Pub Date : 2024-10-08DOI: 10.1016/j.immuni.2024.09.011
Ranit Kedmi, Dan R. Littman
The immune system recognizes a multitude of innocuous antigens from food and intestinal commensal microbes toward which it orchestrates appropriate, non-inflammatory responses. This process requires antigen-presenting cells (APCs) that induce T cells with either regulatory or effector functions. Compromised APC function disrupts the T cell balance, leading to inflammation and dysbiosis. Although their precise identities continue to be debated, it has become clear that multiple APC lineages direct the differentiation of distinct microbiota-specific CD4+ T cell programs. Here, we review how unique APC subsets instruct T cell differentiation and function in response to microbiota and dietary antigens. These discoveries provide new opportunities to investigate T cell-APC regulatory networks controlling immune homeostasis and perturbations associated with inflammatory and allergic diseases.
免疫系统能识别食物和肠道共生微生物中的多种无害抗原，并对其做出适当的非炎症反应。这一过程需要抗原递呈细胞（APC）诱导具有调节或效应功能的 T 细胞。APC 功能受损会破坏 T 细胞的平衡，导致炎症和菌群失调。尽管对它们的确切身份仍有争议，但已经清楚的是，多种 APC 系指导着不同微生物群特异性 CD4+ T 细胞程序的分化。在这里，我们回顾了独特的 APC 亚群是如何指导 T 细胞分化和功能以应对微生物群和饮食抗原的。这些发现为研究控制免疫稳态以及与炎症和过敏性疾病相关的干扰的 T 细胞-APC 调控网络提供了新的机会。
{"title":"Antigen-presenting cells as specialized drivers of intestinal T cell functions","authors":"Ranit Kedmi, Dan R. Littman","doi":"10.1016/j.immuni.2024.09.011","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.09.011","url":null,"abstract":"The immune system recognizes a multitude of innocuous antigens from food and intestinal commensal microbes toward which it orchestrates appropriate, non-inflammatory responses. This process requires antigen-presenting cells (APCs) that induce T cells with either regulatory or effector functions. Compromised APC function disrupts the T cell balance, leading to inflammation and dysbiosis. Although their precise identities continue to be debated, it has become clear that multiple APC lineages direct the differentiation of distinct microbiota-specific CD4<sup>+</sup> T cell programs. Here, we review how unique APC subsets instruct T cell differentiation and function in response to microbiota and dietary antigens. These discoveries provide new opportunities to investigate T cell-APC regulatory networks controlling immune homeostasis and perturbations associated with inflammatory and allergic diseases.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":32.4,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142385778","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}
Pub Date : 2024-10-08DOI: 10.1016/j.immuni.2024.09.006
Eric D. Garcia, Jonah R. Chan
The meningeal lymphatics system plays diverse roles in facilitating neuroimmune function at brain borders, yet its specific contribution toward glial function and homeostasis is not known. In this issue of Immunity, Das Neves et al. (2024) describe a novel role for the meningeal lymphatics in maintaining oligodendrocyte survival and myelination.
脑膜淋巴系统在促进脑边界神经免疫功能方面发挥着多种作用，但其对神经胶质功能和平衡的具体贡献尚不清楚。在本期《免疫》杂志上，Das Neves 等人（2024 年）描述了脑膜淋巴管在维持少突胶质细胞存活和髓鞘化方面的新作用。
{"title":"Oligodendrocytes go with the flow: Meningeal lymphatics promote myelin integrity","authors":"Eric D. Garcia, Jonah R. Chan","doi":"10.1016/j.immuni.2024.09.006","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.09.006","url":null,"abstract":"The meningeal lymphatics system plays diverse roles in facilitating neuroimmune function at brain borders, yet its specific contribution toward glial function and homeostasis is not known. In this issue of <em>Immunity</em>, Das Neves et al. (2024) describe a novel role for the meningeal lymphatics in maintaining oligodendrocyte survival and myelination.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":32.4,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142384335","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}
Pub Date : 2024-10-08DOI: 10.1016/j.immuni.2024.09.005
Thomas Korn
Understanding the nature of human autoantigen-specific CD4+ T cells is limited by the difficulty of characterizing these cells ex vivo. In this issue of Immunity, Saggau et al. use ARTE technology to profile CD4+ T cells specific to disease-relevant autoantigens and find that such cells develop an exhausted phenotype that includes FOXP3 expression and persist for extended periods of time.
