specific CD8+ effector T cells were required for LZT. Our findings may explain how tolerance protects from allergic diseases, which could allow for the development of new strategies for allergy prevention.

Authors

Ulrike Luckey, Marcus Maurer, Talkea Schmidt, Nadine Lorenz, Beate Seebach, Martin Metz, Kerstin Steinbrink

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Figure 7

CD8+ DCs are the critical source for TNF in LZT.

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CD8+ DCs are the critical source for TNF in LZT. (A) LZT assessed by...
(A) LZT assessed by measuring CHS responses after challenge in tolerized (white bars) or mock-tolerized (solvent-treated; black bars) WT mice and Tnf–/– mice that were then sensitized, and in tolerized or solvent-treated WT mice or Tnf–/– mice that were first injected with CD4+ or CD8+ lymph node cells from naive WT mice and then sensitized. 1 of 3 independent experiments with similar results is shown (5–6 mice per group and per experiment). (B) Percentage of TNF-positive CD8+ T cells and TNF-positive CD8+CD11c+ DCs obtained from tolerized, sensitized, and challenged WT mice as assessed by flow cytometry (staining for intracellular TNF) before and after restimulation with TNBS in vitro 24 hours after challenge (during the effector phase of LZT). Pooled data of 3 to 5 independent experiments with similar results (5 mice per group per experiment) (upper panel) and from 1 representative experiment (lower panels) are shown. (C) Percentage of TNF-positive CD8+CD11c+ DCs obtained before challenge (during the LZT induction phase) or after challenge (during the LZT effector phase) from tolerized mice that had been sensitized and challenged or mock-tolerized (solvent-treated) animals. Cells were analyzed by intracellular FACS staining for TNF before or after restimulation with TNBS. Pooled data of 3 to 5 independent experiments with similar results (5 mice per group per experiment) are demonstrated. Data are shown as mean ± SD. *P < 0.05; **P < 0.01.