Science Immunology最新文献

{"title":"Allergen-induced airway matrix remodeling in mice can be prevented or reversed by targeting chitinase-like proteins","authors":"James E. Parkinson,&nbsp;Hannah E. Tompkins,&nbsp;Amlan Chakraborty,&nbsp;Matthew O. Burgess,&nbsp;Rebecca J. Dodd,&nbsp;Antony D. Adamson,&nbsp;Andrew S. MacDonald,&nbsp;Julie E. Gibbs,&nbsp;Hannah J. Durrington,&nbsp;Judith E. Allen,&nbsp;Tara E. Sutherland","doi":"10.1126/sciimmunol.adk6707","DOIUrl":"10.1126/sciimmunol.adk6707","url":null,"abstract":"<div >Chitinase-like proteins (CLPs) are established biomarkers of inflammation and airway remodeling in asthma, yet their direct contribution toward disease pathogenesis is unknown. In a mouse model of type 2/type 17 airway inflammation induced by house dust mite, ragweed, and <i>Aspergillus fumigatus</i> (DRA) allergens, we demonstrate that murine CLPs Ym1 (<i>Chil3</i>) and Ym2 (<i>Chil4</i>) exert distinct and potent effects on airway extracellular matrix (ECM) composition during chronic lung pathology. Using both Ym1-knockout (<i>Chil3</i>^−/−) and Ym2-knockdown (<i>Chil4</i>^KD/KD) mice, we found that these CLPs have fundamental roles in airway remodeling that are independent of interleukin-13 (IL-13) and IL-17A signaling pathways. Antibody-mediated inhibition of CLPs after pathology has developed reverses airway remodeling independently of chronic inflammation. However, this inhibition is not sufficient to reduce airway hyperresponsiveness (AHR) in allergic animals. Instead, the absence of CLPs increases epithelial damage and leads to a loss of bronchial epithelial integrity. This work disentangles chronic IL-13 and IL-17A signaling from the development of allergic airway pathology and reveals CLPs as orchestrators of airway remodeling that can produce both protective and adverse outcomes.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 111","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145088986","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}

{"title":"Nuclear polarization to the immune synapse facilitates an early transcriptional burst","authors":"Yukako Asano,&nbsp;Claire Y. Ma,&nbsp;Martin M. Limback-Stokin,&nbsp;Adam M. Rochussen,&nbsp;Jane C. Stinchcombe,&nbsp;Gillian M. Griffiths","doi":"10.1126/sciimmunol.adt5909","DOIUrl":"10.1126/sciimmunol.adt5909","url":null,"abstract":"<div >Target cell recognition by cytotoxic T lymphocytes (CTLs) triggers rapid delivery of cytolytic granules to the immune synapse directed by the centrosome. Recent studies have also identified a rapid burst of T cell receptor (TCR)–activated transcription that contributes to CTL-mediated killing. To determine how de novo transcription might be coordinated with intracellular polarization, we asked when transcription factor translocation to the nucleus occurs relative to TCR activation and centrosome polarization within individual CTLs. Upon target cell recognition, the nucleus polarized to and contacted the immune synapse, preceding centrosome docking. The nucleus distorted as it moved, with transcription factors NFAT and NF-κB accumulating in the nucleus during polarization. Inhibition or deletion of myosin IIA prevented both nuclear polarization and transcription factor translocation. Thus, nuclear polarization facilitates an early transcriptional burst that occurs as CTLs encounter targets and the consequent delivery of newly synthesized cytokines to the immune synapse.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 111","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145088988","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}

