Nature Immunology最新文献_第5页

Lipids rewire T cell exhaustion 脂质重新连接T细胞衰竭

IF 30.5 1区医学

Nature Immunology Pub Date : 2025-06-27 DOI: 10.1038/s41590-025-02177-9

Marie-Elen Tuchel, Annette Oxenius

引用次数: 0

Restriction of innate Tγδ17 cell plasticity by an AP-1 regulatory axis AP-1调控轴对先天t - γδ17细胞可塑性的限制

IF 30.5 1区医学

Nature Immunology Pub Date : 2025-06-27 DOI: 10.1038/s41590-025-02206-7

Morgan E. Parker, Naren U. Mehta, Tzu-Chieh Liao, William H. Tomaszewski, Stephanie A. Snyder, Julia Busch, Maria Ciofani

{"title":"Restriction of innate Tγδ17 cell plasticity by an AP-1 regulatory axis","authors":"Morgan E. Parker, Naren U. Mehta, Tzu-Chieh Liao, William H. Tomaszewski, Stephanie A. Snyder, Julia Busch, Maria Ciofani","doi":"10.1038/s41590-025-02206-7","DOIUrl":"https://doi.org/10.1038/s41590-025-02206-7","url":null,"abstract":"Interleukin-17 (IL-17)-producing γδ T (Tγδ17) cells are innate-like mediators of intestinal barrier immunity. Although IL-17-producing helper T cell and group 3 innate lymphoid cell plasticity have been extensively studied, the mechanisms governing Tγδ17 cell effector flexibility remain undefined. Here, we combined type 3 fate mapping with single-cell ATAC-sequencing/RNA-sequencing multiome profiling to define the cellular features and regulatory networks underlying Tγδ17 cell plasticity. During homeostasis, Tγδ17 cell effector identity was stable across tissues, including for intestinal T-bet+ Tγδ17 cells that restrained interferon-γ production. However, Salmonella enterica subsp. enterica serovar Typhimurium infection induced intestinal Vγ6+ Tγδ17 cell conversion into type 1 effectors, with loss of IL-17A production and partial RORγt downregulation. Multiome analysis revealed a trajectory along Vγ6+ Tγδ17 cell effector conversion, with TIM-3 marking ex-Tγδ17 cells with enhanced type 1 functionality. Last, we characterized and validated a critical AP-1 regulatory axis centered around JUNB and FOSL2 that controls Vγ6+ Tγδ17 cell plasticity by stabilizing type 3 identity and restricting type 1 effector conversion.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"7 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144500409","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

Microglia loss triggers glial stress and white matter damage in human leukodystrophy 在人类脑白质营养不良中，小胶质细胞的丢失会引发胶质细胞应激和白质损伤

IF 30.5 1区医学

Nature Immunology Pub Date : 2025-06-26 DOI: 10.1038/s41590-025-02194-8

引用次数: 0

Mutations in the human CSF1R gene impact microglia’s maintenance of brain white matter integrity 人CSF1R基因突变影响小胶质细胞对脑白质完整性的维持

IF 30.5 1区医学

Nature Immunology Pub Date : 2025-06-26 DOI: 10.1038/s41590-025-02195-7

Siling Du, Yingyue Zhou, Dian Li, Julia Lier, Marina Cella, Mari Tada, Hideomi Hamasaki, Junjie Wu, Zhangying Cai, Jennifer L. Orthmann-Murphy, Akiyoshi Kakita, Jonathan Kipnis, Caroline G. Bergner, Marco Colonna

{"title":"Mutations in the human CSF1R gene impact microglia’s maintenance of brain white matter integrity","authors":"Siling Du, Yingyue Zhou, Dian Li, Julia Lier, Marina Cella, Mari Tada, Hideomi Hamasaki, Junjie Wu, Zhangying Cai, Jennifer L. Orthmann-Murphy, Akiyoshi Kakita, Jonathan Kipnis, Caroline G. Bergner, Marco Colonna","doi":"10.1038/s41590-025-02195-7","DOIUrl":"https://doi.org/10.1038/s41590-025-02195-7","url":null,"abstract":"Microglia, the brain’s resident macrophages, depend on interleukin-34 and colony-stimulating factor 1 (CSF1) for their development and maintenance, engaging the CSF1 receptor (CSF1R). Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), a neurodegenerative disorder affecting the brain’s white matter, is caused by heterozygous pathogenic mutations in the CSF1R gene. This study investigated molecular mechanisms underlying ALSP using single-nucleus RNA sequencing on postmortem brain specimens. Results showed a significant reduction in microglia in ALSP brains, with remaining cells exhibiting a unique activation signature. This reduction correlated with decreased myelinating oligodendrocytes (OLs) and increased neuropilin-2+ OLs with a stress-response and anti-apoptotic signature, driven by STAT3 and fibroblast growth factor receptor pathways. Additionally, astrocytes displayed maladaptive activation and stress responses. These findings underscore microglia’s crucial role in supporting OL myelination and limiting astrocyte repair responses, suggesting therapeutic strategies balancing CSF1R, fibroblast growth factor receptor and STAT3 pathways for ALSP and other genetically caused microgliopathies.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"17 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144488427","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

