Science Immunology最新文献

C/EBPα activates Irf8 expression in myeloid progenitors at the +56-kb enhancer to initiate cDC1 development C/EBPα激活髓系祖细胞中+ 56kb增强子上的Irf8表达，启动cDC1的发展

IF 17.6 1区医学

Science Immunology Pub Date : 2025-05-16 DOI: 10.1126/sciimmunol.adt5899

Jing Chen, Tian-Tian Liu, Feiya Ou, Ray A. Ohara, Suin Jo, Joshua Luke Postoak, Takeshi Egawa, Ryan B. Day, Theresa L. Murphy, Kenneth M. Murphy, Sunkyung Kim

{"title":"C/EBPα activates Irf8 expression in myeloid progenitors at the +56-kb enhancer to initiate cDC1 development","authors":"Jing Chen, Tian-Tian Liu, Feiya Ou, Ray A. Ohara, Suin Jo, Joshua Luke Postoak, Takeshi Egawa, Ryan B. Day, Theresa L. Murphy, Kenneth M. Murphy, Sunkyung Kim","doi":"10.1126/sciimmunol.adt5899","DOIUrl":"10.1126/sciimmunol.adt5899","url":null,"abstract":"<div >Development of type 1 conventional dendritic cells (cDC1s) underlies the capacity to generate antiviral and antitumor immune responses. Here, we identify the basis for cDC1 development from its earliest progenitors, determining the hierarchy of several required transcription factors and uncovering a series of mandatory cis interactions between constituent enhancers within the <i>Irf8</i> superenhancer. We produced in vivo mutations of two C/EBPα binding sites that comprise the <i>Irf8</i> +56–kilobase (kb) enhancer that markedly reduced IRF8 expression in all myeloid progenitors and impaired cDC1 development. These sites did not bind RUNX1 or RUNX3, and C/EBPα expression was instead regulated by their action at the <i>Cebpa</i> +37-kb enhancer, placing RUNX factors upstream of <i>Cebpa</i> in regulating <i>Irf8</i>. Last, we demonstrate that cis interactions between the +56-kb <i>Irf8</i> enhancer and the previously reported +41- and +32-kb <i>Irf8</i> enhancers are mandatory in the sequential progression of these stage-specific constituent elements.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 107","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144067020","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

Cross-regulation between the nervous system and type 2 immunity 神经系统和2型免疫之间的交叉调节

IF 17.6 1区医学

Science Immunology Pub Date : 2025-05-16 DOI: 10.1126/sciimmunol.adp6450

Nicholas M. Mroz, Pailin Chiaranunt, Anna V. Molofsky, Ari B. Molofsky

引用次数: 0

ILC3s promote intestinal tuft cell hyperplasia and anthelmintic immunity through RANK signaling ILC3s通过RANK信号通路促进肠簇细胞增生和驱虫免疫

IF 17.6 1区医学

Science Immunology Pub Date : 2025-05-16 DOI: 10.1126/sciimmunol.adn1491

Hongkai Xu, Yibo Wang, Wenyan Wang, Yang-Xin Fu, Ju Qiu, Yan Shi, Lei Yuan, Chen Dong, Xiaoyu Hu, Ye-Guang Chen, Xiaohuan Guo

{"title":"ILC3s promote intestinal tuft cell hyperplasia and anthelmintic immunity through RANK signaling","authors":"Hongkai Xu, Yibo Wang, Wenyan Wang, Yang-Xin Fu, Ju Qiu, Yan Shi, Lei Yuan, Chen Dong, Xiaoyu Hu, Ye-Guang Chen, Xiaohuan Guo","doi":"10.1126/sciimmunol.adn1491","DOIUrl":"10.1126/sciimmunol.adn1491","url":null,"abstract":"<div >Helminth infections, particularly in developing countries, remain a notable health burden worldwide. Group 3 innate lymphoid cells (ILC3s) are enriched in the intestine and play a critical role in immunity against extracellular bacteria and fungi. However, whether ILC3s are involved in intestinal helminth infection is still unclear. Here, we report that helminth infection reprograms ILC3s, which, in turn, promote anthelmintic immunity. ILC3-derived RANKL [receptor activator of NF-κB (nuclear factor κB) ligand] synergizes with interleukin-13 (IL-13) to facilitate intestinal tuft cell expansion after helminth infection, which further activates the tuft cell–group 2 innate lymphoid cell (ILC2) circuit to control helminth infection. Deletion of RANKL in ILC3s or deletion of RANK or its downstream adaptor RelB in intestinal epithelial cells substantially diminishes tuft cell hyperplasia and dampens anthelmintic immunity. Thus, ILC3s play an indispensable role in protecting against helminth infection through the regulation of intestinal tuft cell hyperplasia and type 2 immunity.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 107","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144066830","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