对人类自身抗原特异性 CD4+ T 细胞性质的了解受到了限制，因为很难对这些细胞进行体内外特征描述。在本期《免疫》（Immunity）杂志上，Saggau 等人利用 ARTE 技术分析了与疾病相关的自身抗原特异性 CD4+ T 细胞，发现这些细胞形成了包括 FOXP3 表达在内的衰竭表型，并能长期存在。
{"title":"An autoreactive T cell’s perception of a land of plenty","authors":"Thomas Korn","doi":"10.1016/j.immuni.2024.09.005","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.09.005","url":null,"abstract":"Understanding the nature of human autoantigen-specific CD4<sup>+</sup> T cells is limited by the difficulty of characterizing these cells <em>ex vivo</em>. In this issue of <em>Immunity</em>, Saggau et al. use ARTE technology to profile CD4<sup>+</sup> T cells specific to disease-relevant autoantigens and find that such cells develop an exhausted phenotype that includes FOXP3 expression and persist for extended periods of time.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":32.4,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142384336","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}
Pub Date : 2024-10-08Epub Date: 2024-08-19DOI: 10.1016/j.immuni.2024.07.022
Yiquan Wang, Huibin Lv, Qi Wen Teo, Ruipeng Lei, Akshita B Gopal, Wenhao O Ouyang, Yuen-Hei Yeung, Timothy J C Tan, Danbi Choi, Ivana R Shen, Xin Chen, Claire S Graham, Nicholas C Wu
Despite decades of antibody research, it remains challenging to predict the specificity of an antibody solely based on its sequence. Two major obstacles are the lack of appropriate models and the inaccessibility of datasets for model training. In this study, we curated >5,000 influenza hemagglutinin (HA) antibodies by mining research publications and patents, which revealed many distinct sequence features between antibodies to HA head and stem domains. We then leveraged this dataset to develop a lightweight memory B cell language model (mBLM) for sequence-based antibody specificity prediction. Model explainability analysis showed that mBLM could identify key sequence features of HA stem antibodies. Additionally, by applying mBLM to HA antibodies with unknown epitopes, we discovered and experimentally validated many HA stem antibodies. Overall, this study not only advances our molecular understanding of the antibody response to the influenza virus but also provides a valuable resource for applying deep learning to antibody research.
尽管抗体研究已经进行了几十年，但仅凭序列预测抗体的特异性仍然是一项挑战。两个主要障碍是缺乏合适的模型和无法获得用于模型训练的数据集。在这项研究中，我们通过挖掘研究出版物和专利，整理了超过 5,000 种流感血凝素（HA）抗体，发现了 HA 头域和茎域抗体之间许多不同的序列特征。然后，我们利用这个数据集开发了一个轻量级记忆B细胞语言模型（mBLM），用于基于序列的抗体特异性预测。模型可解释性分析表明，mBLM 可以识别 HA 干抗体的关键序列特征。此外，通过将 mBLM 应用于具有未知表位的 HA 抗体，我们发现并通过实验验证了许多 HA 干抗体。总之，这项研究不仅推进了我们对流感病毒抗体反应的分子理解，还为将深度学习应用于抗体研究提供了宝贵的资源。
{"title":"An explainable language model for antibody specificity prediction using curated influenza hemagglutinin antibodies.","authors":"Yiquan Wang, Huibin Lv, Qi Wen Teo, Ruipeng Lei, Akshita B Gopal, Wenhao O Ouyang, Yuen-Hei Yeung, Timothy J C Tan, Danbi Choi, Ivana R Shen, Xin Chen, Claire S Graham, Nicholas C Wu","doi":"10.1016/j.immuni.2024.07.022","DOIUrl":"10.1016/j.immuni.2024.07.022","url":null,"abstract":"<p><p>Despite decades of antibody research, it remains challenging to predict the specificity of an antibody solely based on its sequence. Two major obstacles are the lack of appropriate models and the inaccessibility of datasets for model training. In this study, we curated >5,000 influenza hemagglutinin (HA) antibodies by mining research publications and patents, which revealed many distinct sequence features between antibodies to HA head and stem domains. We then leveraged this dataset to develop a lightweight memory B cell language model (mBLM) for sequence-based antibody specificity prediction. Model explainability analysis showed that mBLM could identify key sequence features of HA stem antibodies. Additionally, by applying mBLM to HA antibodies with unknown epitopes, we discovered and experimentally validated many HA stem antibodies. Overall, this study not only advances our molecular understanding of the antibody response to the influenza virus but also provides a valuable resource for applying deep learning to antibody research.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":25.5,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11464180/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142008755","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}
Pub Date : 2024-10-08DOI: 10.1016/j.immuni.2024.09.010
Andrew J. Gunderson
PD-1 blockade partially reverses T cell exhaustion in cancer patients, but broad responses are still limited. Three studies recently published in Cell illuminate how abrogating LAG-3 and PD-1 synergize to further push effector T cell functionality via distinct molecular mechanisms.
