Science Translational Medicine最新文献

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Systematic analysis of cellular cross-talk reveals a role for SEMA6D-TREM2 regulating microglial function in Alzheimer’s disease 细胞串扰的系统分析揭示了SEMA6D-TREM2在阿尔茨海默病中调节小胶质细胞功能的作用
IF 14.6 1区 医学
Science Translational Medicine Pub Date : 2025-07-30 DOI: 10.1126/scitranslmed.adx0027
Ricardo D’Oliveira Albanus, Gina M. Finan, Logan Brase, Nicholas Sweeney, Tae Yeon Kim, Shuo Chen, Yeonsu Ryoo, Joseph Park, Qi Guo, Abhirami Kannan, Mariana Acquarone, Shih-Feng You, Brenna C. Novotny, Emily M. Mace, Patricia M. Ribeiro Pereira, John C. Morris, David M. Holtzman, Eric McDade, Martin Farlow, Jasmeer P. Chhatwal, Bruno A. Benitez, Laura Piccio, Richard J. Perrin, Greg T. Sutherland, Qin Ma, Celeste M. Karch, Doo Yeon Kim, Rudolph E. Tanzi, Hongjun Fu, Oscar Harari, Tae-Wan Kim
{"title":"Systematic analysis of cellular cross-talk reveals a role for SEMA6D-TREM2 regulating microglial function in Alzheimer’s disease","authors":"Ricardo D’Oliveira Albanus,&nbsp;Gina M. Finan,&nbsp;Logan Brase,&nbsp;Nicholas Sweeney,&nbsp;Tae Yeon Kim,&nbsp;Shuo Chen,&nbsp;Yeonsu Ryoo,&nbsp;Joseph Park,&nbsp;Qi Guo,&nbsp;Abhirami Kannan,&nbsp;Mariana Acquarone,&nbsp;Shih-Feng You,&nbsp;Brenna C. Novotny,&nbsp;Emily M. Mace,&nbsp;Patricia M. Ribeiro Pereira,&nbsp;John C. Morris,&nbsp;David M. Holtzman,&nbsp;Eric McDade,&nbsp;Martin Farlow,&nbsp;Jasmeer P. Chhatwal,&nbsp;Bruno A. Benitez,&nbsp;Laura Piccio,&nbsp;Richard J. Perrin,&nbsp;Greg T. Sutherland,&nbsp;Qin Ma,&nbsp;Celeste M. Karch,&nbsp;Doo Yeon Kim,&nbsp;Rudolph E. Tanzi,&nbsp;Hongjun Fu,&nbsp;Oscar Harari,&nbsp;Tae-Wan Kim","doi":"10.1126/scitranslmed.adx0027","DOIUrl":"10.1126/scitranslmed.adx0027","url":null,"abstract":"<div >Cellular cross-talk, mediated by membrane receptors and their ligands, is crucial for brain homeostasis and can contribute to neurodegenerative diseases such as Alzheimer’s disease (AD). To find cross-talk dysregulations involved in AD, we reconstructed cross-talk networks from single-nucleus transcriptional profiles of 67 clinically and neuropathologically well-characterized controls and AD brain donors from the Knight Alzheimer Disease Research Center and the Dominantly Inherited Alzheimer Network cohorts. We predicted a role for TREM2 and additional AD risk genes mediating neuron-microglia cross-talk in AD. We identified a gene network mediating neuron-microglia cross-talk through TREM2 and neuronal SEMA6D, which we predicted is disrupted in late AD stages. Using spatial transcriptomics on the human brain, we observed that the SEMA6D-TREM2 cross-talk gene network is activated near Aβ plaques and SEMA6D-expressing cells. Using tissue immunostaining of human brains, we found that SEMA6D colocalizes with Aβ plaques and TREM2-activated microglia. In addition, we found that plaque-proximal SEMA6D abundance decreased with the disease stage, which correlated with a reduction in microglial activation near plaques. These findings suggest that the loss of SEMA6D signaling impairs microglial activation and Αβ clearance. To validate this hypothesis, we leveraged <i>TREM2</i> knockout human induced pluripotent stem cell–derived microglia and observed that SEMA6D induces microglial activation and Aβ plaque phagocytosis in a TREM2-dependent manner. In summary, we demonstrate that characterizing cellular cross-talk networks can yield insights into AD biology, provide additional context to understand AD genetic risk, and find previously unknown therapeutic targets and pathways.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 809","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144737636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Erratum for the Research Article “Engineering a highly elastic human protein–based sealant for surgical applications” by N. Annabi et al. N. Annabi等人的研究文章“为外科应用设计高弹性人类蛋白基密封剂”的勘误。