Chimeric autoantibody receptor T cells clonally eliminate B cells producing autoantibodies against IFN-γ 嵌合自身抗体受体T细胞克隆消除产生IFN-γ自身抗体的B细胞

IF 17.6 1区医学

Science Immunology Pub Date : 2025-05-09 DOI: 10.1126/sciimmunol.adm8186

Jhan-Jie Peng, Jing-Ya Ding, Yingxi Xu, Han-Po Shih, You-Ning Lin, Tsai-Yi Wu, Yu-Fang Lo, Chia-Chi Lo, Chu-Fu Yeh, Chen-Yen Kuo, Kun-Hua Tu, Shang-Yu Wang, Wei-Te Lei, Ting-Shu Wu, Huang-Shen Lin, Chen-Hsiang Lee, Wen-Chi Huang, Yi-Chun Chen, Yuag-Meng Liu, Zhi-Yuan Shi, Ya-Ting Chang, Ling-Shan Syue, Po-Lin Chen, Soon-Hian Teh, Chia-Huei Chou, Mao-Wang Ho, Chih-Yu Chi, Ping-Chih Ho, Cheng-Lung Ku

{"title":"Chimeric autoantibody receptor T cells clonally eliminate B cells producing autoantibodies against IFN-γ","authors":"Jhan-Jie Peng, Jing-Ya Ding, Yingxi Xu, Han-Po Shih, You-Ning Lin, Tsai-Yi Wu, Yu-Fang Lo, Chia-Chi Lo, Chu-Fu Yeh, Chen-Yen Kuo, Kun-Hua Tu, Shang-Yu Wang, Wei-Te Lei, Ting-Shu Wu, Huang-Shen Lin, Chen-Hsiang Lee, Wen-Chi Huang, Yi-Chun Chen, Yuag-Meng Liu, Zhi-Yuan Shi, Ya-Ting Chang, Ling-Shan Syue, Po-Lin Chen, Soon-Hian Teh, Chia-Huei Chou, Mao-Wang Ho, Chih-Yu Chi, Ping-Chih Ho, Cheng-Lung Ku","doi":"10.1126/sciimmunol.adm8186","DOIUrl":"10.1126/sciimmunol.adm8186","url":null,"abstract":"<div >Neutralizing anti–interferon-γ (IFN-γ) autoantibodies (nAIGAs) impair IFN-γ–mediated immunity, predisposing patients with nAIGAs to infection by nontuberculous mycobacteria, <i>Talaromyces marneffei</i>, and other intracellular pathogens. Current clinical management relies on continuous antimicrobial therapy, with no treatment offering sustained benefits. Here, we developed human chimeric autoantibody receptor (CAAR) T cells targeting autoreactive B cells expressing nAIGA B cell receptors (BCRs) using an IFN-γ receptor–irresponsive IFN-γ variant as bait. By exploiting a mouse model of nAIGA BCR-expressing B cell leukemia, we found that IFN-γ CAAR T cells lack off-target toxicity, including IFN-γ receptor cross-reactive toxicity and Fc-redirected toxicity. IFN-γ CAAR T cells substantially reduced circulating AIGAs secreted from target cells in vivo. Further, IFN-γ CAAR T cells effectively eliminated autoreactive B cells in ex vivo cultures of peripheral blood mononuclear cells from patients with nAIGAs. Together, these results demonstrate that IFN-γ CAAR T cells may be a promising strategy to ameliorate nAIGA-associated infections by eliminating autoreactive B cells.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 107","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adm8186","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143930550","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

Uptake of lipids from ascites drives NK cell metabolic dysfunction in ovarian cancer 从腹水中摄取脂质驱动卵巢癌NK细胞代谢功能障碍

