Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 118, Issue 49, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2026763118
Keywords
peripheral immunological tolerance; regulatory T cells; Foxp3; OX40; autoreactive T cells
Categories
Funding
- Ministry of Education, Culture, Sports, Science, and Technology of Japan [JP21229014, JP17109012, JP21H05044, JP26253065, JP19H01051, JP19KO7514]
- Keio Gijuku Academic Development Fund
- Research Grants for Life Sciences and Medicine, Keio University Medical Science Fund
- Kanae Foundation for the Promotion of Medical Science
- LEO Pharma Research Foundation
- AMED [JP21gm1110009, JPam0401005, JP21zf0127003h]
- Waksman Foundation of Japan Inc.
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The study analyzed peripheral tolerance using the Dsg3 antigen and found that Treg-mediated peripheral deletion of autoreactive T cells is a key mechanism to avoid undesired autoimmunity, which is dependent on the OX40 signaling pathway.
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 mechanismto avoid undesired autoimmunity besides thymic tolerance.
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