1. Peripheral tolerance by Treg via constraining OX40 signal in autoreactive T cells against desmoglein 3, a target antigen in pemphigus
- Author
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Masayuki Amagai, Osamu Nureki, Naoko Wada, Yutaka Kurebayashi, Jun Yamagami, Akihiko Yoshimura, Shohei Hori, Hisashi Nomura, Hiromi Ito, Miho Mukai, Hiroshi Nishimasu, Takeshi Matsui, Setsuko Mise-Omata, Hayato Takahashi, Aki Kamata, and Hisato Iriki
- Subjects
Male ,T cell ,Biology ,medicine.disease_cause ,T-Lymphocytes, Regulatory ,Autoimmunity ,Abatacept ,Mice ,Antigen ,medicine ,Animals ,education ,Immune Checkpoint Inhibitors ,Mice, Knockout ,education.field_of_study ,Multidisciplinary ,Desmoglein 3 ,Estrogen Antagonists ,FOXP3 ,Peripheral tolerance ,Biological Sciences ,Adoptive Transfer ,Coculture Techniques ,In vitro ,DNA-Binding Proteins ,Tamoxifen ,medicine.anatomical_structure ,Gene Expression Regulation ,Immunology ,Female ,Bone marrow ,Pemphigus - Abstract
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 Dsg3(−/−) 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.
- Published
- 2021