IF 17.6 1区医学

Science Immunology Pub Date : 2025-05-09 DOI: 10.1126/sciimmunol.adr4795

Karen Slattery, Cong-Hui Yao, Eimear Mylod, John Scanlan, Barry Scott, Joseph Patrick Crowley, Orla McGowan, Gavin McManus, Martin Brennan, Katie O’Brien, Kate Glennon, Edward Corry, Ann Treacy, Rafael J. Argüello, Clair M. Gardiner, Marcia C. Haigis, Donal J. Brennan, Lydia Lynch

{"title":"Uptake of lipids from ascites drives NK cell metabolic dysfunction in ovarian cancer","authors":"Karen Slattery, Cong-Hui Yao, Eimear Mylod, John Scanlan, Barry Scott, Joseph Patrick Crowley, Orla McGowan, Gavin McManus, Martin Brennan, Katie O’Brien, Kate Glennon, Edward Corry, Ann Treacy, Rafael J. Argüello, Clair M. Gardiner, Marcia C. Haigis, Donal J. Brennan, Lydia Lynch","doi":"10.1126/sciimmunol.adr4795","DOIUrl":"10.1126/sciimmunol.adr4795","url":null,"abstract":"<div >High-grade serous ovarian cancer (HGSOC) remains an urgent unmet clinical need, with more than 70% of patients presenting with metastatic disease. Many patients develop large volumes of ascites, which promotes metastasis and is associated with poor therapeutic response and survival. Immunotherapy trials have shown limited success, highlighting the need to better understand HGSOC immunology. Here, we analyzed cytotoxic lymphocytes [natural killer (NK), T, and innate T cells] from patients with HGSOC and observed widespread dysfunction across primary and metastatic sites. Although nutrient rich, ascites was immunosuppressive for all lymphocyte subsets. NK cell dysfunction was driven by uptake of polar lipids, with associated dysregulation in lipid storage. Phosphatidylcholine was a key immunosuppressive metabolite, disrupting NK cell membrane order and cytotoxicity. Blocking lipid uptake through SR-B1 protected NK cell antitumor functions in ascites. These findings offer insights into immune suppression in HGSOC and have important implications for the design of future immunotherapies.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 107","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adr4795","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143930563","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

How dengue defies dogma: An extrafollicular tale 登革热如何挑战教条：一个滤泡外的故事

IF 17.6 1区医学

Science Immunology Pub Date : 2025-05-02 DOI: 10.1126/sciimmunol.ady4137

Jordan Polster, David R. Martinez

引用次数: 0

Distinct type I and II interferon responses direct cortical and medullary thymic epithelial cell development 不同的I型和II型干扰素反应直接胸腺皮层和髓质上皮细胞的发育

IF 17.6 1区医学

Science Immunology Pub Date : 2025-05-02 DOI: 10.1126/sciimmunol.ado4720

Abdulvasey Mohammed, Wenqing Wang, Martin Arreola, Benjamin D. Solomon, Priscila F. Slepicka, Kelsea M. Hubka, Hanh Dan Nguyen, Zihao Zheng, Michael G. Chavez, Christine Y. Yeh, Doo Kyung Kim, Michael R. Ma, Elisabeth Martin, Li Li, Anca M. Pasca, Virginia D. Winn, Casey A. Gifford, Veronika R. Kedlian, Jong-Eun Park, Purvesh Khatri, Georg A. Hollander, Maria Grazia Roncarolo, Vittorio Sebastiano, Sarah A. Teichmann, Andrew J. Gentles, Katja G. Weinacht

{"title":"Distinct type I and II interferon responses direct cortical and medullary thymic epithelial cell development","authors":"Abdulvasey Mohammed, Wenqing Wang, Martin Arreola, Benjamin D. Solomon, Priscila F. Slepicka, Kelsea M. Hubka, Hanh Dan Nguyen, Zihao Zheng, Michael G. Chavez, Christine Y. Yeh, Doo Kyung Kim, Michael R. Ma, Elisabeth Martin, Li Li, Anca M. Pasca, Virginia D. Winn, Casey A. Gifford, Veronika R. Kedlian, Jong-Eun Park, Purvesh Khatri, Georg A. Hollander, Maria Grazia Roncarolo, Vittorio Sebastiano, Sarah A. Teichmann, Andrew J. Gentles, Katja G. Weinacht","doi":"10.1126/sciimmunol.ado4720","DOIUrl":"10.1126/sciimmunol.ado4720","url":null,"abstract":"<div >Advances in genomics have redefined our understanding of thymic epithelial heterogeneity and architecture, yet signals driving thymic epithelial differentiation remain incompletely understood. Here, we elucidated pathways instructing human thymic epithelial cell development in the context of other anterior foregut–derived organs. Activation of interferon response gene regulatory networks distinguished epithelial cells of the thymus from those of other anterior foregut–derived organs. Thymic cortex and medulla epithelia displayed distinctive interferon-responsive signatures defined by lineage-specific chromatin accessibility. We explored the effects of type I and II interferons on thymic epithelial progenitor differentiation from induced pluripotent stem cells. Type II interferon was essential for expressing proteasome and antigen-presenting molecules, whereas type I or II interferons were essential for inducing different cytokines in thymic epithelial progenitor cells. Our findings suggest that interferons are critical to cortical and medullary thymic epithelial cell differentiation.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 107","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143898134","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

