PD-1 expressing islet-specific CD4+ T cells promote bystander tolerance and prevent autoimmunity.

IF 3.2 4区 医学 Q3 CELL BIOLOGY
Jeniffer D Loaiza Naranjo, Vivian Zhang, Rathna Ravichandran, Anne-Sophie Bergot, Ranjeny Thomas, Emma E Hamilton-Williams
{"title":"PD-1 expressing islet-specific CD4<sup>+</sup> T cells promote bystander tolerance and prevent autoimmunity.","authors":"Jeniffer D Loaiza Naranjo, Vivian Zhang, Rathna Ravichandran, Anne-Sophie Bergot, Ranjeny Thomas, Emma E Hamilton-Williams","doi":"10.1111/imcb.70044","DOIUrl":null,"url":null,"abstract":"<p><p>Loss of T-cell tolerance to multiple islet antigens is a key feature of autoimmune type 1 diabetes. In this study, we investigated the requirement for programmed death 1 (PD-1) expression by CD4<sup>+</sup> T cells in the maintenance of self-tolerance via bystander suppression of autoreactive CD8<sup>+</sup> T cells using nonobese diabetic mice. We used CRISPR/Cas9 to selectively knockout PD-1 in islet antigen-specific BDC2.5 CD4<sup>+</sup> T cells and observed the impact on bystander tolerance of 8.3 CD8<sup>+</sup> T cells, specific for a different islet antigen. Loss of PD-1 promoted the proliferation, Th1-like effector-memory phenotype, islet infiltration and expression of cytotoxic markers by BDC2.5 cells. PD-1-deficient BDC2.5 cells were impaired in their regulation of 8.3 cells, which proliferated more, developed an effector-memory phenotype and increased expression of effector molecules. While antigen-presenting cell maturation and migration into the pancreatic lymph node were not impacted by loss of PD-1 expression from BDC2.5 cells, migration of BDC2.5 cells out of the lymph node was required for enhanced activation of the CD8<sup>+</sup> T cells. Together, these events led to accelerated diabetes progression, suggesting that PD-1 expression by CD4<sup>+</sup> T cells promotes a tolerogenic microenvironment and restraining autoreactive CD8<sup>+</sup> T cells.</p>","PeriodicalId":179,"journal":{"name":"Immunology & Cell Biology","volume":" ","pages":""},"PeriodicalIF":3.2000,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Immunology & Cell Biology","FirstCategoryId":"2","ListUrlMain":"https://doi.org/10.1111/imcb.70044","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Loss of T-cell tolerance to multiple islet antigens is a key feature of autoimmune type 1 diabetes. In this study, we investigated the requirement for programmed death 1 (PD-1) expression by CD4+ T cells in the maintenance of self-tolerance via bystander suppression of autoreactive CD8+ T cells using nonobese diabetic mice. We used CRISPR/Cas9 to selectively knockout PD-1 in islet antigen-specific BDC2.5 CD4+ T cells and observed the impact on bystander tolerance of 8.3 CD8+ T cells, specific for a different islet antigen. Loss of PD-1 promoted the proliferation, Th1-like effector-memory phenotype, islet infiltration and expression of cytotoxic markers by BDC2.5 cells. PD-1-deficient BDC2.5 cells were impaired in their regulation of 8.3 cells, which proliferated more, developed an effector-memory phenotype and increased expression of effector molecules. While antigen-presenting cell maturation and migration into the pancreatic lymph node were not impacted by loss of PD-1 expression from BDC2.5 cells, migration of BDC2.5 cells out of the lymph node was required for enhanced activation of the CD8+ T cells. Together, these events led to accelerated diabetes progression, suggesting that PD-1 expression by CD4+ T cells promotes a tolerogenic microenvironment and restraining autoreactive CD8+ T cells.

表达胰岛特异性CD4+ T细胞的PD-1促进旁观者耐受和预防自身免疫。
t细胞对多种胰岛抗原的耐受性丧失是自身免疫性1型糖尿病的一个关键特征。在这项研究中,我们利用非肥胖糖尿病小鼠,通过旁观者抑制自身反应性CD8+ T细胞,研究了CD4+ T细胞表达程序性死亡1 (PD-1)在维持自身耐受性中的需求。我们使用CRISPR/Cas9选择性敲除胰岛抗原特异性BDC2.5 CD4+ T细胞中的PD-1,并观察8.3 CD8+ T细胞对不同胰岛抗原特异性的旁观者耐受性的影响。PD-1的缺失促进了BDC2.5细胞的增殖、th1样效应记忆表型、胰岛浸润和细胞毒性标志物的表达。pd -1缺失的BDC2.5细胞对8.3细胞的调节功能受损,8.3细胞增殖增加,产生效应记忆表型,效应分子表达增加。虽然BDC2.5细胞PD-1表达缺失不影响抗原提呈细胞的成熟和向胰腺淋巴结的迁移,但BDC2.5细胞向淋巴结外的迁移是增强CD8+ T细胞活化所必需的。总之,这些事件导致糖尿病加速进展,表明CD4+ T细胞表达PD-1促进了耐受性微环境并抑制了自身反应性CD8+ T细胞。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Immunology & Cell Biology
Immunology & Cell Biology 医学-免疫学
CiteScore
7.50
自引率
2.50%
发文量
98
审稿时长
4-8 weeks
期刊介绍: The Australasian Society for Immunology Incorporated (ASI) was created by the amalgamation in 1991 of the Australian Society for Immunology, formed in 1970, and the New Zealand Society for Immunology, formed in 1975. The aim of the Society is to encourage and support the discipline of immunology in the Australasian region. It is a broadly based Society, embracing clinical and experimental, cellular and molecular immunology in humans and animals. The Society provides a network for the exchange of information and for collaboration within Australia, New Zealand and overseas. ASI members have been prominent in advancing biological and medical research worldwide. We seek to encourage the study of immunology in Australia and New Zealand and are active in introducing young scientists to the discipline.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信