Tomoyoshi Tamura, Changde Cheng, Ana B Villaseñor-Altamirano, Kohei Yamada, Kohei Ikeda, Kei Hayashida, Jaivardhan A Menon, Xi Dawn Chen, Hattie Chung, Jack Varon, Jiani Chen, Jiyoung Choi, Aidan M Cullen, Jingyu Guo, Xi Lin, Benjamin A Olenchock, Mayra A Pinilla-Vera, Reshmi Manandhar, Muhammad Dawood Amir Sheikh, Peter C Hou, Patrick R Lawler, William M Oldham, Raghu R Seethala, Rebecca M Baron, Erin A Bohula, David A Morrow, Richard S Blumberg, Fei Chen, Louis T Merriam, Alexandra J Weissman, Michael B Brenner, Xiang Chen, Fumito Ichinose, Edy Y Kim
{"title":"Diverse NKT cells regulate early inflammation and neurological outcomes after cardiac arrest and resuscitation.","authors":"Tomoyoshi Tamura, Changde Cheng, Ana B Villaseñor-Altamirano, Kohei Yamada, Kohei Ikeda, Kei Hayashida, Jaivardhan A Menon, Xi Dawn Chen, Hattie Chung, Jack Varon, Jiani Chen, Jiyoung Choi, Aidan M Cullen, Jingyu Guo, Xi Lin, Benjamin A Olenchock, Mayra A Pinilla-Vera, Reshmi Manandhar, Muhammad Dawood Amir Sheikh, Peter C Hou, Patrick R Lawler, William M Oldham, Raghu R Seethala, Rebecca M Baron, Erin A Bohula, David A Morrow, Richard S Blumberg, Fei Chen, Louis T Merriam, Alexandra J Weissman, Michael B Brenner, Xiang Chen, Fumito Ichinose, Edy Y Kim","doi":"10.1126/scitranslmed.adq5796","DOIUrl":null,"url":null,"abstract":"<p><p>Neurological injury drives most deaths and morbidity among patients hospitalized for out-of-hospital cardiac arrest (OHCA). Despite its clinical importance, there are no effective pharmacological therapies targeting post-cardiac arrest (CA) neurological injury. Here, we analyzed circulating immune cells from a large cohort of patients with OHCA, finding that lymphopenia independently associated with poor neurological outcomes. Single-cell RNA sequencing of immune cells showed that T cells with features of both innate T cells and natural killer (NK) cells were increased in patients with favorable neurological outcomes. We more specifically identified an early increase in circulating diverse NKT (dNKT) cells in a separate cohort of patients with OHCA who had good neurological outcomes. These cells harbored a diverse T cell receptor repertoire but were consistently specific for sulfatide antigen. In mice, we found that sulfatide-specific dNKT cells trafficked to the brain after CA and resuscitation. In the brains of mice lacking NKT cells (<i>Cd1d</i><sup>-/-</sup>), we observed increased inflammatory chemokine and cytokine expression and accumulation of macrophages when compared with wild-type mice. <i>Cd1d</i><sup>-/-</sup> mice also had increased neuronal injury, neurological dysfunction, and worse mortality after CA. To therapeutically enhance dNKT cell activity, we treated mice with sulfatide lipid after CA, showing that it improved neurological function. Together, these data show that sulfatide-specific dNKT cells are associated with good neurological outcomes after clinical OHCA and are neuroprotective in mice after CA. Strategies to enhance the number or function of dNKT cells may thus represent a treatment approach for CA.</p>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 776","pages":"eadq5796"},"PeriodicalIF":15.8000,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Science Translational Medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1126/scitranslmed.adq5796","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Neurological injury drives most deaths and morbidity among patients hospitalized for out-of-hospital cardiac arrest (OHCA). Despite its clinical importance, there are no effective pharmacological therapies targeting post-cardiac arrest (CA) neurological injury. Here, we analyzed circulating immune cells from a large cohort of patients with OHCA, finding that lymphopenia independently associated with poor neurological outcomes. Single-cell RNA sequencing of immune cells showed that T cells with features of both innate T cells and natural killer (NK) cells were increased in patients with favorable neurological outcomes. We more specifically identified an early increase in circulating diverse NKT (dNKT) cells in a separate cohort of patients with OHCA who had good neurological outcomes. These cells harbored a diverse T cell receptor repertoire but were consistently specific for sulfatide antigen. In mice, we found that sulfatide-specific dNKT cells trafficked to the brain after CA and resuscitation. In the brains of mice lacking NKT cells (Cd1d-/-), we observed increased inflammatory chemokine and cytokine expression and accumulation of macrophages when compared with wild-type mice. Cd1d-/- mice also had increased neuronal injury, neurological dysfunction, and worse mortality after CA. To therapeutically enhance dNKT cell activity, we treated mice with sulfatide lipid after CA, showing that it improved neurological function. Together, these data show that sulfatide-specific dNKT cells are associated with good neurological outcomes after clinical OHCA and are neuroprotective in mice after CA. Strategies to enhance the number or function of dNKT cells may thus represent a treatment approach for CA.
期刊介绍:
Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research.
The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases.
The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine.
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