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2′-O-Methyl-guanosine RNA fragments antagonize TLR7 and TLR8 to limit autoimmunity 2′- o -甲基鸟苷RNA片段可拮抗TLR7和TLR8,限制自身免疫
IF 30.5 1区 医学 Q1 IMMUNOLOGY Pub Date : 2026-02-10 DOI: 10.1038/s41590-026-02429-2
Arwaf S. Alharbi, Sunil Sapkota, Zhikuan Zhang, Ruitao Jin, Erandi Rupasinghe, W. Samantha N. Jayasekara, Dingyi Yu, Mary Speir, Lorna Wilkinson-White, Liza Cubeddu, Julia I. Ellyard, Refaya Rezwan, Daniel S. Wenholz, Alexandra L. McAllan, Rui Gao, Le Ying, Rasan M. Sathiqu, Hani Hosseini Far, Josiah Bones, Sitong He, Marina R. Alexander, Kim A. Lennox, Paul J. Hertzog, Claudia A. Nold-Petry, Cameron R. Stewart, Carola G. Vinuesa, Mark A. Behlke, Umeharu Ohto, Olivier F. Laczka, Roland Gamsjaeger, Ben Corry, Toshiyuki Shimizu, Michael P. Gantier
Recognition of RNA fragments by Toll-like receptor 7 (TLR7) and TLR8 helps to initiate the innate immune response against pathogens. An outstanding question is why RNA fragments generated during clearance of apoptotic cells fail to activate TLR7 and TLR8 signaling. Here we show that select 2′-O-methyl (2′-OMe) guanosine RNA fragments, including those derived from host RNAs, function as potent TLR7 and TLR8 antagonists and reduce TLR7 sensing in vivo. Mechanistically, these fragments bind to an antagonistic site on these proteins via their 5′-end 2′-OMe guanosine. These findings indicate that host RNAs evade detection because abundant ribosomal 2′-OMe-modified fragments naturally antagonize TLR7 and TLR8. Crucially, rare TLR7 and TLR8 mutations at this antagonist binding site decrease inhibition by 2′-OMe guanosine RNA fragments, leading to autoimmunity in patients. Collectively, this work redefines TLR7 and TLR8 sensing by introducing 2′-OMe guanosine as a natural immune checkpoint for their activation.
toll样受体7 (TLR7)和TLR8对RNA片段的识别有助于启动针对病原体的先天免疫反应。一个悬而未决的问题是为什么凋亡细胞清除过程中产生的RNA片段不能激活TLR7和TLR8信号。本研究表明,精选的2 ' - o -甲基(2 ' -OMe)鸟苷RNA片段,包括来自宿主RNA的片段,在体内可作为TLR7和TLR8的有效拮抗剂,并减少TLR7的感知。从机制上讲,这些片段通过它们的5 ‘端2 ’ -OMe鸟苷结合到这些蛋白质的拮抗位点上。这些发现表明,宿主rna逃避检测是因为丰富的核糖体2 ' - ome修饰片段自然拮抗TLR7和TLR8。至关重要的是,该拮抗剂结合位点罕见的TLR7和TLR8突变降低了2 ' -OMe鸟苷RNA片段的抑制作用,导致患者产生自身免疫。总的来说,这项工作通过引入2 ' -OMe鸟苷作为激活TLR7和TLR8的天然免疫检查点,重新定义了TLR7和TLR8的传感。
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引用次数: 0
IL-4–STAT6 signaling delays protective CD8+ T cell bystander activation by antagonizing IL-18 sensing IL-4-STAT6信号通过拮抗IL-18传感延迟保护性CD8+ T细胞的激活
IF 30.5 1区 医学 Q1 IMMUNOLOGY Pub Date : 2026-02-10 DOI: 10.1038/s41590-026-02430-9
Nicholas J. Maurice, Talia S. Dalzell, Trevor N. Tankersley, Ka Hyun Rhee, Katharine E. Block, Nicholas N. Jarjour, Taylor A. DePauw, Sarah M. Wall, Sara E. Hamilton, Stephen C. Jameson
Memory CD8+ T (Tmem) cells are activated into innate-like killers by cytokines, including interleukin-12 (IL-12), IL-15 and IL-18; but mechanisms regulating this phenomenon (termed bystander activation) are unclear. Here we show that basal IL-4 signals antagonize IL-18 sensing and subsequent interferon-γ production during Tmem cell bystander activation. IL-4 treatment can act directly on Tmem cells in a STAT6-dependent manner to limit interferon-γ-mediated control of a bystander bacterial infection. IL-4 does not simply block bystander activation but tunes effector molecule expression. Strain-specific defects in bystander activation of homeostatic Tmem cells partially relates to IL-4 exposure, but these differences are erased in Tmem cells produced by T cell antigen receptor activation, leading to uniform IL-18 receptor expression and capacity for bystander activation/cytotoxicity. Our data demonstrate that bystander activation by inflammatory cytokines is subject to regulation by both IL-4 and prior antigen experience. These findings underscore the importance of the cytokine milieu in dictating bystander-mediated pathogen control.
