Nature Immunology最新文献_第2页

LARP4-mediated hypertranslation drives T cell dysfunction in tumors larp4介导的超翻译驱动肿瘤中的T细胞功能障碍

IF 30.5 1区医学

Nature Immunology Pub Date : 2025-07-22 DOI: 10.1038/s41590-025-02232-5

Yi Liu, Haochen Ni, Jie Li, Jing Yang, Ivann Sekielyk, Bryan E. Snow, Zihao Zhang, Feifan Zhang, Michael St. Paul, Jinyi Han, Meghan Kates, Shaofeng Liu, Yawei Zhang, Zurui Huang, Yin Xu, Samuel D. Saibil, Tak W. Mak, Dali Han, Meng Michelle Xu

{"title":"LARP4-mediated hypertranslation drives T cell dysfunction in tumors","authors":"Yi Liu, Haochen Ni, Jie Li, Jing Yang, Ivann Sekielyk, Bryan E. Snow, Zihao Zhang, Feifan Zhang, Michael St. Paul, Jinyi Han, Meghan Kates, Shaofeng Liu, Yawei Zhang, Zurui Huang, Yin Xu, Samuel D. Saibil, Tak W. Mak, Dali Han, Meng Michelle Xu","doi":"10.1038/s41590-025-02232-5","DOIUrl":"https://doi.org/10.1038/s41590-025-02232-5","url":null,"abstract":"Adoptive T cell therapies have therapeutic potential for treating solid tumors, but long-term efficacy is limited by reduced functional fitness and poor persistence within the tumor microenvironment. Here we show that intratumoral T cells undergo translatome remodeling, transitioning into a hypertranslational state as they acquire dysfunctional traits. The RNA-binding protein LARP4 is a translation regulator that drives hypertranslation and dysfunction by selectively enhancing the translation of nuclear-encoded oxidative phosphorylation (OXPHOS) mRNAs in exhausted T cells, disrupting OXPHOS subunit balance and causing mitochondrial dysfunction. Knockout of Larp4 in tumor-specific CD8+ T cells reduces hypertranslation, restores mitochondrial function, mitigates exhaustion and enhances effector persistence, resulting in enhanced anti-tumor responses. Additionally, LARP4 knockdown in chimeric antigen receptor T cells prevents terminal exhaustion and improves the response to liquid and solid tumors. This study highlights translation dysregulation as a determinant of T cell dysfunction in tumors.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"14 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144677307","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

T cells require mitochondria to proliferate, function and generate memory T细胞需要线粒体来增殖、发挥功能和产生记忆

IF 30.5 1区医学

Nature Immunology Pub Date : 2025-07-22 DOI: 10.1038/s41590-025-02226-3

引用次数: 0

Spatial proteomics of Alzheimer’s disease-specific human microglial states 阿尔茨海默病特异性人类小胶质细胞状态的空间蛋白质组学

IF 30.5 1区医学

Nature Immunology Pub Date : 2025-07-22 DOI: 10.1038/s41590-025-02203-w

Dunja Mrdjen, Bryan J. Cannon, Meelad Amouzgar, YeEun Kim, Candace Liu, Kausalia Vijayaragavan, Christine Camacho, Angie Spence, Erin F. McCaffrey, Anusha Bharadwaj, Dmitry Tebaykin, Syed Bukhari, Marc Bosse, Felix J. Hartmann, Adam Kagel, John Paul Oliveria, Koya Yakabi, Geidy E. Serrano, Maria M. Corrada, Claudia H. Kawas, Robert Tibshirani, Thomas G. Beach, M. Ryan Corces, Will Greenleaf, R. Michael Angelo, Thomas Montine, Sean C. Bendall

