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.

Deletion of cognate CD8 T cells by immature dendritic cells: a novel role for perforin, granzyme A, TREM-1, and TLR7

“…In these earlier studies, many and diverse mechanisms of action were suggested, including immune-specific tolerance through the induction of T-regulatory cells, IL-10 secretion, and IL-2 inhibition 3,9,12,37 ; nonspecific inhibition through the NO system 10,38-40 ; inhibition via indoleamine 2,3-dioxygenase 37,41 ; and apoptosis through death receptors including Fas, TRAIL, and TNF. [13][14][15]17,39,42,43 Likewise, our results suggest that BM-derived DCs obtained after culturing of whole BM with either GM-CSF (supplemental Figure 4) or FLT3 ligand 44 (supplemental Figure 5) do not exhibit detectable levels of perforin or appreciable killing of cognate 2C CD8 T cells. Therefore, our results suggest that the perforin ϩ imDCs grown in our study from purified HSCs represent a novel subpopulation found in a small percentage in the spleen under steady state, which nevertheless can expand in the spleen after GM-CSF administration in vivo.…”

“…This is in contrast to the killing exerted by tolerogenic CD11c CD8 ϩ mature DCs shown to be dependent on TNF-␣. 14 These results and the rapid nature of the killing observed, strongly suggested the possibility that a perforinmediated mechanism might mediate the deletion of the alloreactive CD8 ϩ T cells by the imDCs. To further address this point, we first tested the expression of perforin in imDCs by immunostaining ( Figure 3A) and by Western blotting ( Figure 3B).…”

“…7,[9][10][11][12] At the same time, imDCs can become immunogenic on maturation/activation in the presence of a danger signal such as lipopolysaccharide (LPS). However, this simplistic paradigm was recently challenged by the demonstration that fully mature DCs can also induce tolerance under the appropriate conditions, [13][14][15][16][17] suggesting a more complex decision-making process in which the net effect of Ag dose, DC lineage, DC maturation and activation state, and the cytokine milieu at the site of inflammation determine whether immunogenic or tolerogenic DC activity will prevail. 18 The tolerogenic potential of immature or mature DCs can be further extended to the resolution of inflammatory responses to pathogens.…”

Treatment with Dexamethasone and Monophosphoryl Lipid A Removes Disease-Associated Transcriptional Signatures in Monocyte-Derived Dendritic Cells from Rheumatoid Arthritis Patients and Confers Tolerogenic Features

“…In particular, research has focused on the generation of tolerogenic DCs (TolDCs) capable of modulating antigen-specific immune responses (6, 7). TolDCs may induce antigen-specific tolerance through induction of anergy, deletion of auto-reactive T cells (8, 9), generation and expansion of regulatory T cells (Treg) (10, 11), and/or the establishment of an anti-inflammatory environment through secretion of IL-10 and/or transforming growth factor beta (TGF-β) (12). …”

Tolerance-like mediated suppression by mesenchymal stem cells in patients with dust mite allergy–induced asthma

“…We have show refractoriness of PBMCs to rechallenged DM using 2 methods: preconditioning with MSCs and repeated exposure to low-dose DM and MSCs (Figs 5 and 6). Other studies have reported on killing of T cells by tolerogenic DCs, 44 which could be explored in future studies.…”