缺失“自我缺失”机制:犬NK细胞Ly49表达的建模和检测

Q3 Medicine
Alicia A Gingrich, Aryana M Razmara, Phillip W Gingrich, Robert B Rebhun, William J Murphy, Michael S Kent, C Titus Brown, Justin B Siegel, Robert J Canter
{"title":"缺失“自我缺失”机制:犬NK细胞Ly49表达的建模和检测","authors":"Alicia A Gingrich, Aryana M Razmara, Phillip W Gingrich, Robert B Rebhun, William J Murphy, Michael S Kent, C Titus Brown, Justin B Siegel, Robert J Canter","doi":"10.4049/immunohorizons.2300092","DOIUrl":null,"url":null,"abstract":"<p><p>NK cells are a key focus in immuno-oncology, based on their ability to eliminate malignant cells without prior sensitization. Dogs are valuable models for translational immunotherapy studies, especially for NK cells, where critical species differences exist between mice and humans. Given that the mechanism for recognition of \"self\" by canine NK cells is currently unknown, we sought to evaluate expression of Ly49 in canine NK cells using in silico and high-throughput techniques. We interrogated the identified polymorphism/mutation in canine Ly49 and assessed the potential impact on structure using computational modeling of three-dimensional protein structure and protein-protein docking of canine Ly49 with MHC class I (MHC-I). Bulk and single-cell RNA-sequencing analysis was performed to detect gene expression of Ly49/KLRA1 in resting and activated NK cells. Tertiary protein structure demonstrated significant structural similarity to the known murine system. Molecular docking of canine Ly49 with MHC-I was favorable, converging at a single low-energy conformation. RNA sequencing revealed expression of Ly49/KLRA1 in both resting and activated NK cells and demonstrated almost exclusive expression of the gene in the NK cluster at the single-cell level. Despite prior reports of a mutated, nonfunctional canine Ly49, our data support that the protein product is predicted to bind to MHC-I in a comparable conformation to the murine system and is expressed in canine NK cells with upregulation following activation. Taken together, these data suggest that Ly49 is capable of recognizing MHC-I and therefore regulating NK cell function in dogs.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10696421/pdf/","citationCount":"0","resultStr":"{\"title\":\"Missing a \\\"Missing Self\\\" Mechanism: Modeling and Detection of Ly49 Expression in Canine NK Cells.\",\"authors\":\"Alicia A Gingrich, Aryana M Razmara, Phillip W Gingrich, Robert B Rebhun, William J Murphy, Michael S Kent, C Titus Brown, Justin B Siegel, Robert J Canter\",\"doi\":\"10.4049/immunohorizons.2300092\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>NK cells are a key focus in immuno-oncology, based on their ability to eliminate malignant cells without prior sensitization. Dogs are valuable models for translational immunotherapy studies, especially for NK cells, where critical species differences exist between mice and humans. Given that the mechanism for recognition of \\\"self\\\" by canine NK cells is currently unknown, we sought to evaluate expression of Ly49 in canine NK cells using in silico and high-throughput techniques. We interrogated the identified polymorphism/mutation in canine Ly49 and assessed the potential impact on structure using computational modeling of three-dimensional protein structure and protein-protein docking of canine Ly49 with MHC class I (MHC-I). Bulk and single-cell RNA-sequencing analysis was performed to detect gene expression of Ly49/KLRA1 in resting and activated NK cells. Tertiary protein structure demonstrated significant structural similarity to the known murine system. Molecular docking of canine Ly49 with MHC-I was favorable, converging at a single low-energy conformation. RNA sequencing revealed expression of Ly49/KLRA1 in both resting and activated NK cells and demonstrated almost exclusive expression of the gene in the NK cluster at the single-cell level. Despite prior reports of a mutated, nonfunctional canine Ly49, our data support that the protein product is predicted to bind to MHC-I in a comparable conformation to the murine system and is expressed in canine NK cells with upregulation following activation. Taken together, these data suggest that Ly49 is capable of recognizing MHC-I and therefore regulating NK cell function in dogs.</p>\",\"PeriodicalId\":94037,\"journal\":{\"name\":\"ImmunoHorizons\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2023-11-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10696421/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ImmunoHorizons\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.4049/immunohorizons.2300092\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"Medicine\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ImmunoHorizons","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.4049/immunohorizons.2300092","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"Medicine","Score":null,"Total":0}
引用次数: 0

摘要

NK细胞是免疫肿瘤学的一个关键焦点,基于它们在没有事先致敏的情况下消除恶性细胞的能力。狗是翻译免疫治疗研究的有价值的模型,特别是NK细胞,其中小鼠和人类之间存在关键的物种差异。鉴于犬NK细胞识别“自我”的机制目前尚不清楚,我们试图利用硅和高通量技术评估Ly49在犬NK细胞中的表达。我们研究了犬Ly49的多态性/突变,并利用三维蛋白质结构计算模型和犬Ly49与MHC I类(MHC-I)的蛋白-蛋白对接来评估其对结构的潜在影响。在静息NK细胞和活化NK细胞中,采用大量和单细胞rna测序检测Ly49/KLRA1基因的表达。三级蛋白结构与已知的小鼠系统具有显著的结构相似性。犬Ly49与mhc - 1的分子对接是有利的,会聚在单一的低能构象上。RNA测序结果显示,Ly49/KLRA1在静止NK细胞和活化NK细胞中均有表达,且在单细胞水平上,该基因在NK细胞簇中几乎完全表达。尽管之前有犬Ly49突变的报道,但我们的数据支持该蛋白产物以与小鼠系统相似的构象与mhc - 1结合,并在犬NK细胞中表达,激活后上调。综上所述,这些数据表明Ly49能够识别mhc - 1,从而调节狗的NK细胞功能。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Missing a "Missing Self" Mechanism: Modeling and Detection of Ly49 Expression in Canine NK Cells.

NK cells are a key focus in immuno-oncology, based on their ability to eliminate malignant cells without prior sensitization. Dogs are valuable models for translational immunotherapy studies, especially for NK cells, where critical species differences exist between mice and humans. Given that the mechanism for recognition of "self" by canine NK cells is currently unknown, we sought to evaluate expression of Ly49 in canine NK cells using in silico and high-throughput techniques. We interrogated the identified polymorphism/mutation in canine Ly49 and assessed the potential impact on structure using computational modeling of three-dimensional protein structure and protein-protein docking of canine Ly49 with MHC class I (MHC-I). Bulk and single-cell RNA-sequencing analysis was performed to detect gene expression of Ly49/KLRA1 in resting and activated NK cells. Tertiary protein structure demonstrated significant structural similarity to the known murine system. Molecular docking of canine Ly49 with MHC-I was favorable, converging at a single low-energy conformation. RNA sequencing revealed expression of Ly49/KLRA1 in both resting and activated NK cells and demonstrated almost exclusive expression of the gene in the NK cluster at the single-cell level. Despite prior reports of a mutated, nonfunctional canine Ly49, our data support that the protein product is predicted to bind to MHC-I in a comparable conformation to the murine system and is expressed in canine NK cells with upregulation following activation. Taken together, these data suggest that Ly49 is capable of recognizing MHC-I and therefore regulating NK cell function in dogs.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
CiteScore
3.70
自引率
0.00%
发文量
0
审稿时长
4 weeks
×
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