{"title":"LAGging behind no more: PD-1 has a new immunotherapy partner","authors":"Andrew J. Gunderson","doi":"10.1016/j.immuni.2024.09.010","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.09.010","url":null,"abstract":"PD-1 blockade partially reverses T cell exhaustion in cancer patients, but broad responses are still limited. Three studies recently published in <em>Cell</em> illuminate how abrogating LAG-3 and PD-1 synergize to further push effector T cell functionality via distinct molecular mechanisms.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":32.4,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142384341","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}
Pub Date : 2024-10-08DOI: 10.1016/j.immuni.2024.09.008
Zhuoqiong Qiu, Wei Li
It’s crucial for skin to establish efficient defense strategies. Liu et al. reveal that the transcription factor ZNF750 recruits the histone demethylase KDM1A to silence pattern recognition receptors in the outer epidermis, making their expression limited to deeper, undifferentiated keratinocytes to address threats penetrating the skin.
{"title":"Superficial ice and deep blaze: A defense strategy of the skin","authors":"Zhuoqiong Qiu, Wei Li","doi":"10.1016/j.immuni.2024.09.008","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.09.008","url":null,"abstract":"It’s crucial for skin to establish efficient defense strategies. Liu et al. reveal that the transcription factor ZNF750 recruits the histone demethylase KDM1A to silence pattern recognition receptors in the outer epidermis, making their expression limited to deeper, undifferentiated keratinocytes to address threats penetrating the skin.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":32.4,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142384279","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}
Pub Date : 2024-10-07DOI: 10.1016/j.immuni.2024.09.004
Simone Caielli, Preetha Balasubramanian, Juan Rodriguez-Alcazar, Uthra Balaji, Lauren Robinson, Zurong Wan, Jeanine Baisch, Cynthia Smitherman, Lynnette Walters, Paola Sparagana, Djamel Nehar-Belaid, Radu Marches, Lorien Nassi, Katie Stewart, Julie Fuller, Jacques F. Banchereau, Jinghua Gu, Tracey Wright, Virginia Pascual
Opsonization of red blood cells that retain mitochondria (Mito+ RBCs), a feature of systemic lupus erythematosus (SLE), triggers type I interferon (IFN) production in macrophages. We report that monocytes (Mos) co-produce IFN and mature interleukin-1β (mIL-1β) upon Mito+ RBC opsonization. IFN expression depended on cyclic GMP-AMP synthase (cGAS) and RIG-I-like receptors’ (RLRs) sensing of Mito+ RBC-derived mitochondrial DNA (mtDNA) and mtRNA, respectively. Interleukin-1β (IL-1β) production was initiated by the RLR antiviral signaling adaptor (MAVS) pathway recognition of Mito+ RBC-derived mtRNA. This led to the cytosolic release of Mo mtDNA, which activated the inflammasome. Importantly, mIL-1β secretion was independent of gasdermin D (GSDMD) and pyroptosis but relied on IFN-inducible myxovirus-resistant protein 1 (MxA), which facilitated the incorporation of mIL-1β into a trans-Golgi network (TGN)-mediated secretory pathway. RBC internalization identified a subset of blood Mo expressing IFN-stimulated genes (ISGs) that released mIL-1β and expanded in SLE patients with active disease.