IF 14.6 1区 医学
Science Translational Medicine Pub Date : 2025-07-30 DOI: 10.1126/scitranslmed.aea4285
{"title":"Erratum for the Research Article “Engineering a highly elastic human protein–based sealant for surgical applications” by N. Annabi et al.","authors":"","doi":"10.1126/scitranslmed.aea4285","DOIUrl":"10.1126/scitranslmed.aea4285","url":null,"abstract":"","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 809","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144740575","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
AGPAT4 targeted covalent inhibitor potentiates targeted therapy to overcome cancer cell plasticity in hepatocellular carcinoma mouse models AGPAT4靶向共价抑制剂增强靶向治疗以克服肝癌小鼠模型中的癌细胞可塑性
IF 14.6 1区 医学
Science Translational Medicine Pub Date : 2025-07-30 DOI: 10.1126/scitranslmed.adn9472
Kai-Yu Ng, Tin-Yan Koo, Ianto Bosheng Huang, Terence Kin-Wah Lee, Tsz-Lok Fong, Ya Gao, Tin-Lok Wong, Yuan Gao, Jing-Ping Yun, Xin-Yuan Guan, Ming Liu, Clive Yik-Sham Chung, Stephanie Ma
{"title":"AGPAT4 targeted covalent inhibitor potentiates targeted therapy to overcome cancer cell plasticity in hepatocellular carcinoma mouse models","authors":"Kai-Yu Ng,&nbsp;Tin-Yan Koo,&nbsp;Ianto Bosheng Huang,&nbsp;Terence Kin-Wah Lee,&nbsp;Tsz-Lok Fong,&nbsp;Ya Gao,&nbsp;Tin-Lok Wong,&nbsp;Yuan Gao,&nbsp;Jing-Ping Yun,&nbsp;Xin-Yuan Guan,&nbsp;Ming Liu,&nbsp;Clive Yik-Sham Chung,&nbsp;Stephanie Ma","doi":"10.1126/scitranslmed.adn9472","DOIUrl":"10.1126/scitranslmed.adn9472","url":null,"abstract":"<div >The development of cancerous cells leads to considerable changes in metabolic processes to meet the demands of tumor growth. Tumor lineage plasticity has been identified as a key factor in therapy resistance and tumor recurrence. Herein, we showed one aspect of this plasticity to be abnormal glycerophospholipid metabolism, specifically the presence of a metabolic protein called 1-acylglycerol-3-phosphate <i>o</i>-acyltransferase 4 (AGPAT4). We identified AGPAT4 as an oncofetal protein that is abundant in embryonic stem cells and hepatocellular carcinoma (HCC) tumor cells but is low or absent in most normal tissues. We demonstrated that AGPAT4 is a functional regulator of tumor lineage plasticity, which correlates with enhanced metastasis and resistance to sorafenib. Heightened plasticity was induced as a result of increased AGPAT4-mediated conversion of LPA (lysophosphatidic acid) to phosphatidic acid (PA), which then acts on its downstream mTOR/S6K/S6 signaling pathway. Inhibition of Agpat4 by the AAV8-mediated liver-directed strategy in an immunocompetent HCC mouse model reduced tumorigenicity and stemness and sensitized tumors to sorafenib. Through a chemical biology approach, a cysteine-reacting compound that specifically targets AGPAT4 at the Cys<sup>228</sup> residue and therefore hinders its acyltransferase activity was identified and found to work synergistically with sorafenib in suppressing HCC in tumor xenograft models derived from patients with preclinical HCC and sorafenib-resistant HCC. Toxicological analysis revealed minimal side effects associated with the covalent inhibitor. In conclusion, the plasticity of tumor lineages induced by AGPAT4 represents a potential target for HCC treatment and could expand the effectiveness of sorafenib treatment, offering new possibilities for HCC therapy.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 809","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144737506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Viral spike antigen clearance and augmented recovery in children with post-COVID multisystem inflammatory syndrome treated with larazotide 拉唑肽治疗儿童covid后多系统炎症综合征的病毒刺突抗原清除和增强恢复
