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

Research output: Contribution to journalArticle

10 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
JournalEBioMedicine
DOIs
Publication statusAccepted/In press - 2018 Jan 1

Fingerprint

Desmoglein 3
T-cells
Langerhans Cells
Regulatory T-Lymphocytes
Autoimmunity
Keratinocytes
Antigens
Interleukin-2
Pemphigus
Autoantigens
Autoimmune Diseases
C-Type Lectins
T-Lymphocytes
Interleukin-2 Receptors
Cell Adhesion Molecules
Peripheral Tolerance
Antigen-Presenting Cells
Epidermis
Antibodies

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Kitashima, D. Y., Kobayashi, T., Woodring, T., Idouchi, K., Doebel, T., Voisin, B., ... Nagao, K. (Accepted/In press). Langerhans Cells Prevent Autoimmunity via Expansion of Keratinocyte Antigen-Specific Regulatory T Cells. EBioMedicine. https://doi.org/10.1016/j.ebiom.2017.12.022

Langerhans Cells Prevent Autoimmunity via Expansion of Keratinocyte Antigen-Specific Regulatory T Cells. / Kitashima, Daniela Y.; Kobayashi, Tetsuro; Woodring, Therese; Idouchi, Kacey; Doebel, Thomas; Voisin, Benjamin; Adachi, Takeya; Ouchi, Takeshi; Takahashi, Hayato; Nishifuji, Koji; Kaplan, Daniel H.; Clausen, Björn E.; Amagai, Masayuki; Nagao, Keisuke.

In: EBioMedicine, 01.01.2018.

Research output: Contribution to journalArticle

Kitashima, DY, Kobayashi, T, Woodring, T, Idouchi, K, Doebel, T, Voisin, B, Adachi, T, Ouchi, T, Takahashi, H, Nishifuji, K, Kaplan, DH, Clausen, BE, Amagai, M & Nagao, K 2018, 'Langerhans Cells Prevent Autoimmunity via Expansion of Keratinocyte Antigen-Specific Regulatory T Cells', EBioMedicine. https://doi.org/10.1016/j.ebiom.2017.12.022
Kitashima, Daniela Y. ; Kobayashi, Tetsuro ; Woodring, Therese ; Idouchi, Kacey ; Doebel, Thomas ; Voisin, Benjamin ; Adachi, Takeya ; Ouchi, Takeshi ; Takahashi, Hayato ; Nishifuji, Koji ; Kaplan, Daniel H. ; Clausen, Björn E. ; Amagai, Masayuki ; Nagao, Keisuke. / Langerhans Cells Prevent Autoimmunity via Expansion of Keratinocyte Antigen-Specific Regulatory T Cells. In: EBioMedicine. 2018.
@article{d967b59bf7e14be4b812d8c0a7e36cd4,
title = "Langerhans Cells Prevent Autoimmunity via Expansion of Keratinocyte Antigen-Specific Regulatory T Cells",
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.",
keywords = "Autoimmune disease, Langerhans cells, Pemphigus, Regulatory T cells",
author = "Kitashima, {Daniela Y.} and Tetsuro Kobayashi and Therese Woodring and Kacey Idouchi and Thomas Doebel and Benjamin Voisin and Takeya Adachi and Takeshi Ouchi and Hayato Takahashi and Koji Nishifuji and Kaplan, {Daniel H.} and Clausen, {Bj{\"o}rn E.} and Masayuki Amagai and Keisuke Nagao",
year = "2018",
month = "1",
day = "1",
doi = "10.1016/j.ebiom.2017.12.022",
language = "English",
journal = "EBioMedicine",
issn = "2352-3964",
publisher = "Elsevier BV",

}

TY - JOUR

T1 - Langerhans Cells Prevent Autoimmunity via Expansion of Keratinocyte Antigen-Specific Regulatory T Cells

AU - Kitashima, Daniela Y.

AU - Kobayashi, Tetsuro

AU - Woodring, Therese

AU - Idouchi, Kacey

AU - Doebel, Thomas

AU - Voisin, Benjamin

AU - Adachi, Takeya

AU - Ouchi, Takeshi

AU - Takahashi, Hayato

AU - Nishifuji, Koji

AU - Kaplan, Daniel H.

AU - Clausen, Björn E.

AU - Amagai, Masayuki

AU - Nagao, Keisuke

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

KW - Autoimmune disease

KW - Langerhans cells

KW - Pemphigus

KW - Regulatory T cells

UR - http://www.scopus.com/inward/record.url?scp=85039909572&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85039909572&partnerID=8YFLogxK

U2 - 10.1016/j.ebiom.2017.12.022

DO - 10.1016/j.ebiom.2017.12.022

M3 - Article

C2 - 29307572

AN - SCOPUS:85039909572

JO - EBioMedicine

JF - EBioMedicine

SN - 2352-3964

ER -