记忆性CD8+ T (Tmem)细胞被白细胞介素-12 (IL-12)、IL-15和IL-18等细胞因子激活为先天类杀手;但调节这种现象的机制(称为旁观者激活)尚不清楚。本研究表明,在Tmem细胞旁观者激活过程中,基础IL-4信号可拮抗IL-18感应和随后的干扰素-γ产生。IL-4治疗可以以stat6依赖的方式直接作用于Tmem细胞,以限制干扰素-γ介导的旁观者细菌感染的控制。IL-4不是简单地阻断旁观者的激活,而是调节效应分子的表达。稳态Tmem细胞旁观者激活的菌株特异性缺陷部分与IL-4暴露有关,但这些差异在T细胞抗原受体激活产生的Tmem细胞中被消除,导致IL-18受体表达和旁观者激活/细胞毒性能力一致。我们的数据表明,炎症细胞因子的旁观者激活受到IL-4和先前抗原经验的调节。这些发现强调了细胞因子环境在决定旁观者介导的病原体控制中的重要性。
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引用次数: 0
Flt3L-mediated tumor cDC1 expansion enhances immunotherapy by priming stem-like CD8+ T cells in lymph nodes flt3l介导的肿瘤cDC1扩增通过在淋巴结中启动干细胞样CD8+ T细胞来增强免疫治疗
IF 30.5 1区 医学 Q1 IMMUNOLOGY Pub Date : 2026-02-10 DOI: 10.1038/s41590-026-02419-4
Junyun Lai, Cheok Weng Chan, Jesse D. Armitage, Katherine M. Audsley, Yu-Kuan Huang, Emily B. Derrick, Laura S. Carstensen, Christina M. Scheffler, Matt E. Jones, Kevin Sek, Nicola Principe, Joelle S. Kim, Imran G. House, Amanda X. Y. Chen, Kah Min Yap, Jim Middelburg, Isabelle Munoz, Dat Nguyen, Junming Tong, Thang X. Hoang, Kirsten L. Todd, Maximilien Evrard, Jonathan Chee, Laura K. Mackay, Alistair R. R. Forrest, Ian A. Parish, Anthony Bosco, Jason Waithman, Paul A. Beavis, Phillip K. Darcy
Immune checkpoint blockade (ICB) evokes antitumor immunity through the reinvigoration of T cell responses. T cell differentiation status controls response, with less differentiated cells having an enhanced capacity to proliferate after ICB. Given that conventional type 1 dendritic cells (cDC1) maintain precursor exhausted T cells (TPEX), we hypothesized that expansion of cDC1s with Flt3L could enhance responses to ICB. Here we show that treatment with Fms-related tyrosine kinase 3 ligand (Flt3L) expands CD62L+SLAMF6+CD8+ T cells in the tumor through a mechanism that requires XCR1+ dendritic cells to traffic to the tumor-draining lymph node. The combination of Flt3L and anti-CTLA-4 enhanced therapeutic responses. Combination therapy is associated with the emergence of a CD8+ T cell subset characterized by the expression of Il21r and oligoclonal expansion of CD8+ T cells within tumors through a mechanism that is dependent on lymph node egress.