IF 14.6 1区 医学
Science Translational Medicine Pub Date : 2025-07-30 DOI: 10.1126/scitranslmed.adu4284
Lael M. Yonker, Abigail S. Kane, Zoe Swank, Lena Papadakis, Victoria Kenyon, Samuel Han, Rosiane Lima, Lauren B. Guthrie, Bryan Alvarez-Carcamo, Manuella Lahoud-Rahme, Duraisamy Balaguru, Ryan W. Carroll, Josephine Lok, Chadi El Saleeby, David R. Walt, Alessio Fasano
{"title":"Viral spike antigen clearance and augmented recovery in children with post-COVID multisystem inflammatory syndrome treated with larazotide","authors":"Lael M. Yonker,&nbsp;Abigail S. Kane,&nbsp;Zoe Swank,&nbsp;Lena Papadakis,&nbsp;Victoria Kenyon,&nbsp;Samuel Han,&nbsp;Rosiane Lima,&nbsp;Lauren B. Guthrie,&nbsp;Bryan Alvarez-Carcamo,&nbsp;Manuella Lahoud-Rahme,&nbsp;Duraisamy Balaguru,&nbsp;Ryan W. Carroll,&nbsp;Josephine Lok,&nbsp;Chadi El Saleeby,&nbsp;David R. Walt,&nbsp;Alessio Fasano","doi":"10.1126/scitranslmed.adu4284","DOIUrl":"10.1126/scitranslmed.adu4284","url":null,"abstract":"<div >Multisystem inflammatory syndrome (MIS) is a severe disease that occurs weeks to months after acute infection with SARS-CoV-2, often occurring in children (MISC). Symptoms include high fever, rash, nausea, diarrhea, and abdominal pain. Children with MISC can develop cardiovascular injury including ventricular failure, coronary artery aneurysms, or shock. Current treatment strategies for these postacute sequelae of COVID-19 primarily target the hyperinflammatory response. However, a potential role for viral spike protein translocated via zonulin-mediated trafficking from gastrointestinal reservoirs of SARS-CoV-2 into the circulation has been suggested. Here, we report results from a phase 2a randomized, double-blind, placebo-controlled clinical trial testing the zonulin antagonist larazotide in 12 children with MISC with a median age of 5.7 years. Children were enrolled during hospitalization for acute MISC and were treated with adjuvant larazotide therapy four times daily for 3 weeks. Patients were monitored for 24 weeks for safety follow-up. No larazotide-related adverse events were reported. The concentration of SARS-CoV-2 spike protein antigen in blood samples correlated with inflammatory markers, including interferon-γ (IFN-γ) (<i>P</i> = 0.004) and interleukin-6 (IL-6) (<i>P</i> &lt; 0.0001), and with gastrointestinal symptoms as assessed by the PedsQL GI symptom score (<i>P</i> = 0.003). Children treated with larazotide displayed faster resolution of gastrointestinal symptoms, faster clearance of spike antigen, and a faster return to usual activities. Our findings suggest that larazotide treatment may be safe in children and may improve resolution of symptoms when used as an adjuvant therapy for MISC.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 809","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144737509","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Hindbrain octadecaneuropeptide gliotransmission as a therapeutic target for energy balance control without nausea or emesis 后脑八肽胶质传递作为能量平衡控制的治疗靶点,无恶心或呕吐
