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 6

LZT is associated with increased TNF/p75-induced apoptosis in CHS effector CD8+ T cells.

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LZT is associated with increased TNF/p75-induced apoptosis in CHS effect...
(A–D) Apoptosis in lymph node cells obtained 24 hours after challenge from tolerized and sensitized Tnf–/– and corresponding WT mice (A and B) and from p75–/– and corresponding WT mice (C and D). CD8+ T cell apoptosis was detected by flow cytometry (annexin V staining, pooled cells obtained from 5–6 animals). 1 of 4 experiments with similar results (A and C) and pooled data of 4 experiments (B and D) are shown. (E and F) Percentages of apoptotic Thy1.2+ CD8+ T cells as assessed by flow cytometry (annexin V+/CD8+) in lymph node cells obtained after challenge with TNCB from TNCB-tolerized or mock-tolerized Thy1.1+ mice that were then reconstituted with T cells isolated from TNCB-sensitized Thy1.2+ mice (E) or in lymph node cells obtained after challenge with DNFB from TNCB-tolerized or mock-tolerized Thy1.1+ mice that had been reconstituted with T cells isolated from DNFB-sensitized Thy1.2+ mice (F). For analyses, gate was set on Thy1.2+ T cells (derived from the sensitized donor mice). 1 of 3 independent experiments with similar results is shown. 5 per group per experiment were used. Data are shown as mean ± SD. *P < 0.05; **P < 0.01.