Beneficial role of GZMK+CD8+ T cells in neurodegeneration GZMK+CD8+ T细胞在神经退行性变中的有益作用

IF 30.5 1区医学

Nature Immunology Pub Date : 2025-06-25 DOI: 10.1038/s41590-025-02209-4

引用次数: 0

Granzyme K+ CD8 T cells slow tauopathy progression by targeting microglia 颗粒酶K+ CD8 T细胞通过靶向小胶质细胞减缓tau病的进展

IF 30.5 1区医学

Nature Immunology Pub Date : 2025-06-24 DOI: 10.1038/s41590-025-02198-4

Hannah D. Mason, Yvonne L. Latour, Christopher T. Boughter, Kory R. Johnson, Dragan Maric, Cayce E. Dorrier, Vivian A. Guedes, Chen Lai, Patrick C. Duncker, Alexis M. Johnson, Monica Manglani, Jessica M. Gill, Daniel P. Perl, Martin Meier-Schellersheim, Dorian B. McGavern

{"title":"Granzyme K+ CD8 T cells slow tauopathy progression by targeting microglia","authors":"Hannah D. Mason, Yvonne L. Latour, Christopher T. Boughter, Kory R. Johnson, Dragan Maric, Cayce E. Dorrier, Vivian A. Guedes, Chen Lai, Patrick C. Duncker, Alexis M. Johnson, Monica Manglani, Jessica M. Gill, Daniel P. Perl, Martin Meier-Schellersheim, Dorian B. McGavern","doi":"10.1038/s41590-025-02198-4","DOIUrl":"https://doi.org/10.1038/s41590-025-02198-4","url":null,"abstract":"Neurodegenerative diseases activate innate and adaptive immune responses that can either slow or accelerate disease progression. Here, we sought to define beneficial immune pressures that emerge during tauopathy development in mice and humans. Using mice that express mutant human tau in neurons, we observed that microglia slowed tauopathy development by controlling the spread of phosphorylated tau (pTau) in the central nervous system and blood. However, over time microglia converted into distressed antigen-presenting cells, acquired neuronal transcripts and were targeted by resident, clonally expanded CD8+ T cells. These cells did not express traditional effector molecules, such as IFNγ, TNF or granzymes a/b/c, but instead deposited granzyme K (GZMK) onto microglia and were regulated by immune checkpoint proteins (TIGIT, PD-1), as blockade of TIGIT and PD-1 enhanced disease progression. GZMK+CD8+ T cells also targeted microglia in pTau-rich human brain lesions resulting from age, Alzheimer’s disease or chronic traumatic encephalopathy. Deletion of CD8+ T cells in mice promoted the emergence of distressed microglia containing neuronal transcripts, markedly enhanced pTau spread and accelerated neurological decline. These data demonstrate that GZMK+CD8+ T cells are a signature of tauopathy development and could potentially be harnessed to slow disease progression.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"25 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144371140","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

Neuroprotective liver portal area macrophages attenuate hepatic inflammation

IF 30.5 1区医学

Nature Immunology Pub Date : 2025-06-19 DOI: 10.1038/s41590-025-02190-y

Mengli Xu, Zheng Liu, Qi Pan, Zhenzhen Cai, Xinlin Li, Songlin Huang, Xinru Wang, Yilun Xu, Jiayang Liu, Yujie Zhai, Jie Yang, Borui Li, Zhan Fan, Yafang Lu, Lulu Gao, Yutong Han, Qingming Luo, Zhihong Zhang