{"title":"Single-cell multiomics identifies Tcf1 and Lef1 as key initiators of early thymic progenitor fate","authors":"Xin Zhao,&nbsp;Shengen Shawn Hu,&nbsp;Wen-Han Lee,&nbsp;Johannes L. Zakrzewski,&nbsp;Qing-Sheng Mi,&nbsp;Rachel K. Rosenstein,&nbsp;Chongzhi Zang,&nbsp;Xiaoke Ma,&nbsp;Hai-Hui Xue","doi":"10.1126/sciimmunol.adq8970","DOIUrl":"10.1126/sciimmunol.adq8970","url":null,"abstract":"<div >Bone marrow–derived multipotent hematopoietic progenitors seed the thymus and generate early thymic progenitors (ETPs). However, the factors governing ETP formation remain poorly defined. Using single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin with sequencing (scATAC-seq), we dissected the heterogeneity of transcriptomic and chromatin accessibility landscapes in murine ETPs. Whereas Tcf1⁻ ETPs exhibited higher proliferative capacity, Tcf1⁺ ETPs appeared to be immediate, more robust precursors to T lineage–specified early thymocytes. Prethymic ablation of Tcf1 and its homolog Lef1 severely impaired ETP formation in vivo. Whereas ablating Tcf1 alone had limited impact, loss of both Tcf1 and Lef1 impaired transcriptional activation of <i>Notch1</i> and Notch pathway effector molecules, including <i>Hes1</i> and <i>Hhex</i>, accompanied by aberrantly induced B cell and myeloid gene programs. Acute deletion of both factors compromised Notch pathway, glycolysis, and T cell gene programs in emergent ETPs ex vivo. Thus, Tcf1 and Lef1 act upstream of the Notch pathway, functioning as prethymic initiators of ETP fate and intrathymic gatekeepers of ETP identity and T lineage potential.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 111","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145043473","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}

{"title":"METTL1-mediated m7G methylation of Sarm1 mRNA promotes macrophage inflammatory responses and multiple organ injury","authors":"Chao Hou,&nbsp;Xin-ru Zhang,&nbsp;Jie Wei,&nbsp;Jia-nan Wang,&nbsp;Jian Gao,&nbsp;Zhi-juan Wang,&nbsp;Shuai-shuai Xie,&nbsp;Tong Chen,&nbsp;Tao Sun,&nbsp;Tian Pu,&nbsp;Ju-tao Yu,&nbsp;Xiao-guo Suo,&nbsp;Zi-ye Mei,&nbsp;Fan-rong Zhang,&nbsp;Juan Jin,&nbsp;Wen-man Zhao,&nbsp;Yu-xian Shen,&nbsp;Xiao-ming Meng","doi":"10.1126/sciimmunol.adv4810","DOIUrl":"10.1126/sciimmunol.adv4810","url":null,"abstract":"<div >RNA modifications regulate phenotype and function of macrophages by regulating RNA translation, splicing, and stability. However, the role of <i>N</i>⁷-methylguanosine (m⁷G) modification in macrophages and inflammation remains unexplored. In this study, we observed elevated levels of the methyltransferase METTL1 and m⁷G modifications in macrophages from mouse and human tissues during acute kidney injury (AKI). METTL1 deficiency in myeloid cells mitigated multiorgan inflammation induced by cecal ligation and puncture and renal ischemia/reperfusion. Genetic deletion of METTL1 inhibited macrophage proinflammatory responses. We identified internal <i>Sarm1</i> messenger RNA (mRNA) as a target of m⁷G modification that controls macrophage metabolic reprogramming. METTL1 deficiency in macrophages inhibited metabolic reprogramming, which was reversed by SARM1 overexpression that induced NAD⁺ decline. Pharmacologically, SA91-0178, a specific METTL1 inhibitor, effectively alleviated tissue injury during septic inflammation. Collectively, our findings suggest that m⁷G modification enhances the stability of <i>Sarm1</i> mRNA, thereby resulting in NAD⁺ imbalance in macrophages, indicating that METTL1 may serve as a potential therapeutic target for systemic inflammation.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 111","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adv4810","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999172","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}

{"title":"Enkephalin-producing regulatory T cells in the skin restrain local inflammation through control of nociception","authors":"Alejandra Mendoza,&nbsp;Regina Bou-Puerto,&nbsp;Juan Sebastian Jara,&nbsp;Stanislav Dikiy,&nbsp;Paolo Giovanelli,&nbsp;Danilo Correa,&nbsp;Susanna Manenti,&nbsp;Emma S. Andretta,&nbsp;Chitra L. Dahia,&nbsp;Alexander Y. Rudensky","doi":"10.1126/sciimmunol.adz6869","DOIUrl":"10.1126/sciimmunol.adz6869","url":null,"abstract":"<div >The skin integrates diverse signals discerned by sensory neurons and immune cells to elicit adaptive responses to a range of stresses. Considering interactions between nervous and immune systems, we examined whether regulatory T (T_reg) cells, which suppress systemic and local inflammation, can modulate activation of peripheral neurons. Acute T_reg cell “loss of function” increased neuronal activation to noxious stimuli independently of their immunosuppressive function. This activity was mediated by a T_reg cell subset capable of production of enkephalins encoded by the gene <i>Penk</i>, whose expression is facilitated by combined TCR and glucocorticoid receptor signaling. Punctual selective depletion of <i>Penk</i>-expressing T_reg cells or specific ablation of <i>Penk</i> in T_reg cells increased neuronal activation in response to noxious stimuli and associated inflammation. Our study indicates that a population of tissular T_reg cells exhibits neuromodulatory activity to restrain local inflammation in the skin.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 111","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adz6869","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999188","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}