免疫检查点阻断(ICB)通过激活T细胞反应唤起抗肿瘤免疫。T细胞分化状态控制反应,较少分化的细胞在ICB后具有增强的增殖能力。考虑到传统的1型树突状细胞(cDC1)维持前体耗竭T细胞(TPEX),我们假设用Flt3L扩增cDC1s可以增强对ICB的反应。本研究表明,fms相关酪氨酸激酶3配体(Flt3L)治疗通过XCR1+树突状细胞运输到肿瘤引流淋巴结的机制,扩大了肿瘤中的CD62L+SLAMF6+CD8+ T细胞。Flt3L联合抗ctla -4增强了治疗反应。联合治疗与CD8+ T细胞亚群的出现有关,其特征是通过依赖于淋巴结出口的机制表达Il21r和肿瘤内CD8+ T细胞的寡克隆扩增。
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引用次数: 0
Retraction Note: DCs induce CD40-independent immunoglobulin class switching through BLyS and APRIL. 注:dc通过BLyS和APRIL诱导cd40非依赖性免疫球蛋白类转换。
IF 27.6 1区 医学 Q1 IMMUNOLOGY Pub Date : 2026-02-09 DOI: 10.1038/s41590-026-02446-1
Mikhail B Litinskiy, Bernardetta Nardelli, David M Hilbert, Bing He, Andras Schaffer, Paolo Casali, Andrea Cerutti
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引用次数: 0
Distinct spatial organization governs oral mucosal immunity. 不同的空间组织支配着口腔黏膜免疫。
IF 27.6 1区 医学 Q1 IMMUNOLOGY Pub Date : 2026-02-09 DOI: 10.1038/s41590-025-02398-y
Vasileios I Theofilou, David Fraser, Eleni Kanasi, Laurie Brenchley, Teresa Greenwell-Wild, Emmanuel E Adade, Alex M Valm, Iyadh Douagi, Yasmine Belkaid, Duy T Tran, Drake W Williams, Niki M Moutsopoulos

Immune responsiveness at barrier surfaces is tailored to the exposures of each tissue. In the oral mucosa, mechanisms by which a permeable epithelium coexists with diverse microbiota and maintains integrity during inflammatory pathology remain poorly understood. We compile a multiomics spatial map of this exposed mucosal microenvironment and uncover remarkable immune zonation with organization that is preserved even during inflammatory disease. At the tooth interface, we identify a dynamic epithelium underlined by a layer of neutrophils and a zone of antigen-presenting cell-lymphocyte aggregates. During disease, inflammatory zones expand and organize into immature tertiary lymphoid structures, suggesting local antibody production. Location-specific transcriptomes support a role for the stromal compartment in the spatial organization of immunity. This preserved immune zonation meets the demands for continuous protection of this vulnerable interface and suggests unique tissue-specific wiring of immunity at the human oral mucosal barrier.

在屏障表面的免疫反应是量身定制的每个组织的暴露。在口腔黏膜中,通透性上皮与多种微生物群共存并在炎症病理过程中保持完整性的机制尚不清楚。我们编制了这种暴露的粘膜微环境的多组学空间图,并揭示了即使在炎症性疾病期间也保留的显着的免疫带组织。在牙齿界面,我们发现了一个由中性粒细胞层和抗原呈递细胞-淋巴细胞聚集区强调的动态上皮。在疾病期间,炎症区扩大并组织成不成熟的三级淋巴结构,提示局部产生抗体。位置特异性转录组支持间质室在免疫空间组织中的作用。这种保留的免疫分区满足了持续保护这一脆弱界面的需求,并表明在人类口腔粘膜屏障处存在独特的组织特异性免疫线路。
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引用次数: 0
Publisher Correction: The differentiation and function of heterogeneous thymic dendritic cell subsets require signals provided by distinct thymocyte cell types. 发布者更正:异质胸腺树突状细胞亚群的分化和功能需要不同胸腺细胞类型提供的信号。
IF 27.6 1区 医学 Q1 IMMUNOLOGY Pub Date : 2026-02-06 DOI: 10.1038/s41590-026-02449-y
Jayashree Srinivasan, Colin R Moore, Aparna Calindi, Bryan R Helm, Yilin Yang, John F Moore, Hilary J Selden, Cody N Heiser, Qi Liu, Ken S Lau, Lauren I R Ehrlich
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引用次数: 0
Antigen specificity of clonally enriched CD8+ T cells in multiple sclerosis. 克隆富集CD8+ T细胞在多发性硬化症中的抗原特异性。
IF 27.6 1区 医学 Q1 IMMUNOLOGY Pub Date : 2026-02-05 DOI: 10.1038/s41590-025-02412-3
Fumie Hayashi, Kristen Mittl, Ravi Dandekar, Josiah Gerdts, Ebtesam Hassan, Ryan D Schubert, Lindsay Oshiro, Rita Loudermilk, Ariele Greenfield, Danillo G Augusto, Gregory Havton, Shriya Anumarlu, Arhan Surapaneni, Akshaya Ramesh, Edwina Tran, Kanishka Koshal, Kerry Kizer, Joanna Dreux, Alaina K Cagalingan, Florian Schustek, Lena Flood, Tamson Moore, Lisa L Kirkemo, Isabelle J Fisher, Tiffany Cooper, Meagan Harms, Refujia Gomez, Claire D Clelland, Leah Sibener, Bruce A C Cree, Stephen L Hauser, Jill A Hollenbach, Marvin Gee, Michael R Wilson, Scott S Zamvil, Joseph J Sabatino

CD8+ T cells are the dominant clonally expanded lymphocyte population in multiple sclerosis (MS) lesions but their clonal identity, function and antigen specificity are not well understood. A comprehensive single-cell RNA-sequencing and T cell receptor-sequencing analysis of the cerebrospinal fluid and blood from individuals in the MS and control cohorts revealed a subset of 23 highly expanded and activated CD8+ T cell clonotypes that were enriched predominantly in the cerebrospinal fluid in the MS cohort. Using unbiased and targeted antigen discovery approaches, six CD8+ T cell clonotypes recognizing Epstein-Barr virus (EBV) antigens and multiple novel mimotopes were identified. Although the majority of mimotopes did not elicit functional responses, three of the expanded CD8+ T cell receptors from patients with MS were reactive to EBV. EBV DNA and transcripts were detected in cerebrospinal fluid, including in patients with MS who had highly expanded EBV-specific CD8+ T cells. These findings shed vital insight into the role of CD8+ T cells in MS and support an important role of EBV in MS immunopathology.

