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

研究成果: Article査読

2 被引用数 (Scopus)

抄録

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.

本文言語English
論文番号e2026763118
ジャーナルProceedings of the National Academy of Sciences of the United States of America
118
49
DOI
出版ステータスPublished - 2021 12月 7

ASJC Scopus subject areas

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