Open AccessPeripheral tolerance by Treg via constraining OX40 signal in autoreactive T cells against desmoglein 3, a target antigen in pemphigus
Author(s) -
Hisato Iriki,
Hayato Takahashi,
Naoko Wada,
Hisashi Nomura,
Masayuki Mukai,
Aki Kamata,
Hiromi Ito,
Jun Yamagami,
Toshinori Matsui,
Yutaka Kurebayashi,
Setsuko Mise-Omata,
Hiroshi Nishimasu,
Osamu Nureki,
Akihiko Yoshimura,
Shohei Hori,
Masayuki Amagai
Publication year - 2021
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2026763118
Subject(s) - immunology , desmoglein 3 , peripheral tolerance , foxp3 , adoptive cell transfer , antigen , biology , immune tolerance , humanized mouse , t cell , autoimmunity , central tolerance , pemphigus , microbiology and biotechnology , immune system , autoimmune disease , antibody
Significance Immune tolerance is crucial to prevent harmful immune reactions against self-antigens and well operated by central thymic tolerance and peripheral tissue tolerance. However, peripheral tolerance had been investigated under influence from thymic tolerance. We successfully decoupled peripheral tolerance from thymic tolerance by utilizing autoantigen-deficient thymus. Experiments revealed that self-antigen presentation in steady state initiated proliferation but subsequent disappearance of autoreactive CD4+ T cells in draining lymph nodes. After screening of representative candidates, including Ctla4, autoimmune regulator, and Pd-1, the mechanism was found to depend on regulatory T cell (Treg) function that constrained OX40 signaling of the T cells. This study presented fundamental, but potent, Treg-mediated tolerance mechanisms of peripheral tissues to prevent autoimmunity as compensatory roles for central tolerance.