Sebocytes contribute to skin inflammation by promoting the differentiation of Th17 cells M. Mattii1,¶, M. Lovászi2,¶, N. Garzorz3, A. Atenhan1, M. Quaranta1, F. Lauffer3, A. Konstantinow3, M. Küpper1, C.C. Zouboulis4, L. Kemeny5, K. Eyerich3, C.B. Schmidt-Weber1, D. Törőcsik2,‖, S. Eyerich1,‖ 1ZAUM – Center for Allergy and Environment, Technische Universität and Helmholtz Center Munich, Member of the German Center for Lung Research (DZL), Munich, Germany 2Department of Dermatology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary 3Department of Dermatology and Allergy, Technische Universität Munich, Munich, Germany 4Departments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, Dessau, Germany 5Department of Dermatology and Allergology, University of Szeged, Hungary Br J Dermatol. 2017 Aug 11. doi: 10.1111/bjd.15879.

Introduction What is already known about this topic? Sebocytes are part of the pilosebaceous unit and produce lipids for moisturizing the skin They were long regarded as bystander cells during skin inflammation with no impact on the immune response  

Objective To analyze the functional communication between human sebocytes and T cells with a focus on T cellular effector function and differentiation of naïve T cells

Methods Immunofluorescence of acne sections and healthy skin for CD4 and IL-17 Migration assays of human T cells towards supernatants derived from unstimulated or pre- stimulated SZ95 sebocytes In vitro stimulation of naïve and effector T cells in the presence of unstimulated or pre-stimulated SZ95 sebocyte supernatant Mixed leukocyte reaction with DCs that have been generated in the presence of SZ95 supernatant

Results - CD4+IL-17+ T cells surround the pilosebaceous unit CD4+ IL-17+ Th17 cells only sparsely surround the pilosebaceous unit, but are enriched in acne lesions

Results - SZ95 sebocytes induce the migration of T cells via secretion of CXCL-8 Supernatant of SZ95 sebocytes attracts CD3+ T cells in a CXCL-8 dependant manner CD4+ effector T cells represent the main migratory subset IFN-g prestimulation of SZ95 sebocytes fosters migration of T cells

Results - Sebocyte supernatant polarizes naive T cells into Th17 cells by secretion of key polarizing cytokines Dendritic cells cell have been differentiated in presence of SZ95 sebocyte supernatant induce the differentiation of naïve T cells into IL-17 and IL-22 producing T cells SZ95 sebocytes themselves secrete a combination of Th17 polarizing cytokines and induce the differentiation of aCD3/aCD28 stimulated naïve T cells into Th17 cells

Discussion Sebocytes are not only bystanders during skin inflammation, but actively modulate immune responses via secretion of chemokines and cytokines Sebocytes actively recruit neutrophils, monocytes and T cells into the skin by secretion of CXCl-8 Sebocytes do not affect cytokine secretion of effector T cells, but enhance the differentiation of naïve T cells into Th17 cells mediated by IL-1b, IL-6 and TGF-b secretion P. acnes further enhances Th17 differentiation Th17 cells surround the pilosebaceous unit in acne lesions and are potentially involved in pathological processes during inflammation

Discussion The data suggest that sebocytes contribute to maintenance of barrier integrity by: homeostatic priming of Th17 cells initiation of effective inflammatory responses and reduction of pathogenic IFN-g production to reach homeostasis after inflammation

Conclusions What does this study add? We show that sebocytes actively contribute to inflammatory processes by recruitment of immune cells into the skin and by skewing T cell differentiation towards Th17

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