{"title":"Spatial proteomics of Alzheimer’s disease-specific human microglial states","authors":"Dunja Mrdjen, Bryan J. Cannon, Meelad Amouzgar, YeEun Kim, Candace Liu, Kausalia Vijayaragavan, Christine Camacho, Angie Spence, Erin F. McCaffrey, Anusha Bharadwaj, Dmitry Tebaykin, Syed Bukhari, Marc Bosse, Felix J. Hartmann, Adam Kagel, John Paul Oliveria, Koya Yakabi, Geidy E. Serrano, Maria M. Corrada, Claudia H. Kawas, Robert Tibshirani, Thomas G. Beach, M. Ryan Corces, Will Greenleaf, R. Michael Angelo, Thomas Montine, Sean C. Bendall","doi":"10.1038/s41590-025-02203-w","DOIUrl":"https://doi.org/10.1038/s41590-025-02203-w","url":null,"abstract":"Microglia are implicated in aging, neurodegeneration and Alzheimer’s disease (AD). Low-plex protein imaging does not capture cellular states and interactions in the human brain, which differs from rodent models. Here we used multiplexed ion beam imaging to spatially map cellular states and niches in cognitively normal human brains, identifying a spectrum of proteomic microglial profiles. Defined by immune activation states that were skewed across brain regions and compartmentalized according to microenvironments, this spectrum enables the identification of proteomic trends across the microglia of ten cognitively normal individuals and orthogonally with single-nuclei epigenetic analysis, revealing associated molecular functions. Notably, AD tissues exhibit regulatory shifts in the immunologically active cells at the end of the proteomic spectrum, including enrichment of CD33 and CD44 and decreases in HLA-DR, P2RY12 and ApoE expression. These findings establish an in situ, single-cell spatial proteomic framework for AD-specific microglial states.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"52 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144677309","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

The role of gut microbial metabolites in the T cell lifecycle 肠道微生物代谢物在T细胞生命周期中的作用

IF 30.5 1区医学

Nature Immunology Pub Date : 2025-07-21 DOI: 10.1038/s41590-025-02227-2

Melissa Tran, Jun R. Huh, A. Sloan Devlin

引用次数: 0

Giardia helps the immune system pick its battles 贾第鞭毛虫帮助免疫系统选择战斗

IF 30.5 1区医学

Nature Immunology Pub Date : 2025-07-21 DOI: 10.1038/s41590-025-02229-0

Christian A. Howard, Christopher A. Hunter

引用次数: 0

DNA hypomethylation traits define human regulatory T cells in cutaneous tissue and identify their blood recirculating counterparts DNA低甲基化特征定义了皮肤组织中的人类调节性T细胞，并识别了它们的血液循环对应体

IF 30.5 1区医学

Nature Immunology Pub Date : 2025-07-16 DOI: 10.1038/s41590-025-02210-x

Niklas Beumer, Charles D. Imbusch, Tamara Kaufmann, Lisa Schmidleithner, Kathrin Gütter, Philipp Stüve, Harriet Marchel, Dieter Weichenhan, Marion Bähr, Brigitte Ruhland, Federico Marini, Lieke Sanderink, Uwe Ritter, Malte Simon, Kathrin Luise Braband, Morten Michael Voss, Sara Salome Helbich, Delia Mihaela Mihoc, Agnes Hotz-Wagenblatt, Hadrian Nassabi, Andreas Eigenberger, Lukas Prantl, Claudia Gebhard, Michael Rehli, Nicholas Strieder, Kartikeya Singh, Christian Schmidl, Christoph Plass, Jochen Huehn, Thomas Hehlgans, Julia K. Polansky, Benedikt Brors, Michael Delacher, Markus Feuerer