{"title":"Type I IFN drives unconventional IL-1β secretion in lupus monocytes","authors":"Simone Caielli, Preetha Balasubramanian, Juan Rodriguez-Alcazar, Uthra Balaji, Lauren Robinson, Zurong Wan, Jeanine Baisch, Cynthia Smitherman, Lynnette Walters, Paola Sparagana, Djamel Nehar-Belaid, Radu Marches, Lorien Nassi, Katie Stewart, Julie Fuller, Jacques F. Banchereau, Jinghua Gu, Tracey Wright, Virginia Pascual","doi":"10.1016/j.immuni.2024.09.004","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.09.004","url":null,"abstract":"Opsonization of red blood cells that retain mitochondria (Mito<sup>+</sup> RBCs), a feature of systemic lupus erythematosus (SLE), triggers type I interferon (IFN) production in macrophages. We report that monocytes (Mos) co-produce IFN and mature interleukin-1β (mIL-1β) upon Mito<sup>+</sup> RBC opsonization. IFN expression depended on cyclic GMP-AMP synthase (cGAS) and RIG-I-like receptors’ (RLRs) sensing of Mito<sup>+</sup> RBC-derived mitochondrial DNA (mtDNA) and mtRNA, respectively. Interleukin-1β (IL-1β) production was initiated by the RLR antiviral signaling adaptor (MAVS) pathway recognition of Mito<sup>+</sup> RBC-derived mtRNA. This led to the cytosolic release of Mo mtDNA, which activated the inflammasome. Importantly, mIL-1β secretion was independent of gasdermin D (GSDMD) and pyroptosis but relied on IFN-inducible myxovirus-resistant protein 1 (MxA), which facilitated the incorporation of mIL-1β into a <em>trans</em>-Golgi network (TGN)-mediated secretory pathway. RBC internalization identified a subset of blood Mo expressing IFN-stimulated genes (ISGs) that released mIL-1β and expanded in SLE patients with active disease.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":32.4,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142383809","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}
Pub Date : 2024-10-04DOI: 10.1016/j.immuni.2024.09.003
Julia M. Messmer, Calvin Thommek, Manuel Piechutta, Varun Venkataramani, Rebekka Wehner, Dana Westphal, Marc Schubert, Chanté D. Mayer, Maike Effern, Anna S. Berghoff, Daniel Hinze, Iris Helfrich, Dirk Schadendorf, Wolfgang Wick, Michael Hölzel, Matthia A. Karreman, Frank Winkler
To improve immunotherapy for brain tumors, it is important to determine the principal intracranial site of T cell recruitment from the bloodstream and their intracranial route to brain tumors. Using intravital microscopy in mouse models of intracranial melanoma, we discovered that circulating T cells preferably adhered and extravasated at a distinct type of venous blood vessel in the tumor vicinity, peritumoral venous vessels (PVVs). Other vascular structures were excluded as alternative T cell routes to intracranial melanomas. Anti-PD-1/CTLA-4 immune checkpoint inhibitors increased intracranial T cell motility, facilitating migration from PVVs to the tumor and subsequently inhibiting intracranial tumor growth. The endothelial adhesion molecule ICAM-1 was particularly expressed on PVVs, and, in samples of human brain metastases, ICAM-1 positivity of PVV-like vessels correlated with intratumoral T cell infiltration. These findings uncover a distinct mechanism by which the immune system can access and control brain tumors and potentially influence other brain pathologies.