IF 15.8 1区 医学
Science Translational Medicine Pub Date : 2025-07-23 DOI: 10.1126/scitranslmed.adu6764
Caroline E. Geisler, Kylie S. Chichura, Oleksandr Orativskyi, Jiayin Hu, Drew L. Belser, Caitlyn M. Pelletier, Tito Borner, Caitlin Baumer-Harrison, Bart C. De Jonghe, Richard C. Crist, Benjamin C. Reiner, Robert P. Doyle, Matthew R. Hayes
{"title":"Hindbrain octadecaneuropeptide gliotransmission as a therapeutic target for energy balance control without nausea or emesis","authors":"Caroline E. Geisler,&nbsp;Kylie S. Chichura,&nbsp;Oleksandr Orativskyi,&nbsp;Jiayin Hu,&nbsp;Drew L. Belser,&nbsp;Caitlyn M. Pelletier,&nbsp;Tito Borner,&nbsp;Caitlin Baumer-Harrison,&nbsp;Bart C. De Jonghe,&nbsp;Richard C. Crist,&nbsp;Benjamin C. Reiner,&nbsp;Robert P. Doyle,&nbsp;Matthew R. Hayes","doi":"10.1126/scitranslmed.adu6764","DOIUrl":"10.1126/scitranslmed.adu6764","url":null,"abstract":"<div >Glia play a dynamic role in central nutrient sensing and appetite regulation yet represent underexplored targets in treating dysregulated energy balance. Glia within the dorsal vagal complex of the hindbrain synthesize the anorexigenic peptide octadecaneuropeptide (ODN), the influence and therapeutic potential of which remain to be explored. We demonstrate that hindbrain-targeted ODN induced weight loss, counteracted glucoprivation, and improved glucose clearance in rats. Furthermore, blocking central ODN signaling attenuated the anorectic response to GLP-1R agonists in rats. Peripheral administration of an ODN derivative, TDN, improved insulin sensitivity assessed by hyperinsulinemic-euglycemic clamp in obese mice and induced weight loss without pica behavior, a proxy for nausea in rats, or emesis in the musk shrew, a vomiting mammalian model. Central ODN and TDN treatment in rats was not accompanied by changes in core body temperature, physical activity, or heart rate. This work highlights hindbrain ODN signaling as an important modulator of energy balance and demonstrates the potential for targeting this gliopeptide system to treat dysregulated feeding and metabolic activity without side effects.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 808","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144684777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Human inner ear fluid imbalance detected by optical coherence tomography correlates with hearing loss 光学相干断层扫描检测的人内耳液体不平衡与听力损失相关
IF 15.8 1区 医学
Science Translational Medicine Pub Date : 2025-07-23 DOI: 10.1126/scitranslmed.adv3783
Wihan Kim, Dorothy W. Pan, Bong Jik Kim, Zihan Yang, Marcela Moran Mojica, Joni K. Doherty, Seiji B. Shibata, Brian E. Applegate, John S. Oghalai
{"title":"Human inner ear fluid imbalance detected by optical coherence tomography correlates with hearing loss","authors":"Wihan Kim,&nbsp;Dorothy W. Pan,&nbsp;Bong Jik Kim,&nbsp;Zihan Yang,&nbsp;Marcela Moran Mojica,&nbsp;Joni K. Doherty,&nbsp;Seiji B. Shibata,&nbsp;Brian E. Applegate,&nbsp;John S. Oghalai","doi":"10.1126/scitranslmed.adv3783","DOIUrl":"10.1126/scitranslmed.adv3783","url":null,"abstract":"<div >Hearing loss and vertigo occur when there is an imbalance between the two inner ear fluids, endolymph and perilymph. The inner ear is a small delicate structure encased in dense bone deep in the base of the skull, making it challenging to image with high resolution. Because the fluid chambers are so small, there is no reliable way to measure their balance in a living patient to guide therapy. Here, we translated the technology of optical coherence