Regulatory T Cell Insufficiency in Autoimmune Diabetes Is Driven by Selective Loss of Neuropilin-1 on Intraislet Regulatory T Cells.

IF 3.6 3区 医学 Q2 IMMUNOLOGY
Stephanie Grebinoski, Gwenyth Pieklo, Qianxia Zhang, Anabelle Visperas, Jian Cui, Jordana Goulet, Hanxi Xiao, Erin A Brunazzi, Carly Cardello, Andrés A Herrada, Jishnu Das, Creg J Workman, Dario A A Vignali
{"title":"Regulatory T Cell Insufficiency in Autoimmune Diabetes Is Driven by Selective Loss of Neuropilin-1 on Intraislet Regulatory T Cells.","authors":"Stephanie Grebinoski, Gwenyth Pieklo, Qianxia Zhang, Anabelle Visperas, Jian Cui, Jordana Goulet, Hanxi Xiao, Erin A Brunazzi, Carly Cardello, Andrés A Herrada, Jishnu Das, Creg J Workman, Dario A A Vignali","doi":"10.4049/jimmunol.2300216","DOIUrl":null,"url":null,"abstract":"<p><p>Approaches to reverse or limit regulatory T cell (Treg) insufficiency are of great interest for development of immunotherapeutic treatments for autoimmune patients, including type 1 diabetes. Treg insufficiency is heavily implicated in the progression of autoimmune diabetes in the NOD mouse model and is characterized by defects in Treg numbers, development, and/or function. Utilizing a Treg-centric screen, we show that intraislet Tregs have a uniquely dysfunctional phenotype, hallmarked by an almost complete lack of neuropilin-1 (Nrp1), a cell surface receptor required to maintain Treg stability. Intraislet Nrp1- Tregs exhibit hallmark features of fragility, including reduced suppressive capacity, decreased CD73 and Helios, and increased Rorγt and Tbet. Intraislet Nrp1- Tregs also exhibit decreased Foxp3 expression on a per cell basis, suggesting that Nrp1 may also be required for long-term Treg stability. Mechanistically, Treg-restricted augmentation of Nrp1 expression limited the onset of autoimmune diabetes in NOD mice suggesting that Nrp1 critically impacts intraislet Treg function. Transcriptional analysis showed that Nrp1 restoration led to an increase in markers and pathways of TCR signaling, survival, and suppression, and when Nrp1 protein expression is examined by cellular indexing of transcriptomes and epitopes by sequencing, significant differences were observed between Nrp1+ and Nrp1- Tregs in all tissues, particularly in markers of Treg fragility. This translated into substantive differences between Nrp1+ and Nrp1- Tregs that afforded the former with a competitive advantage in the islets. Taken together, these data suggest that maintenance of Nrp1 expression and signaling on Tregs limits diabetes onset and may serve as a strategy to combat Treg insufficiency in autoimmune disease.</p>","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":null,"pages":null},"PeriodicalIF":3.6000,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11371503/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of immunology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.4049/jimmunol.2300216","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Approaches to reverse or limit regulatory T cell (Treg) insufficiency are of great interest for development of immunotherapeutic treatments for autoimmune patients, including type 1 diabetes. Treg insufficiency is heavily implicated in the progression of autoimmune diabetes in the NOD mouse model and is characterized by defects in Treg numbers, development, and/or function. Utilizing a Treg-centric screen, we show that intraislet Tregs have a uniquely dysfunctional phenotype, hallmarked by an almost complete lack of neuropilin-1 (Nrp1), a cell surface receptor required to maintain Treg stability. Intraislet Nrp1- Tregs exhibit hallmark features of fragility, including reduced suppressive capacity, decreased CD73 and Helios, and increased Rorγt and Tbet. Intraislet Nrp1- Tregs also exhibit decreased Foxp3 expression on a per cell basis, suggesting that Nrp1 may also be required for long-term Treg stability. Mechanistically, Treg-restricted augmentation of Nrp1 expression limited the onset of autoimmune diabetes in NOD mice suggesting that Nrp1 critically impacts intraislet Treg function. Transcriptional analysis showed that Nrp1 restoration led to an increase in markers and pathways of TCR signaling, survival, and suppression, and when Nrp1 protein expression is examined by cellular indexing of transcriptomes and epitopes by sequencing, significant differences were observed between Nrp1+ and Nrp1- Tregs in all tissues, particularly in markers of Treg fragility. This translated into substantive differences between Nrp1+ and Nrp1- Tregs that afforded the former with a competitive advantage in the islets. Taken together, these data suggest that maintenance of Nrp1 expression and signaling on Tregs limits diabetes onset and may serve as a strategy to combat Treg insufficiency in autoimmune disease.

自身免疫性糖尿病的调节性 T 细胞不足是由胰岛内调节性 T 细胞神经蛋白酶-1 的选择性丧失驱动的。
逆转或限制调节性 T 细胞(Treg)不足的方法对于开发包括 1 型糖尿病在内的自身免疫性患者的免疫治疗方法具有重大意义。Treg不足与NOD小鼠模型中自身免疫性糖尿病的进展有很大关系,其特征是Treg数量、发育和/或功能的缺陷。通过以 Treg 为中心的筛选,我们发现小鼠体内的 Treg 具有独特的功能障碍表型,其特征是几乎完全缺乏神经蛋白-1(Nrp1),而神经蛋白-1 是维持 Treg 稳定性所必需的细胞表面受体。小鼠体内 Nrp1- Tregs 表现出脆弱的特征,包括抑制能力降低、CD73 和 Helios 减少以及 Rorγt 和 Tbet 增加。小鼠体内的 Nrp1- Tregs 还表现出每个细胞的 Foxp3 表达减少,这表明 Nrp1 也可能是 Treg 长期稳定所必需的。从机理上讲,限制Treg的Nrp1表达增加限制了NOD小鼠自身免疫性糖尿病的发病,这表明Nrp1对小鼠体内Treg的功能有关键影响。转录分析表明,Nrp1 的恢复导致 TCR 信号转导、存活和抑制的标记物和通路增加,当通过转录组细胞索引和表位测序检查 Nrp1 蛋白表达时,在所有组织中观察到 Nrp1+ 和 Nrp1- Tregs 之间存在显著差异,特别是在 Treg 脆弱性标记物方面。这转化成了 Nrp1+ 和 Nrp1- Tregs 之间的实质性差异,使前者在胰岛中具有竞争优势。综上所述,这些数据表明,维持 Nrp1 在 Tregs 上的表达和信号传导可限制糖尿病的发病,并可作为一种策略来对抗自身免疫性疾病中的 Treg 不足。
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
Journal of immunology
Journal of immunology 医学-免疫学
CiteScore
8.20
自引率
2.30%
发文量
495
审稿时长
1 months
期刊介绍: The JI publishes novel, peer-reviewed findings in all areas of experimental immunology, including innate and adaptive immunity, inflammation, host defense, clinical immunology, autoimmunity and more. Special sections include Cutting Edge articles, Brief Reviews and Pillars of Immunology. The JI is published by The American Association of Immunologists (AAI)
×
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:481959085
Book学术官方微信