{"title":"T lymphocyte recruitment to melanoma brain tumors depends on distinct venous vessels","authors":"Julia M. Messmer, Calvin Thommek, Manuel Piechutta, Varun Venkataramani, Rebekka Wehner, Dana Westphal, Marc Schubert, Chanté D. Mayer, Maike Effern, Anna S. Berghoff, Daniel Hinze, Iris Helfrich, Dirk Schadendorf, Wolfgang Wick, Michael Hölzel, Matthia A. Karreman, Frank Winkler","doi":"10.1016/j.immuni.2024.09.003","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.09.003","url":null,"abstract":"To improve immunotherapy for brain tumors, it is important to determine the principal intracranial site of T cell recruitment from the bloodstream and their intracranial route to brain tumors. Using intravital microscopy in mouse models of intracranial melanoma, we discovered that circulating T cells preferably adhered and extravasated at a distinct type of venous blood vessel in the tumor vicinity, peritumoral venous vessels (PVVs). Other vascular structures were excluded as alternative T cell routes to intracranial melanomas. Anti-PD-1/CTLA-4 immune checkpoint inhibitors increased intracranial T cell motility, facilitating migration from PVVs to the tumor and subsequently inhibiting intracranial tumor growth. The endothelial adhesion molecule ICAM-1 was particularly expressed on PVVs, and, in samples of human brain metastases, ICAM-1 positivity of PVV-like vessels correlated with intratumoral T cell infiltration. These findings uncover a distinct mechanism by which the immune system can access and control brain tumors and potentially influence other brain pathologies.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":32.4,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142374137","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}
Pub Date : 2024-10-03DOI: 10.1016/j.immuni.2024.09.001
Zebing Rao, Shaorui Liu, Zhicheng Li, Qiuying Wang, Feng Gao, Han Peng, Deshan Ren, Yang Zang, Hui Li, Yan Li, Qi Hu, Danyang He, Heping Xu
Group 2 innate lymphoid cells (ILC2s) play a crucial role in allergic diseases by coordinating a complex network of various effector cell lineages involved in type 2 inflammation. However, their function in regulating airway neutrophil infiltration, a deleterious symptom of severe asthma, remains unknown. Here, we observed ILC2-dependent neutrophil accumulation in the bronchoalveolar lavage fluid (BALF) of allergic mouse models. Chromatography followed by proteomics analysis identified the alarmin high mobility group box-1 (HMGB1) in the supernatant of lung ILC2s initiated neutrophil chemotaxis. Genetic perturbation of Hmgb1 in ILC2s reduced BALF neutrophil numbers and alleviated airway inflammation. HMGB1 was loaded onto the membrane of lipid droplets (LDs) released from activated lung ILC2s. Genetic inhibition of LD accumulation in ILC2s significantly decreased extracellular HMGB1 abundance and BALF neutrophil infiltration. These findings unveil a previously uncharacterized extracellular LD-mediated immune signaling delivery pathway by which ILC2s regulate airway neutrophil infiltration during allergic inflammation.
{"title":"Alarmin-loaded extracellular lipid droplets induce airway neutrophil infiltration during type 2 inflammation","authors":"Zebing Rao, Shaorui Liu, Zhicheng Li, Qiuying Wang, Feng Gao, Han Peng, Deshan Ren, Yang Zang, Hui Li, Yan Li, Qi Hu, Danyang He, Heping Xu","doi":"10.1016/j.immuni.2024.09.001","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.09.001","url":null,"abstract":"Group 2 innate lymphoid cells (ILC2s) play a crucial role in allergic diseases by coordinating a complex network of various effector cell lineages involved in type 2 inflammation. However, their function in regulating airway neutrophil infiltration, a deleterious symptom of severe asthma, remains unknown. Here, we observed ILC2-dependent neutrophil accumulation in the bronchoalveolar lavage fluid (BALF) of allergic mouse models. Chromatography followed by proteomics analysis identified the alarmin high mobility group box-1 (HMGB1) in the supernatant of lung ILC2s initiated neutrophil chemotaxis. Genetic perturbation of <em>Hmgb1</em> in ILC2s reduced BALF neutrophil numbers and alleviated airway inflammation. HMGB1 was loaded onto the membrane of lipid droplets (LDs) released from activated lung ILC2s. Genetic inhibition of LD accumulation in ILC2s significantly decreased extracellular HMGB1 abundance and BALF neutrophil infiltration. These findings unveil a previously uncharacterized extracellular LD-mediated immune signaling delivery pathway by which ILC2s regulate airway neutrophil infiltration during allergic inflammation.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":32.4,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142369159","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}