tomography (OCT) for use in the human inner ear. Peering through the otic capsule bone during mastoid surgery, we imaged the lateral and posterior semicircular canals of patients with Ménière’s disease or vestibular schwannoma and measured the endolymph-to-perilymph ratio. Compared with normal controls, both patient groups demonstrated increased endolymph and reduced perilymph, a disorder termed endolymphatic hydrops. OCT imaging demonstrated good repeatability for measuring the endolymph-to-perilymph ratio. Our data indicate that increased endolymph-to-perilymph ratios correlated with the degree of hearing loss. Thus, small yet meaningful changes in inner ear fluid balance are detectable with this approach with better resolution than gadolinium-enhanced 3 Tesla magnetic resonance imaging, the current gold standard clinical imaging modality. Our findings support the feasibility of imaging the human inner ear during surgical procedures with OCT and demonstrate the ability to detect endolymphatic hydrops. Moreover, this technique permits the measurement of the fluid chambers within the inner ear in real time during surgical procedures with adequate sensitivity to guide the management of complex but common ear diseases.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 808","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144684765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Preexisting immunity to the 2009 pandemic H1N1 virus reduces susceptibility to H5N1 infection and disease in ferrets 先前存在的对2009年H1N1大流行性病毒的免疫力降低了雪貂对H5N1感染和疾病的易感性
IF 15.8 1区 医学
Science Translational Medicine Pub Date : 2025-07-23 DOI: 10.1126/scitranslmed.adw4856
Katherine H. Restori, Veronika Weaver, Devanshi R. Patel, Grace A. Merrbach, Kayla M. Septer, Cassandra J. Field, Michael J. Bernabe, Ethan M. Kronthal, Allen Minns, Scott E. Lindner, Seema S. Lakdawala, Valerie Le Sage, Troy C. Sutton
{"title":"Preexisting immunity to the 2009 pandemic H1N1 virus reduces susceptibility to H5N1 infection and disease in ferrets","authors":"Katherine H. Restori,&nbsp;Veronika Weaver,&nbsp;Devanshi R. Patel,&nbsp;Grace A. Merrbach,&nbsp;Kayla M. Septer,&nbsp;Cassandra J. Field,&nbsp;Michael J. Bernabe,&nbsp;Ethan M. Kronthal,&nbsp;Allen Minns,&nbsp;Scott E. Lindner,&nbsp;Seema S. Lakdawala,&nbsp;Valerie Le Sage,&nbsp;Troy C. Sutton","doi":"10.1126/scitranslmed.adw4856","DOIUrl":"10.1126/scitranslmed.adw4856","url":null,"abstract":"<div >Zoonotic infections with emerging influenza viruses occur in the context of population-wide immunity to seasonal strains. Because of the worldwide spread of highly pathogenic clade 2.3.4.4b H5N1 influenza viruses in wild birds, there have been numerous spillover events into mammals. This includes a recent spillover into dairy cows that started an ongoing outbreak across the United States. Human infections with avian and bovine origin H5N1 influenza viruses have been documented, raising concern that these viruses may cause a pandemic. Therefore, using a ferret model, we evaluated the impact of preexisting, infection-elicited immunity on susceptibility to H5N1 infection and on severity of disease. Preexisting immunity to the 2009 pandemic H1N1 influenza virus prevented severe H5N1 disease and reduced susceptibility to infection through direct contact with an infected donor ferret. These studies demonstrate that preexisting immunity to influenza viruses, especially the 2009 pandemic H1N1 virus, is a barrier to infection and disease caused by clade 2.3.4.4b H5N1 viruses.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 808","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.adw4856","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144684766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Tissue-resident memory CD4+ T cells infiltrate the CNS in progressive multiple sclerosis and contribute to chronic autoimmunity in mice 进行性多发性硬化症小鼠的组织常驻记忆CD4 + T细胞浸润中枢神经系统并参与慢性自身免疫
