Imiquimod-induced dermatitis impairs thymic tolerance of autoreactive CD4+ T cells to desmoglein 3

Hisato Iriki, Miho Mukai, Hiromi Ito, Yutaka Kurebayashi, Masayuki Amagai, Hayato Takahashi

Research output: Contribution to journalArticlepeer-review

Abstract

Background: The thymus plays an essential role in removing autoreactive T cells. Autoantigen-expressing thymic epithelial cells (TECs) contribute to the tolerogenic process. The thymus transiently shrinks as an acute thymic involution (ATI) under various inflammatory conditions. However, whether ATI occurs during local skin inflammation remains unclear, as does its influence on thymic immune tolerance. Objective: We investigated whether imiquimod-induced dermatitis causes ATI and impairs thymic immune tolerance against desmoglein 3 (Dsg3), an epidermal autoantigen of pemphigus vulgaris. Methods: 5% imiquimod cream was applied daily, at 62.5 mg/day (high dose group) or 31.25 mg/day (low dose group), for 1 week on the back of wild-type mice, and to wild-type mice that had undergone bone-marrow transplantation from Dsg3-specific T-cell receptor (TCR) transgenic-Rag2−/− mice. Next, thymocytes, TECs and other immune cells were analyzed by flow cytometry. TEC-associated Dsg3 expression was also analyzed by immunofluorescence staining. Results: Thymus weight and thymocyte number in all developmental stages decreased in a dose-dependent manner under imiquimod-induced dermatitis. The number of total TECs, specifically medullary, but not cortical, TECs, decreased in high and low dose groups. Accordingly, the number of Dsg3-experssing UEA-1+keratin 5+mTEC decreased in the thymus during imiquimod-induced dermatitis. Although Dsg3-sepcific transgenic thymocytes was usually deleted in the thymus under physiological condition by central tolerance, Dsg3-sepcific transgenic CD4+CD8 thymocytes significantly increased in number under imiquimod-induced dermatitis. Conclusion: These findings indicate a crosstalk between skin and thymus in adult mice and suggest that skin inflammation may impair thymic tolerance to autoantigens, such as Dsg3.

Original languageEnglish
Pages (from-to)166-174
Number of pages9
JournalJournal of Dermatological Science
Volume100
Issue number3
DOIs
Publication statusPublished - 2020 Dec

Keywords

  • Acute thymic involution
  • Autoimmunity
  • Central tolerance
  • Cortical thymic epithelial cells
  • Desmoglein 3
  • Imiquimod
  • Immunological tolerance
  • Medullary thymic epitherial cells
  • Negetive selection
  • Pemphigus vulgaris
  • Thymic epitherial cells
  • Thymic tolerance
  • Toll like receptor 7
  • Toll like receptor 9

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Dermatology

Fingerprint Dive into the research topics of 'Imiquimod-induced dermatitis impairs thymic tolerance of autoreactive CD4<sup>+</sup> T cells to desmoglein 3'. Together they form a unique fingerprint.

Cite this