{"title":"DNA hypomethylation traits define human regulatory T cells in cutaneous tissue and identify their blood recirculating counterparts","authors":"Niklas Beumer, Charles D. Imbusch, Tamara Kaufmann, Lisa Schmidleithner, Kathrin Gütter, Philipp Stüve, Harriet Marchel, Dieter Weichenhan, Marion Bähr, Brigitte Ruhland, Federico Marini, Lieke Sanderink, Uwe Ritter, Malte Simon, Kathrin Luise Braband, Morten Michael Voss, Sara Salome Helbich, Delia Mihaela Mihoc, Agnes Hotz-Wagenblatt, Hadrian Nassabi, Andreas Eigenberger, Lukas Prantl, Claudia Gebhard, Michael Rehli, Nicholas Strieder, Kartikeya Singh, Christian Schmidl, Christoph Plass, Jochen Huehn, Thomas Hehlgans, Julia K. Polansky, Benedikt Brors, Michael Delacher, Markus Feuerer","doi":"10.1038/s41590-025-02210-x","DOIUrl":"https://doi.org/10.1038/s41590-025-02210-x","url":null,"abstract":"CD4+ regulatory T (Treg) cells in tissues play crucial immunoregulatory and regenerative roles. Despite their importance, the epigenetics and differentiation of human tissue Treg cells are incompletely understood. Here, we performed genome-wide DNA methylation analysis of human Treg cells from skin and blood and integrated these data into a multiomic framework, including chromatin accessibility and gene expression. This analysis identified programs that governed the tissue adaptation of skin Treg cells. We found that subfamilies of transposable elements represented a major constituent of the hypomethylated landscape in tissue Treg cells. Based on T cell antigen receptor sequence and DNA hypomethylation homologies, our data indicate that blood CCR8+ Treg cells contain recirculating human skin Treg cells. Conversely, differences in chromatin accessibility and gene expression suggest a certain reversal of the tissue adaptation program during recirculation. Our findings provide insights into the biology of human tissue Treg cells, which may help harness these cells for therapeutic purposes.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"108 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144639727","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

Mitochondrial respiration is necessary for CD8+ T cell proliferation and cell fate 线粒体呼吸是CD8+ T细胞增殖和细胞命运的必要条件

IF 30.5 1区医学

Nature Immunology Pub Date : 2025-07-16 DOI: 10.1038/s41590-025-02202-x

Elizabeth M. Steinert, Beatriz Furtado Bruza, Veronika D. Danchine, Rogan A. Grant, Karthik Vasan, Arjun Kharel, Yuqi Zhang, Weiguo Cui, Marten Szibor, Samuel E. Weinberg, Navdeep S. Chandel

{"title":"Mitochondrial respiration is necessary for CD8+ T cell proliferation and cell fate","authors":"Elizabeth M. Steinert, Beatriz Furtado Bruza, Veronika D. Danchine, Rogan A. Grant, Karthik Vasan, Arjun Kharel, Yuqi Zhang, Weiguo Cui, Marten Szibor, Samuel E. Weinberg, Navdeep S. Chandel","doi":"10.1038/s41590-025-02202-x","DOIUrl":"https://doi.org/10.1038/s41590-025-02202-x","url":null,"abstract":"Mitochondrial electron transport chain (ETC) function is linked to the generation of ATP, signaling molecules including reactive oxygen species (ROS), pyrimidines and tricarboxylic acid cycle metabolites1. Mitochondrial electron transport is required for T cell proliferation2,3,4. However, which mitochondrial ETC functions are necessary for each dynamic state of CD8+ T cell responses is unknown. Here we report that impairing mitochondrial complex III function, which diminishes respiration, proton pumping linked to ATP production and superoxide production, decreases peripheral naive numbers, antigen-induced CD8+ T cell proliferation and memory formation. Acute stimulation of mitochondrial complex III-deficient CD8+ T cells induced an exhausted-like phenotype. Expression of Ciona intestinalis alternative oxidase (AOX) in mitochondrial complex III-deficient CD8+ T cells restores respiration without generating ROS or proton pumping, and rescues proliferation and the exhausted phenotype but not naive or memory formation. Thus, T cell development, proliferation and memory formation have distinct requirements for mitochondrial complex III ROS.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"3 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144639726","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

Migrating immune cells globally coordinate protrusive forces 迁移的免疫细胞全局协调突出力

IF 30.5 1区医学

Nature Immunology Pub Date : 2025-07-15 DOI: 10.1038/s41590-025-02211-w

Patricia Reis-Rodrigues, Mario J. Avellaneda, Nikola Canigova, Florian Gaertner, Kari Vaahtomeri, Michael Riedl, Ingrid de Vries, Jack Merrin, Robert Hauschild, Yoshinori Fukui, Alba Juanes Garcia, Michael Sixt