IF 15.8 1区 医学
Science Translational Medicine Pub Date : 2025-07-23 DOI: 10.1126/scitranslmed.adp8109
Aurora Pignata, David Frieser, Carmen Gonzalez-Fierro, Cheng-Chih Hsiao, Hendrik J. Engelenburg, Marine Alis, Ilan Fijalkow, Vincent Cazaentre, Lucie Nozeran, Romain Miranda-Capet, Eloïse Dufourd, Thaïs Vermeulen, Amel Aïda, Carole Le Coz, Klaas Van Gisbergen, Nicolas Blanchard, Jörg Hamann, Joost Smolders, Roland S. Liblau, Frederick Masson
{"title":"Tissue-resident memory CD4+ T cells infiltrate the CNS in progressive multiple sclerosis and contribute to chronic autoimmunity in mice","authors":"Aurora Pignata,&nbsp;David Frieser,&nbsp;Carmen Gonzalez-Fierro,&nbsp;Cheng-Chih Hsiao,&nbsp;Hendrik J. Engelenburg,&nbsp;Marine Alis,&nbsp;Ilan Fijalkow,&nbsp;Vincent Cazaentre,&nbsp;Lucie Nozeran,&nbsp;Romain Miranda-Capet,&nbsp;Eloïse Dufourd,&nbsp;Thaïs Vermeulen,&nbsp;Amel Aïda,&nbsp;Carole Le Coz,&nbsp;Klaas Van Gisbergen,&nbsp;Nicolas Blanchard,&nbsp;Jörg Hamann,&nbsp;Joost Smolders,&nbsp;Roland S. Liblau,&nbsp;Frederick Masson","doi":"10.1126/scitranslmed.adp8109","DOIUrl":"10.1126/scitranslmed.adp8109","url":null,"abstract":"<div >Preventing T cell migration to the central nervous system (CNS) has remarkable therapeutic effects in relapsing-remitting multiple sclerosis (RRMS) but is poorly effective against the progressive form (PMS). Disability progression in PMS likely results from an interplay between smoldering local inflammation and neurodegeneration. The mechanisms sustaining the chronicity of PMS are poorly understood. Here, we investigated the potential role of tissue-resident memory CD4<sup>+</sup> T cells (CD4<sup>+</sup> Trm cells) in sustaining chronic CNS autoimmunity. We showed that CD4<sup>+</sup> Trm cells were present in the CNS of mice with chronic experimental autoimmune encephalomyelitis (EAE) and in brain tissues from persons with PMS. Using flow cytometry and immunohistofluorescence analysis, we revealed the presence of bona fide CD4<sup>+</sup> Trm cells expressing characteristic Trm cell surface markers, including CD69, CXCR6, P2RX7, and CD49a, in the CNS of mice with EAE and in the brains of persons with PMS. These T cells also expressed the transcription factor Hobit in mice with chronic EAE. Single-cell transcriptomic analysis uncovered the transcriptional heterogeneity and inflammatory potential of CD4<sup>+</sup> Trm cells, and, accordingly, these cells localized within CNS inflammatory lesions of mice with EAE and persons with PMS. Last, either genetic or pharmacological depletion of CD4<sup>+</sup> Trm cells combined with antibody-mediated depletion of the recirculating CD4<sup>+</sup> T cell compartment alleviated neurological signs during the chronic phase of EAE. Our results indicate that CD4<sup>+</sup> Trm cells contribute to maintain a chronic inflammatory state in the CNS and suggest that therapeutic strategies for PMS should consider targeting the CNS-resident T cell compartment.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 808","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144684779","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Protective envelope dimer epitope–like antibodies are elicited against dengue virus in children after infection and vaccination 保护包膜二聚体表位样抗体在儿童感染和接种登革热病毒后被诱导
