Jing Chen, Chao Liu, Anna V. Chernatynskaya, Brittney Newby, Todd M. Brusko, Yuan Xu, Jessie M. Barra, Nadine Morgan, Christopher Santarlas, Westley H. Reeves, Hubert M. Tse, Jennifer W. Leiding, Clayton E. Mathews
{"title":"NADPH Oxidase 2–Derived Reactive Oxygen Species Promote CD8+ T Cell Effector Function","authors":"Jing Chen, Chao Liu, Anna V. Chernatynskaya, Brittney Newby, Todd M. Brusko, Yuan Xu, Jessie M. Barra, Nadine Morgan, Christopher Santarlas, Westley H. Reeves, Hubert M. Tse, Jennifer W. Leiding, Clayton E. Mathews","doi":"10.4049/jimmunol.2200691","DOIUrl":null,"url":null,"abstract":"<jats:title>Abstract</jats:title> Oxidants participate in lymphocyte activation and function. We previously demonstrated that eliminating the activity of NADPH oxidase 2 (NOX2) significantly impaired the effectiveness of autoreactive CD8+ CTLs. However, the molecular mechanisms impacting CD8+ T cell function remain unknown. In the present study, we examined the role of NOX2 in both NOD mouse and human CD8+ T cell function. Genetic ablation or chemical inhibition of NOX2 in CD8+ T cells significantly suppressed activation-induced expression of the transcription factor T-bet, the master transcription factor of the Tc1 cell lineage, and T-bet target effector genes such as IFN-γ and granzyme B. Inhibition of NOX2 in both human and mouse CD8+ T cells prevented target cell lysis. We identified that superoxide generated by NOX2 must be converted into hydrogen peroxide to transduce the redox signal in CD8+ T cells. Furthermore, we show that NOX2-generated oxidants deactivate the tumor suppressor complex leading to activation of RheB and subsequently mTOR complex 1. These results indicate that NOX2 plays a nonredundant role in TCR-mediated CD8+ T cell effector function.","PeriodicalId":22698,"journal":{"name":"The Journal of Immunology","volume":"59 1","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2023-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"The Journal of Immunology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.4049/jimmunol.2200691","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
Abstract Oxidants participate in lymphocyte activation and function. We previously demonstrated that eliminating the activity of NADPH oxidase 2 (NOX2) significantly impaired the effectiveness of autoreactive CD8+ CTLs. However, the molecular mechanisms impacting CD8+ T cell function remain unknown. In the present study, we examined the role of NOX2 in both NOD mouse and human CD8+ T cell function. Genetic ablation or chemical inhibition of NOX2 in CD8+ T cells significantly suppressed activation-induced expression of the transcription factor T-bet, the master transcription factor of the Tc1 cell lineage, and T-bet target effector genes such as IFN-γ and granzyme B. Inhibition of NOX2 in both human and mouse CD8+ T cells prevented target cell lysis. We identified that superoxide generated by NOX2 must be converted into hydrogen peroxide to transduce the redox signal in CD8+ T cells. Furthermore, we show that NOX2-generated oxidants deactivate the tumor suppressor complex leading to activation of RheB and subsequently mTOR complex 1. These results indicate that NOX2 plays a nonredundant role in TCR-mediated CD8+ T cell effector function.
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