{"title":"Migrating immune cells globally coordinate protrusive forces","authors":"Patricia Reis-Rodrigues, Mario J. Avellaneda, Nikola Canigova, Florian Gaertner, Kari Vaahtomeri, Michael Riedl, Ingrid de Vries, Jack Merrin, Robert Hauschild, Yoshinori Fukui, Alba Juanes Garcia, Michael Sixt","doi":"10.1038/s41590-025-02211-w","DOIUrl":"https://doi.org/10.1038/s41590-025-02211-w","url":null,"abstract":"Efficient immune responses rely on the capacity of leukocytes to traverse diverse and complex tissues. To meet such changing environmental conditions, leukocytes usually adopt an ameboid configuration, using their forward-positioned nucleus as a probe to identify and follow the path of least resistance among pre-existing pores. We show that, in dense environments where even the largest pores preclude free passage, leukocytes position their nucleus behind the centrosome and organelles. The local compression imposed on the cell body by its surroundings triggers assembly of a central F-actin pool, located between cell front and nucleus. Central actin pushes outward to transiently dilate a path for organelles and nucleus. Pools of central and front actin are tightly coupled and experimental depletion of the central pool enhances actin accumulation and protrusion formation at the cell front. Although this shifted balance speeds up cells in permissive environments, migration in restrictive environments is impaired, as the unleashed leading edge dissociates from the trapped cell body. Our findings establish an actin regulatory loop that balances path dilation with advancement of the leading edge to maintain cellular coherence.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"38 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144629717","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

IL-4 impairs the formation of skin-resident memory CD8+ T cells IL-4损害皮肤驻留记忆CD8+ T细胞的形成

IF 30.5 1区医学

Nature Immunology Pub Date : 2025-07-14 DOI: 10.1038/s41590-025-02207-6

Rut Mora-Buch, Maisie E. Lake, Andrea Sama, Alexandra Y. Chasse, Hasan Akbaba, Vinidhra Mani, Shannon K. Bromley

{"title":"IL-4 impairs the formation of skin-resident memory CD8+ T cells","authors":"Rut Mora-Buch, Maisie E. Lake, Andrea Sama, Alexandra Y. Chasse, Hasan Akbaba, Vinidhra Mani, Shannon K. Bromley","doi":"10.1038/s41590-025-02207-6","DOIUrl":"https://doi.org/10.1038/s41590-025-02207-6","url":null,"abstract":"Local cytokines, including TGFβ, drive CD8+ tissue-resident memory T (TRM) cell differentiation and long-term persistence within tissues. However, the signals that prevent CD8+ TRM cell formation are not well defined. Here we found that IL-4 suppressed CD8+ T cell acquisition of an epithelial TRM cell phenotype. IL-4 inhibited the expression of TGFβ-induced CD103 and CD49a and increased the expression of Eomes by activated CD8+ T cells in vitro and in vivo. This change in phenotype was correlated with prolonged downregulation of TGFβRII, decreased expression of pSmad2/3 and increased expression of inhibitory Smad7. Naive CD8+ T cells exposed to IL-4 during activation exhibited impaired cutaneous CD103+CD8+ TRM cell formation. Additionally, IL-4 produced within atopic dermatitis lesions decreased the expression of CD103 in infiltrating CD8+ T cells and reduced CD8+ TRM cell formation, resulting in reduced protection from cutaneous herpes simplex virus infection. Together, these findings reveal that IL-4 decreases the responsiveness of CD8+ T cells to TGFβ, resulting in impaired formation of CD8+ TRM cells and impaired CD8+ TRM cell-mediated protection from local infection.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"668 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144622207","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

A liver-centric help circuit revives CD8+ T cells via IL-27 以肝脏为中心的帮助回路通过IL-27激活CD8+ T细胞

IF 30.5 1区医学

Nature Immunology Pub Date : 2025-07-08 DOI: 10.1038/s41590-025-02204-9

引用次数: 0