IF 15.8 1区 医学
Science Translational Medicine Pub Date : 2025-07-23 DOI: 10.1126/scitranslmed.adq0571
Patrick I. Mpingabo, Michelle Ylade, Rosemary A. Aogo, Maria Vinna Crisostomo, Devina J. Thiono, Jedas Veronica Daag, Kristal-An Agrupis, Ana Coello Escoto, Guillermo L. Raimundi-Rodriguez, Camila D. Odio, Maria Abad Fernandez, Laura White, Aravinda M. de Silva, Jacqueline Deen, Leah C. Katzelnick
{"title":"Protective envelope dimer epitope–like antibodies are elicited against dengue virus in children after infection and vaccination","authors":"Patrick I. Mpingabo,&nbsp;Michelle Ylade,&nbsp;Rosemary A. Aogo,&nbsp;Maria Vinna Crisostomo,&nbsp;Devina J. Thiono,&nbsp;Jedas Veronica Daag,&nbsp;Kristal-An Agrupis,&nbsp;Ana Coello Escoto,&nbsp;Guillermo L. Raimundi-Rodriguez,&nbsp;Camila D. Odio,&nbsp;Maria Abad Fernandez,&nbsp;Laura White,&nbsp;Aravinda M. de Silva,&nbsp;Jacqueline Deen,&nbsp;Leah C. Katzelnick","doi":"10.1126/scitranslmed.adq0571","DOIUrl":"10.1126/scitranslmed.adq0571","url":null,"abstract":"<div >Cross-reactive antibodies to epitopes that span envelope proteins on the virion surface are hypothesized to protect against dengue virus (DENV) infection and disease. Here, we measured antibodies targeting a quaternary epitope called the envelope dimer epitope (EDE) as well as neutralizing and binding antibodies and evaluated their association with DENV infection, vaccine response, and disease outcome in dengue-vaccinated (<i>n</i> = 164) and dengue-unvaccinated children (<i>n</i> = 88) within a longitudinal cohort in Cebu, Philippines (<i>n</i> = 2996). Antibodies targeting EDE were prevalent and associated with broad neutralization of mature DENV1 to DENV4 virions in those with evidence of at least two prior DENV infections but were mostly absent in those with only one prior infection. Subsequent infection and vaccination boosted titers of EDE-like antibodies, neutralizing antibodies, and DENV-binding antibodies. EDE-like antibodies were associated with reduced risk of symptomatic dengue and more severe dengue and statistically explained the protective effect of binding and neutralizing antibodies on dengue. Thus, antibodies targeting quaternary epitopes help explain the broad cross-protection observed in those with multiple prior DENV exposures, making them useful for evaluation and development of future vaccines and therapeutics.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 808","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144685055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Erratum for the Research Article “Combining a CAR and a chimeric costimulatory receptor enhances T cell sensitivity to low antigen density and promotes persistence” by A. Katsarou et al. a . Katsarou等人的研究文章“结合CAR和嵌合共刺激受体增强T细胞对低抗原密度的敏感性并促进持久性”的勘误。
IF 15.8 1区 医学
Science Translational Medicine Pub Date : 2025-07-23 DOI: 10.1126/scitranslmed.aea1242
{"title":"Erratum for the Research Article “Combining a CAR and a chimeric costimulatory receptor enhances T cell sensitivity to low antigen density and promotes persistence” by A. Katsarou et al.","authors":"","doi":"10.1126/scitranslmed.aea1242","DOIUrl":"10.1126/scitranslmed.aea1242","url":null,"abstract":"","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 808","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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