{"title":"It’s getting hot in here: Heating up the tumor microenvironment with an oral HO-1 inhibitor","authors":"Cait A. McAlindon,&nbsp;Rachael A. Clark","doi":"10.1126/sciimmunol.aeb8328","DOIUrl":"10.1126/sciimmunol.aeb8328","url":null,"abstract":"<div >A new orally bioavailable HO-1 inhibitor enhances tumor clearance after chemotherapy in mice by enhancing the recruitment of CD8 T cells.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 111","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999159","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}

{"title":"Loss-of-function mutations ensure that response to immune checkpoint therapy is NOD2 be denied","authors":"Ana C. Anderson,&nbsp;Manu Rangachari","doi":"10.1126/sciimmunol.aeb8333","DOIUrl":"10.1126/sciimmunol.aeb8333","url":null,"abstract":"<div >Loss-of-function mutations in NOD2 may predict positive response to PD-1 blockade monotherapy in cancer.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 111","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999178","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}

{"title":"DDX55 safeguards naïve T cell homeostasis by suppressing activation-promoting transposable elements","authors":"Mengyue Wu,&nbsp;Kepan Linghu,&nbsp;Qimin Yin,&nbsp;Ping He,&nbsp;Xinyang Yu,&nbsp;Peng Hu,&nbsp;Rongying He,&nbsp;Qinyun Du,&nbsp;Shengli Wang,&nbsp;Xi Chen,&nbsp;Shaohui Wang,&nbsp;Xingyun Wu,&nbsp;Mingfu Zhang,&nbsp;Keren Peng,&nbsp;Xiang Wang,&nbsp;Juxiu Liu,&nbsp;Dong Deng,&nbsp;Guangchao Cao,&nbsp;Kui Wang,&nbsp;Xianli Meng,&nbsp;Quanli Yang,&nbsp;Dezhi Mu,&nbsp;Zhinan Yin,&nbsp;Lu Chen,&nbsp;Jiyu Tong","doi":"10.1126/sciimmunol.adq0457","DOIUrl":"10.1126/sciimmunol.adq0457","url":null,"abstract":"<div >Naïve T cells are maintained in a homeostatic state to preserve a stable T cell pool with diverse T cell receptor (TCR) repertoires, ensuring preparedness for priming. However, the underlying mechanisms controlling naïve T cell homeostasis and priming remain unclear. Leveraging a machine learning–based functional genetic screen, we identified <i>DEAD-box helicase 55</i> (<i>Ddx55</i>) as the top factor responsible for naïve T cell homeostasis. DDX55 was highly expressed in naïve T cells and suppressed enhancer- and promoter-like transposable elements (TEs) near T cell activation–associated genes. <i>Ddx55</i> loss led to derepression of these TEs, resulting in TE-derived R loops and genomic instability, ultimately disrupting naïve T cell homeostasis and abolishing T cell proliferation. Mechanistically, DDX55-targeted TEs harbored myelocytomatosis oncogene (MYC)–binding motifs. DDX55 directly bound MYC and restricted its access to these TE loci, thereby preventing inappropriate TE activation in naïve T cells. Thus, naïve T cells exploit DDX55 as a vital regulator of T cell activation, ensuring their genomic stability and homeostatic maintenance.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 111","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999186","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}