CD8+ T细胞是多发性硬化症(MS)病变中主要的克隆扩增淋巴细胞群,但其克隆特性、功能和抗原特异性尚不清楚。对多发性硬化症和对照组个体的脑脊液和血液进行了全面的单细胞rna测序和T细胞受体测序分析,发现了23个高度扩增和激活的CD8+ T细胞克隆型亚群,这些克隆型主要富集于多发性硬化症队列的脑脊液中。采用无偏倚和靶向抗原发现方法,鉴定出6种识别eb病毒抗原的CD8+ T细胞克隆型和多种新的模位。虽然大多数嵌合体不会引起功能性反应,但MS患者扩增的CD8+ T细胞受体中有3个对EBV有反应。在脑脊液中检测到EBV DNA和转录本,包括在EBV特异性CD8+ T细胞高度扩增的MS患者中。这些发现揭示了CD8+ T细胞在MS中的重要作用,并支持EBV在MS免疫病理中的重要作用。
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引用次数: 0
Immunological knowledge. 免疫学知识。
IF 27.6 1区 医学 Q1 IMMUNOLOGY Pub Date : 2026-02-05 DOI: 10.1038/s41590-025-02415-0
Adelaide Gelineau, Brian D Brown, Edward J Hall, Lucy L Wang, Ronald N Germain, Christophe Benoist
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引用次数: 0
The development of innate lymphoid cells. 先天淋巴样细胞的发育。
IF 27.6 1区 医学 Q1 IMMUNOLOGY Pub Date : 2026-02-04 DOI: 10.1038/s41590-025-02414-1
Arundhoti Das, Yi Ding, Christelle Harly, Avinash Bhandoola

Innate lymphoid cells (ILCs) are a diverse group of immune cells that possess many effector functions of T cells but lack somatically generated receptors. They have crucial roles in early immune responses and in maintaining tissue integrity. We review ILC developmental pathways and progenitors in mice, with a particular focus on adult bone marrow but also addressing fetal liver. We present recent insights into the earliest steps of ILC specification, as well as new evidence for developmental pathways that generate two functionally distinct types of natural killer cells. The anatomical locations where ILC progenitors are identified are outlined and evidence supporting ILC development in tissues examined. In addition, key transcriptional regulators that support ILC development are discussed. Although ILC and T-lineage cells use many of the same transcriptional controllers during development, we present new evidence indicating ILC transcriptional programs diverge from T-lineage programs at the earliest known steps of ILC lineage specification.

先天淋巴样细胞(ILCs)是一类具有许多T细胞效应功能但缺乏体细胞生成受体的免疫细胞。它们在早期免疫反应和维持组织完整性方面起着至关重要的作用。我们回顾了ILC在小鼠中的发育途径和祖细胞,特别关注成人骨髓,但也涉及胎儿肝脏。我们提出了最近对ILC规范的早期步骤的见解,以及产生两种功能不同类型的自然杀伤细胞的发育途径的新证据。概述了ILC祖细胞鉴定的解剖位置,并检查了支持ILC在组织中发育的证据。此外,还讨论了支持ILC发展的关键转录调控因子。尽管ILC和t谱系细胞在发育过程中使用许多相同的转录控制器,但我们提出的新证据表明,在ILC谱系规范的最早已知步骤中,ILC转录程序与t谱系程序不同。
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引用次数: 0
Pregnancy quenches inflammation through neuroimmune crosstalk 怀孕通过神经免疫串扰消除炎症
IF 30.5 1区 医学 Q1 IMMUNOLOGY Pub Date : 2026-02-04 DOI: 10.1038/s41590-026-02418-5
Thomas Korn
{"title":"Pregnancy quenches inflammation through neuroimmune crosstalk","authors":"Thomas Korn","doi":"10.1038/s41590-026-02418-5","DOIUrl":"https://doi.org/10.1038/s41590-026-02418-5","url":null,"abstract":"","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"28 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146116221","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
期刊
Nature Immunology
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