Peripheral tolerance by treg via constraining OX40 signal in autoreactive T cells against desmoglein 3, a target antigen in pemphigus

Hisato Iriki, Hayato Takahashi, Naoko Wada, Hisashi Nomura, Miho Mukai, Aki Kamata, Hiromi Ito, Jun Yamagami, Takeshi Matsui, Yutaka Kurebayashi, Setsuko Mise-Omata, Hiroshi Nishimasu, Osamu Nureki, Akihiko Yoshimura, Shohei Hori, Masayuki Amagai

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9 Citations (Scopus)


Antigen-specific peripheral tolerance is crucial to prevent the development of organ-specific autoimmunity. However, its function decoupled from thymic tolerance remains unclear. We used desmoglein 3 (Dsg3), a pemphigus antigen expressed in keratinocytes, to analyze peripheral tolerance under physiological antigen-expression conditions. Dsg3-deficient thymi were transplanted into athymic mice to create a unique condition in which Dsg3 was expressed only in peripheral tissue but not in the thymus. When bone marrow transfer was conducted from high-avidity Dsg3-specific T cell receptor–transgenic mice to thymus-transplanted mice, Dsg3-specific CD4+ T cells developed in the transplanted thymus but subsequently disappeared in the periphery. Additionally, when Dsg3-specific T cells developed in Dsg32/2 mice were adoptively transferred into Dsg3-sufficient recipients, the T cells disappeared in an antigen-specific manner without inducing autoimmune dermatitis. However, Dsg3-specific T cells overcame this disappearance and thus induced autoimmune dermatitis in Treg-ablated recipients but not in Foxp3-mutant recipients with dysfunctional Tregs. The molecules involved in disappearance were sought by screening the transcriptomes of wild-type and Foxp3-mutant Tregs. OX40 of Tregs was suggested to be responsible. Consistently, when OX40 expression of Tregs was constrained, Dsg3-specific T cells did not disappear. Furthermore, Tregs obtained OX40L from dendritic cells in an OX40-dependent manner in vitro and then suppressed OX40L expression in dendritic cells and Birc5 expression in Dsg3-specific T cells in vivo. Lastly, CRISPR/Cas9-mediated knockout of OX40 signaling in Dsg3-specific T cells restored their disappearance in Treg-ablated recipients. Thus, Treg-mediated peripheral deletion of autoreactive T cells operates as an OX40-dependent regulatory mechanism to avoid undesired autoimmunity besides thymic tolerance.

Original languageEnglish
Article numbere2026763118
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number49
Publication statusPublished - 2021 Dec 7


  • Autoreactive T cells
  • Foxp3
  • OX40
  • Peripheral immunological tolerance
  • Regulatory T cells

ASJC Scopus subject areas

  • General


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