{"title":"Dosing interval is a major factor determining the quality of T cells induced by SARS-CoV-2 mRNA and adenoviral vector vaccines","authors":"Sam M. Murray,&nbsp;Ali Amini,&nbsp;Helen Ferry,&nbsp;Lucy C. Garner,&nbsp;Maria Fransiska Pudjohartono,&nbsp;Barbara Kronsteiner,&nbsp;Sagida Bibi,&nbsp;Andrew J. Pollard,&nbsp;Eleanor Barnes,&nbsp;Teresa Lambe,&nbsp;Susanna Dunachie,&nbsp;Paul Klenerman,&nbsp;Nicholas M. Provine","doi":"10.1126/sciimmunol.adu4610","DOIUrl":"10.1126/sciimmunol.adu4610","url":null,"abstract":"<div >Functional T cell responses are crucial for protective immunity induced by COVID-19 vaccination, but factors influencing the quality of these responses are incompletely understood. We used an activation-induced marker (AIM) assay and single-cell transcriptomic sequencing to analyze SARS-CoV-2 spike-responsive T cells after mild SARS-CoV-2 infection or after one or two doses of mRNA–lipid nanoparticle (mRNA-LNP) or adenoviral-vectored COVID-19 vaccines. Our findings revealed broad functional and clonal heterogeneity in T cells generated by vaccination or infection, including multiple distinct effector populations. T cell function was largely conserved between COVID-19 vaccine platforms but was distinct compared with SARS-CoV-2 infection. Notably, the dosing interval greatly influenced the quality of T cells after two vaccine doses, particularly after mRNA-LNP vaccination, where a longer interval led to reduced inflammatory signaling and increased secondary proliferation. These insights enhance our understanding of SARS-CoV-2–specific T cells and inform the optimization of mRNA vaccination regimens.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 110","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adu4610","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144915926","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}

{"title":"MAIT and other innate-like T cells integrate adaptive immune responses to modulate interval-dependent reactogenicity to mRNA vaccines","authors":"Ali Amini,&nbsp;Lucy C. Garner,&nbsp;Robert H. Shaw,&nbsp;Neil Wrigley Kelly,&nbsp;Sandra Adele,&nbsp;Donal T. Skelly,&nbsp;Wanwisa Dejnirattisai,&nbsp;Melanie Greenland,&nbsp;Xinxue Liu,&nbsp;Amelia Heslington,&nbsp;Carl-Philipp Hackstein,&nbsp;Sam M. Murray,&nbsp;Cristina Riquelme Vano,&nbsp;Lizzie Stafford,&nbsp;Sile Johnson,&nbsp;Katia Sayaf,&nbsp;Maria Fransiska Pudjohartono,&nbsp;Elizabeth A. Clutterbuck,&nbsp;PITCH Consortium‡,&nbsp;Com-COV Study Group‡,&nbsp;Sagida Bibi,&nbsp;Christopher P. Conlon,&nbsp;Tim James,&nbsp;Katie Jeffery,&nbsp;Barbara Kronsteiner,&nbsp;Alexander J. Mentzer,&nbsp;Donal O’Shea,&nbsp;Maheshi N. Ramasamy,&nbsp;Gavin R. Screaton,&nbsp;Matthew D. Snape,&nbsp;Andrew E. Hogan,&nbsp;Eleanor Barnes,&nbsp;Teresa Lambe,&nbsp;Susanna J. Dunachie,&nbsp;Nicholas M. Provine,&nbsp;Paul Klenerman","doi":"10.1126/sciimmunol.adu3337","DOIUrl":"10.1126/sciimmunol.adu3337","url":null,"abstract":"<div >Adenoviral (Ad) vectors and mRNA vaccines exhibit distinct patterns of immune responses and reactogenicity, but underpinning mechanisms remain unclear. We longitudinally compared homologous ChAdOx1 nCoV-19 and BNT162b2 vaccination, focusing on cytokine-responsive innate-like lymphocytes—mucosal-associated invariant T (MAIT) cells and Vδ2⁺ γδ T cells—which sense and tune innate-adaptive cross-talk. Ad priming elicited robust type I interferon (IFN)–mediated innate-like T cell activation, augmenting T cell responses (innate-to-adaptive signaling), which was dampened at boost by antivector immunity. Conversely, mRNA boosting enhanced innate-like responses, driven by prime-induced spike-specific memory T cell–derived IFN-γ (adaptive-to-innate signaling). Extending the dosing interval dampened inflammation at boost because of waning T cell memory. In a separate vaccine trial, preboost spike-specific T cells predicted severe mRNA reactogenicity regardless of the priming platform or interval. Overall, bidirectional innate-like and adaptive cross-talk, and IFN-γ–licensed innate-like T cells, orchestrate interval-dependent early vaccine responses, suggesting modifiable targets for safer, more effective regimens.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 110","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adu3337","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144918904","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}