Apoptotic cells are not all created equal 凋亡细胞并不都是一样的

IF 17.6 1区医学

Science Immunology Pub Date : 2025-05-02 DOI: 10.1126/sciimmunol.adv4682

Amanda O. Wong, Kodi S. Ravichandran

引用次数: 0

Cell type–specific efferocytosis determines functional plasticity of alveolar macrophages 细胞类型特异性的efferocytosis决定了肺泡巨噬细胞的功能可塑性

IF 17.6 1区医学

Science Immunology Pub Date : 2025-05-02 DOI: 10.1126/sciimmunol.adl3852

Julian Better, Mohammad Estiri, Michael Wetstein, Learta Pervizaj-Oruqaj, Christina Malainou, Victoria Ogungbemi-Alt, Maximiliano Ruben Ferrero, Martin Langelage, Irina Kuznetsova, Ana Ivonne Vazquez-Armendariz, Lucas Kimmig, Oleg Pak, Siavash Mansouri, Rajkumar Savai, Jochen Wilhelm, Ioannis Alexopoulos, Natascha Sommer, Susanne Herold, Ulrich Matt

{"title":"Cell type–specific efferocytosis determines functional plasticity of alveolar macrophages","authors":"Julian Better, Mohammad Estiri, Michael Wetstein, Learta Pervizaj-Oruqaj, Christina Malainou, Victoria Ogungbemi-Alt, Maximiliano Ruben Ferrero, Martin Langelage, Irina Kuznetsova, Ana Ivonne Vazquez-Armendariz, Lucas Kimmig, Oleg Pak, Siavash Mansouri, Rajkumar Savai, Jochen Wilhelm, Ioannis Alexopoulos, Natascha Sommer, Susanne Herold, Ulrich Matt","doi":"10.1126/sciimmunol.adl3852","DOIUrl":"10.1126/sciimmunol.adl3852","url":null,"abstract":"<div >Resolution of lung injuries is vital to maintain gas exchange, but there is an increased risk of secondary bacterial infections during this stage. Alveolar macrophages (AMs) are crucial to clear bacteria and control the resolution of inflammation, but environmental cues that switch functional phenotypes of AMs remain incompletely understood. Here, we found that AMs lack the capacity to mount an effective immune response against bacteria during resolution of inflammation. Neutrophil (PMN)–derived myeloperoxidase (MPO) fueled canonical glutaminolysis via the mitochondrial membrane transporter uncoupling protein–2 (UCP2), resulting in decreased mtROS-dependent killing of bacteria and secretion of pro-inflammatory cytokines. MPO-enhanced UCP2 expression inhibited mitochondrial hyperpolarization and boosted efferocytosis irrespective of the presence of bacterial pathogens. Conversely, efferocytosis of other cell types resulted in a distinct anti-inflammatory AM phenotype while maintaining antibacterial phenotypic plasticity. Overall, our findings indicate that the uptake of apoptotic PMNs or MPO switches AMs to prioritize resolution of inflammation over antibacterial responses, a feature that is conserved in murine extrapulmonary macrophages and human AMs.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 107","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143898132","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

Tolerance requires diversity (of antigen presenting cells) 耐受性需要多样性（抗原呈递细胞）

IF 17.6 1区医学

Science Immunology Pub Date : 2025-05-02 DOI: 10.1126/sciimmunol.ady4136

Danielle R. Jacobsen, Stephanie C. Eisenbarth

引用次数: 0