Langerhans cells take up a keratinocyte-expressed autoantigen, desmoglein 3, via langerin.
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Langerhans cells suppress autoimmunity by expanding regulatory T cells.
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IL-2 receptor signaling occurs in Langerhans cells, conditioning them to mediate peripheral tolerance.
Lymphocytes are critical for combating pathogens, but they can cause autoimmune diseases when misdirected against autoantigens. While past experimental models have provided detailed mechanisms utilizing neo-antigens, immune regulation against naturally-expressed autoantigen(s) remains largely unexplored. Herein, we studied immune responses against desmoglein 3, a bona fide autoantigen in pemphigus, and demonstrated that epidermal Langerhans cells (antigen-presenting cells) take up the autoantigen from surrounding keratinocytes via a C-type lectin receptor to induce regulatory T cells, which are critical for immune suppression. IL-2 signaling in Langerhans cells was required to preferentially expand regulatory T cells, providing new insights into mechanisms that regulate autoimmunity.
Abstract
Langerhans cells (LCs) are antigen-presenting cells in the epidermis whose roles in antigen-specific immune regulation remain incompletely understood. Desmoglein 3 (Dsg3) is a keratinocyte cell-cell adhesion molecule critical for epidermal integrity and an autoantigen in the autoimmune blistering disease pemphigus. Although antibody-mediated disease mechanisms in pemphigus are extensively characterized, the T cell aspect of this autoimmune disease still remains poorly understood. Herein, we utilized a mouse model of CD4+ T cell-mediated autoimmunity against Dsg3 to show that acquisition of Dsg3 and subsequent presentation to T cells by LCs depended on the C-type lectin langerin. The lack of LCs led to enhanced autoimmunity with impaired Dsg3-specific regulatory T cell expansion. LCs expressed the IL-2 receptor complex and the disruption of IL-2 signaling in LCs attenuated LC-mediated regulatory T cell expansion in vitro, demonstrating that direct IL-2 signaling shapes LC function. These data establish that LCs mediate peripheral tolerance against an epidermal autoantigen and point to langerin and IL-2 signaling pathways as attractive targets for achieving tolerogenic responses particularly in autoimmune blistering diseases such as pemphigus.
Current affiliation: Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, U.S.A.