{"title":"Neuroprotective liver portal area macrophages attenuate hepatic inflammation","authors":"Mengli Xu, Zheng Liu, Qi Pan, Zhenzhen Cai, Xinlin Li, Songlin Huang, Xinru Wang, Yilun Xu, Jiayang Liu, Yujie Zhai, Jie Yang, Borui Li, Zhan Fan, Yafang Lu, Lulu Gao, Yutong Han, Qingming Luo, Zhihong Zhang","doi":"10.1038/s41590-025-02190-y","DOIUrl":"https://doi.org/10.1038/s41590-025-02190-y","url":null,"abstract":"Tissue macrophages have an important role in the maintenance of liver homeostasis, and their functions are closely related to spatial localization. Here, through integration of whole liver lobe imaging and single-cell RNA sequencing analysis of CX3CR1+ cells in the mouse liver, we identified a dense network of CX3CR1+CD63+ liver portal area macrophages (LPAMs) that exhibited transcriptional and spatial differences compared with CX3CR1+CD207+ liver capsular macrophages. The survival of LPAMs was dependent on colony-stimulating factor 1 receptor (CSF1R). LPAMs colonized the hepatic portal area of mice after birth and were replenished from bone-marrow-derived cells during liver homeostasis. LPAMs efficiently captured antigens derived from hepatocytes and closely interacted with sympathetic nerves around the portal vein. Deletion of LPAMs led to increased neutrophil infiltration and worsened sympathetic nerve degeneration during hepatic nonalcoholic steatohepatitis. In summary, our results provide insights into a distinct subset of nerve-associated portal macrophages that function to maintain liver immune homeostasis.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"24 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144319295","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

Portal macrophages maintain liver homeostasis

IF 30.5 1区医学

Nature Immunology Pub Date : 2025-06-19 DOI: 10.1038/s41590-025-02184-w

Sheau Yng Lim, Hwee Ying Lim, Veronique Angeli

引用次数: 0

Peripheral infection wires T cells in the brain 外周感染会连接大脑中的T细胞

IF 30.5 1区医学

Nature Immunology Pub Date : 2025-06-18 DOI: 10.1038/s41590-025-02200-z

Alexis M. Johnson, John R. Lukens

引用次数: 0

CARD11 signaling regulates CD8+ T cell tumoricidal function CARD11信号调节CD8+ T细胞的杀肿瘤功能

IF 30.5 1区医学

Nature Immunology Pub Date : 2025-06-18 DOI: 10.1038/s41590-025-02192-w

Yu Hu, Qifan Zhao, Yingquan Qin, Song Mei, Benyu Wang, Haoyue Zhou, Linli Han, Yi Zang, Liangjiao Yao, Zhe He, Yingyi Li, Hecheng Li, Peng Zhang, Yan Zhang, Michael J. Lenardo, Wei Lu

{"title":"CARD11 signaling regulates CD8+ T cell tumoricidal function","authors":"Yu Hu, Qifan Zhao, Yingquan Qin, Song Mei, Benyu Wang, Haoyue Zhou, Linli Han, Yi Zang, Liangjiao Yao, Zhe He, Yingyi Li, Hecheng Li, Peng Zhang, Yan Zhang, Michael J. Lenardo, Wei Lu","doi":"10.1038/s41590-025-02192-w","DOIUrl":"https://doi.org/10.1038/s41590-025-02192-w","url":null,"abstract":"Chronic stimulation in the tumor microenvironment can induce exhausted CD8+ T (Tex) cells that have limited tumoricidal activity. Here, we show an inverse correlation between signal strength and Tex cell differentiation by using patient-derived mutations in the T cell receptor (TCR)-signaling protein CARD11. Strong TCR signaling of the E134G mutant inhibits Tex cell differentiation and increases tumor growth. Conversely, reduced TCR signaling by the K215M mutant promotes Tex cell differentiation with better tumor control. These effects are a result of a restrained tumor-specific TCR clonal repertoire of Tex cells that reduces immunopathology but compromises tumoricidal activity. Mechanistically, CARD11 is a TCR signal-strength sensor, controlling the TCR repertoire of Tex cells by regulating the trafficking and homeostasis of the TCR complex. Expanding the TCR repertoire during Tex cell differentiation by fine-tuning the CARD11-mediated TCR signal strength reinvigorated antitumor function and indicates a strategy for improving cancer immunotherapy.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"21 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144311689","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