气候变化领域集成服务门户(CCPortal): Peripheral tolerance by treg via constraining OX40 signal in autoreactive T cells against desmoglein 3, a target antigen in pemphigus

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DOI	10.1073/pnas.2026763118
	Peripheral tolerance by treg via constraining OX40 signal in autoreactive T cells against desmoglein 3, a target antigen in pemphigus
	Iriki H.; Takahashi H.; Wada N.; Nomura H.; Mukai M.; Kamata A.; Ito H.; Yamagami J.; Matsui T.; Kurebayashi Y.; Mise-Omata S.; Nishimasu H.; Nureki O.; Yoshimura A.; Hori S.; Amagai M.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:49
英文摘要	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. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Autoreactive T cells; Foxp3; OX40; Peripheral immunological tolerance; Regulatory T cells
语种	英语
scopus关键词	baculoviral IAP repeat containing protein 5; CD134 antigen; desmoglein 3; gamma interferon; Hermes antigen; interleukin 2 receptor alpha; OX40 ligand; T lymphocyte receptor; transcription factor FOXP3; transcriptome; abatacept; antiestrogen; desmoglein 3; DNA binding protein; Dsg3 protein, mouse; Rag2 protein, mouse; tamoxifen; adoptive transfer; animal cell; animal experiment; animal model; animal tissue; antigen expression; antigen presentation; antigen recognition; antigen specificity; Article; bone marrow transplantation; CD4+ T lymphocyte; cell function; cell interaction; cell maturation; cell proliferation; cell survival; controlled study; CRISPR-CAS9 system; cytokine production; dendritic cell; immunological tolerance; immunoregulation; in vitro study; in vivo study; mouse; nonhuman; pathogenicity; pemphigus; protein expression; protein protein interaction; regulatory mechanism; regulatory T lymphocyte; signal transduction; upregulation; animal; coculture; drug effect; female; gene expression regulation; genetics; immunology; knockout mouse; male; metabolism; pemphigus; pharmacology; regulatory T lymphocyte; Abatacept; Adoptive Transfer; Animals; Coculture Techniques; Desmoglein 3; DNA-Binding Proteins; Estrogen Antagonists; Female; Gene Expression Regulation; Immune Checkpoint Inhibitors; Male; Mice; Mice, Knockout; Pemphigus; T-Lymphocytes, Regulatory; Tamoxifen
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/250959
作者单位	Department of Dermatology, Keio University School of Medicine, Tokyo, 160-8582, Japan; Laboratory for Skin Homeostasis, RIKEN Center for Integrative Medical Sciences, Yokohama City, 230-0045, Japan; Laboratory for Evolutionary Cell Biology of the Skin, School of Bioscience and Biotechnology, Tokyo University of Technology, Tokyo, 192-0982, Japan; Department of Pathology, Keio University School of Medicine, Tokyo, 160-8582, Japan; Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, 160-8582, Japan; Department of Biological Science, Graduate School of Science, University of Tokyo, Tokyo, 113-0033, Japan; Structural Biology Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, 153-8904, Japan; Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, 113-0033, Japan
推荐引用方式 GB/T 7714	Iriki H.,Takahashi H.,Wada N.,et al. Peripheral tolerance by treg via constraining OX40 signal in autoreactive T cells against desmoglein 3, a target antigen in pemphigus[J],2021,118(49).
APA	Iriki H..,Takahashi H..,Wada N..,Nomura H..,Mukai M..,...&Amagai M..(2021).Peripheral tolerance by treg via constraining OX40 signal in autoreactive T cells against desmoglein 3, a target antigen in pemphigus.Proceedings of the National Academy of Sciences of the United States of America,118(49).
MLA	Iriki H.,et al."Peripheral tolerance by treg via constraining OX40 signal in autoreactive T cells against desmoglein 3, a target antigen in pemphigus".Proceedings of the National Academy of Sciences of the United States of America 118.49(2021).