Talkea Schmidt

T cell killing by tolerogenic dendritic cells protects mice from allergy

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.

Myeloid cell populations and fibrogenic parameters in bleomycin- and HOCl-induced fibrosis.

Mouse models resembling systemic sclerosis can be chemically induced by application of bleomycin or hypochloric acid (HOCl). To date, little is known about inflammatory cells and their potential role in scleroderma (Scl)‐related fibrosis. Therefore, we compared both Scl models to define the early immune cell subsets in relation to fibrosis‐related parameters. Both agents induced a significant increase in dermal thickness and collagen deposition after 4 weeks, as hallmarks of Scl. However, clinical skin thickness, densely packed, sirius red‐stained collagen bundles and collagen cross‐links were more pronounced in HOCl‐induced Scl. In parallel, there was a significant upregulation of procollagen α1(I), α‐SMA and TGF‐β transcripts in HOCl animals, whereas IL‐1β and MMP‐13 mRNA levels were significantly increased in bleomycin‐treated mice. Flow cytometric analysis of the Scl skin demonstrated an early cellular infiltrate containing mainly CD19+ B cells, CD4+ T cells, CD11c+ DC and CD11b+ myeloid cells, the latter ones being significantly more prominent after HOCl injection. Subanalysis revealed that Scl mice exhibited a significant increase of inflammatory myeloid CD11b+ Ly6Clow–high CD64low–high cells (HOCl>bleomycin). In particular, in the HOCl model, activated dermal macrophages (CCR2low MHCIIhigh) and monocyte‐derived DC (CCR2high MHCIIhigh) predominated over less activated CD11b+ myeloid cells. In conclusion, the two models differ in certain aspects of the murine and human scleroderma but in the HOCl model, myeloid CD11b+ MHCIIhigh cells correlate with some fibrosis‐related parameters. Therefore, analysis of both models is suggested to cover a comprehensive profile of Scl symptoms but with focus on the HOCl model when the role of early myeloid immune cells will be evaluated.

45th meeting of the Arbeitsgemeinschaft Dermatologische Forschung

1Department of Dermatology, University of Münster, Münster, Germany 2Department of Dermatology, University of Marburg, Marburg, Germany 3Department of Dermatology and Allergy, Technical University Munich, Munich, Germany 4Department of Dermatology and Venerology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 5Department of Dermatology and Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany 6Department of Dermatology and Allergy, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany 7Skin and Endothelium Research Division (SERD), Department of Dermatology, Medical University of Vienna, Vienna, Austria 8Unit for RNA Biology, Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany 9Division for Experimental and Translational Immunodermatology (DETI), Department of Dermatology University Medical Center, Johannes GutenbergUniversity of Mainz, Mainz, Germany 10Department of Dermatology, Laboratory of Experimental Dermatology, University of Magdeburg, Magdeburg, Germany 11Department of Dermatology and Department of Genetics, University of Erlangen-Nürnberg (FAU), Erlangen, Germany