Pub Date : 2024-09-30DOI: 10.1016/j.immuni.2024.08.018
Alexander Lercher, Jin-Gyu Cheong, Michael J. Bale, Chenyang Jiang, Hans-Heinrich Hoffmann, Alison W. Ashbrook, Tyler Lewy, Yue S. Yin, Corrine Quirk, Emma J. DeGrace, Luis Chiriboga, Brad R. Rosenberg, Steven Z. Josefowicz, Charles M. Rice
Pathogen encounter can result in epigenetic remodeling that shapes disease caused by heterologous pathogens. Here, we examined innate immune memory in the context of commonly circulating respiratory viruses. Single-cell analyses of airway-resident immune cells in a disease-relevant murine model of SARS-CoV-2 recovery revealed epigenetic reprogramming in alveolar macrophages following infection. Post-COVID-19 human monocytes exhibited similar epigenetic signatures. In airway-resident macrophages, past SARS-CoV-2 infection increased activity of type I interferon (IFN-I)-related transcription factors and epigenetic poising of antiviral genes. Viral pattern recognition and canonical IFN-I signaling were required for the establishment of this innate immune memory and augmented secondary antiviral responses. Antiviral innate immune memory mounted by airway-resident macrophages post-SARS-CoV-2 was necessary and sufficient to ameliorate secondary disease caused by influenza A virus and curtailed hyperinflammatory dysregulation and mortality. Our findings provide insights into antiviral innate immune memory in the airway that may facilitate the development of broadly effective therapeutic strategies.
病原体相遇会导致表观遗传重塑，从而形成由异源病原体引起的疾病。在此，我们研究了常见呼吸道循环病毒背景下的先天免疫记忆。在一个与疾病相关的 SARS-CoV-2 恢复小鼠模型中，对气道驻留免疫细胞的单细胞分析显示，肺泡巨噬细胞在感染后发生了表观遗传重编程。COVID-19 后的人类单核细胞也表现出类似的表观遗传特征。在气道驻留的巨噬细胞中，过去的 SARS-CoV-2 感染增加了 I 型干扰素（IFN-I）相关转录因子的活性和抗病毒基因的表观遗传学定位。这种先天性免疫记忆的建立需要病毒模式识别和典型的 IFN-I 信号传导，并增强了继发性抗病毒反应。SARS-CoV-2后气道驻留巨噬细胞建立的抗病毒先天性免疫记忆对于改善甲型流感病毒引起的继发性疾病、减少高炎症失调和死亡率是必要且充分的。我们的研究结果为了解气道中的抗病毒先天免疫记忆提供了见解，这可能有助于开发广泛有效的治疗策略。
{"title":"Antiviral innate immune memory in alveolar macrophages following SARS-CoV-2 infection ameliorates secondary influenza A virus disease","authors":"Alexander Lercher, Jin-Gyu Cheong, Michael J. Bale, Chenyang Jiang, Hans-Heinrich Hoffmann, Alison W. Ashbrook, Tyler Lewy, Yue S. Yin, Corrine Quirk, Emma J. DeGrace, Luis Chiriboga, Brad R. Rosenberg, Steven Z. Josefowicz, Charles M. Rice","doi":"10.1016/j.immuni.2024.08.018","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.08.018","url":null,"abstract":"Pathogen encounter can result in epigenetic remodeling that shapes disease caused by heterologous pathogens. Here, we examined innate immune memory in the context of commonly circulating respiratory viruses. Single-cell analyses of airway-resident immune cells in a disease-relevant murine model of SARS-CoV-2 recovery revealed epigenetic reprogramming in alveolar macrophages following infection. Post-COVID-19 human monocytes exhibited similar epigenetic signatures. In airway-resident macrophages, past SARS-CoV-2 infection increased activity of type I interferon (IFN-I)-related transcription factors and epigenetic poising of antiviral genes. Viral pattern recognition and canonical IFN-I signaling were required for the establishment of this innate immune memory and augmented secondary antiviral responses. Antiviral innate immune memory mounted by airway-resident macrophages post-SARS-CoV-2 was necessary and sufficient to ameliorate secondary disease caused by influenza A virus and curtailed hyperinflammatory dysregulation and mortality. Our findings provide insights into antiviral innate immune memory in the airway that may facilitate the development of broadly effective therapeutic strategies.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":32.4,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142360547","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：