Nature Immunology最新文献

{"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":"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. In this Resource paper, the authors use MIBI spatial proteomics to map microglial cell states in brains from cognitively normal humans and those with Alzheimer’s disease.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 8","pages":"1397-1410"},"PeriodicalIF":27.6,"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}

{"title":"The role of gut microbial metabolites in the T cell lifecycle","authors":"Melissa Tran, Jun R. Huh, A. Sloan Devlin","doi":"10.1038/s41590-025-02227-2","DOIUrl":"10.1038/s41590-025-02227-2","url":null,"abstract":"T cells, a cornerstone of the adaptive immune system, have pivotal roles at the host–microorganism interface. The gut microbiome profoundly influences T cell biology by producing a diverse repertoire of small molecules that are sensed by host cells. These microbial metabolites regulate all aspects of the T cell lifecycle, from cell development to differentiation and activation to exhaustion. Recent studies have uncovered microbially derived molecules, including short-chain fatty acids, secondary bile acids and tryptophan metabolites, as potent regulators of T cell function. However, the full scope of microbial metabolite–T cell interactions remains largely unexplored. This Review presents a mechanistic framework linking gut microbial metabolites to discrete stages of T cell fate and function. Expanding our understanding of these intricate host–microbiome interactions will reveal new aspects of immune regulation and inspire microbiome-guided therapeutic strategies for infections, autoimmune diseases and cancer immunotherapy. Tran et al. discuss the role of the gut microbiome and gut microbiome-derived metabolites in T cell biology.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 8","pages":"1246-1257"},"PeriodicalIF":27.6,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144669921","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}

{"title":"Giardia helps the immune system pick its battles","authors":"Christian A. Howard, Christopher A. Hunter","doi":"10.1038/s41590-025-02229-0","DOIUrl":"10.1038/s41590-025-02229-0","url":null,"abstract":"Giardia intestinalis is a protozoan parasite that can cause severe enteric disease. The immune response to this organism provides unexpected benefits to limit gut inflammation.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 8","pages":"1217-1218"},"PeriodicalIF":27.6,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144669920","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}

{"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":"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. Feuerer and colleagues use multiomic analyses to identify DNA methylation, chromatin accessibility and gene expression programs that govern the tissue adaptation of human skin Treg cells.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 8","pages":"1315-1328"},"PeriodicalIF":27.6,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41590-025-02210-x.pdf","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"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":"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 proliferation2–4. 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. Mitochondrial electron transport chain activity provides ATP, generates superoxide, regulates apoptosis and provides the biosynthetic building blocks for growing cells. Here Steinert et al. genetically dissect these functions and find that, in the absence of mitochondrial complex III function, acute stimulation results in CD8+ T cell exhaustion and that mitochondrial complex III reactive oxygen species are required for establishment of naive and memory populations.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 8","pages":"1267-1274"},"PeriodicalIF":27.6,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41590-025-02202-x.pdf","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"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":"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. Sixt and colleagues show that, in environments where even the largest pores preclude free passage, leukocytes position their nucleus behind the centrosome and assemble a central F-actin pool that pushes outward to transiently dilate a path for the nucleus.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 8","pages":"1258-1266"},"PeriodicalIF":27.6,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41590-025-02211-w.pdf","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"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":"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. Bromley and colleagues show that IL-4 decreases the responsiveness of CD8+ T cells to TGFβ, resulting in impaired formation of CD8+ TRM cells.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 8","pages":"1329-1338"},"PeriodicalIF":27.6,"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}

{"title":"A liver-centric help circuit revives CD8+ T cells via IL-27","authors":"","doi":"10.1038/s41590-025-02204-9","DOIUrl":"10.1038/s41590-025-02204-9","url":null,"abstract":"Effector CD4⁺ T cells restore antiviral CD8⁺ T cell function in the liver by licensing Kupffer cells via CD40–CD40L interactions. This triggers IL-27 production and reprograms the hepatic immune environment. This liver-intrinsic pathway of T cell help is relevant for chronic hepatitis B virus infection and may apply to other conditions with persistent antigen stimulation, such as cancer.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 8","pages":"1229-1230"},"PeriodicalIF":27.6,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144577941","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}

{"title":"Author Correction: SKAP-55 regulates integrin adhesion and formation of T cell–APC conjugates","authors":"Hongyan Wang, Eun-Yi Moon, Abdallah Azouz, Xiang Wu, Andrew Smith, Helga Schneider, Nancy Hogg, Christopher E. Rudd","doi":"10.1038/s41590-025-02239-y","DOIUrl":"10.1038/s41590-025-02239-y","url":null,"abstract":"","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 8","pages":"1423-1423"},"PeriodicalIF":27.6,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41590-025-02239-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144577940","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}

{"title":"CD4+ T cells license Kupffer cells to reverse CD8+ T cell dysfunction induced by hepatocellular priming","authors":"Valentina Venzin, Cristian G. Beccaria, Chiara Perucchini, Pietro Delfino, Elisa B. Bono, Leonardo Giustini, Federica Moalli, Marta Grillo, Valeria Fumagalli, Chiara Laura, Pietro Di Lucia, Katharina Reinhard, Jutta Petschenka, Tana Annmarie Omokoko, Anna Celant, Sabrina Ottolini, Keigo Kawashima, Micol Ravà, Marco De Giovanni, Donato Inverso, Mirela Kuka, Patrick T. F. Kennedy, Martin Guilliams, Giulia Casorati, Federica Pedica, Maurilio Ponzoni, Uğur Şahin, Nina Le Bert, Antonio Bertoletti, Fulvia Vascotto, Luca G. Guidotti, Matteo Iannacone","doi":"10.1038/s41590-025-02199-3","DOIUrl":"10.1038/s41590-025-02199-3","url":null,"abstract":"Chronic hepatitis B virus (HBV) infection is marked by dysfunctional HBV-specific CD8+ T cells, and restoring their effector activity is a major therapeutic goal. Here, we generated HBV-specific CD4+ T cell receptor transgenic mice to show that CD4+ effector T cells can prevent and reverse the CD8⁺ T cell dysfunction induced by hepatocellular priming. This rescue enhances antiviral CD8+ T cell function and suppresses viral replication. CD4+ T cell help occurs directly within the liver, independent of secondary lymphoid organs, and requires local antigen recognition. Kupffer cells, rather than dendritic cells, are the critical antigen-presenting platform. CD4+ T cells license Kupffer cells via CD40–CD40L interactions, triggering interleukin (IL)-12 and IL-27 production. IL-12 expands the CD4+ T cell pool, while IL-27 is essential for CD8+ T cell rescue. Exogenous IL-27 similarly restores HBV-specific CD8+ T cell function in mice and in T cells isolated from chronically infected patients. These findings identify IL-27 as a tractable immunotherapeutic target in chronic HBV infection. Here the authors show that CD4+ effector T cells prevent or reverse CD8+ T cell dysfunction by licensing Kupffer cells to trigger IL-27 production, defining a liver-specific immune circuit and a potential target for chronic HBV therapeutics.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 8","pages":"1352-1366"},"PeriodicalIF":27.6,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41590-025-02199-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144515472","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}