Langerhans Cells Prevent Autoimmunity via Expansion of Keratinocyte Antigen-Specific Regulatory T Cells

Daniela Y. Kitashima, Tetsuro Kobayashi, Therese Woodring, Kacey Idouchi, Thomas Doebel, Benjamin Voisin, Takeya Adachi, Takeshi Ouchi, Hayato Takahashi, Koji Nishifuji, Daniel H. Kaplan, Björn E. Clausen, Masayuki Amagai, Keisuke Nagao

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17 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)293-303
Number of pages11
JournalEBioMedicine
Volume27
DOIs
Publication statusPublished - 2018 Jan

Keywords

  • Autoimmune disease
  • Langerhans cells
  • Pemphigus
  • Regulatory T cells

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Kitashima, D. Y., Kobayashi, T., Woodring, T., Idouchi, K., Doebel, T., Voisin, B., Adachi, T., Ouchi, T., Takahashi, H., Nishifuji, K., Kaplan, D. H., Clausen, B. E., Amagai, M., & Nagao, K. (2018). Langerhans Cells Prevent Autoimmunity via Expansion of Keratinocyte Antigen-Specific Regulatory T Cells. EBioMedicine, 27, 293-303. https://doi.org/10.1016/j.ebiom.2017.12.022