Pub Date : 2025-09-12DOI: 10.1016/j.immuni.2025.08.009
Guanrui Liao, Tsuguhisa Nakayama, Bokai Zhu, Ivan T. Lee, Jason Yeung, Yao Yu Yeo, Yuzhou Chang, Cankun Wang, Steven Chun-Kang Liao, Dingani Nkosi, Axel Renteria, Dawn T. Bravo, Jonathan B. Overdevest, Carol H. Yan, David Zarabanda, Philip A. Gall, Sachi S. Dholakia, Nicole A. Borchard, Angela Yang, Dayoung Kim, Sizun Jiang
Chronic rhinosinusitis (CRS) is a common chronic inflammatory disease of the sinonasal cavity affecting millions worldwide. Its complex pathophysiology remains poorly understood, with emerging evidence implicating interactions between diverse immune and epithelial cells in disease progression. We applied single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics to both dissociated and intact human tissues from individuals with CRS with and without nasal polyps and compared them with controls. We revealed mechanisms of macrophage-eosinophil recruitment, CD4+ and CD8+ T cell dysregulation, and mast cell enrichment. We identified key immune-epithelial interactions in tissue remodeling, particularly involving basal progenitor and tuft cells. A distinct basal cell trajectory was implicated in nasal polyp formation. Orthogonal validation with spatial transcriptomics from >100 individuals with CRS revealed conserved tissue remodeling features. Our study provides insights into CRS pathophysiology, highlighting immune-epithelial interactions as potential therapeutic targets in chronic inflammation, also serving as a resource for dissecting immune disease mechanisms.
{"title":"Multi-scaled transcriptomics of chronically inflamed nasal epithelium reveals immune-epithelial dynamics and tissue remodeling in nasal polyp formation","authors":"Guanrui Liao, Tsuguhisa Nakayama, Bokai Zhu, Ivan T. Lee, Jason Yeung, Yao Yu Yeo, Yuzhou Chang, Cankun Wang, Steven Chun-Kang Liao, Dingani Nkosi, Axel Renteria, Dawn T. Bravo, Jonathan B. Overdevest, Carol H. Yan, David Zarabanda, Philip A. Gall, Sachi S. Dholakia, Nicole A. Borchard, Angela Yang, Dayoung Kim, Sizun Jiang","doi":"10.1016/j.immuni.2025.08.009","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.08.009","url":null,"abstract":"Chronic rhinosinusitis (CRS) is a common chronic inflammatory disease of the sinonasal cavity affecting millions worldwide. Its complex pathophysiology remains poorly understood, with emerging evidence implicating interactions between diverse immune and epithelial cells in disease progression. We applied single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics to both dissociated and intact human tissues from individuals with CRS with and without nasal polyps and compared them with controls. We revealed mechanisms of macrophage-eosinophil recruitment, CD4<sup>+</sup> and CD8<sup>+</sup> T cell dysregulation, and mast cell enrichment. We identified key immune-epithelial interactions in tissue remodeling, particularly involving basal progenitor and tuft cells. A distinct basal cell trajectory was implicated in nasal polyp formation. Orthogonal validation with spatial transcriptomics from >100 individuals with CRS revealed conserved tissue remodeling features. Our study provides insights into CRS pathophysiology, highlighting immune-epithelial interactions as potential therapeutic targets in chronic inflammation, also serving as a resource for dissecting immune disease mechanisms.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"51 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145043310","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 : 2025-09-09DOI: 10.1016/j.immuni.2025.08.011
Petter Brodin, Feng Wang, Bo Zhu, Timothy Hammond, Catherine P. Lu, Florian Wimmers, Alexandra Zhernakova, Wanlu Liu, Kari Nadeau, Martin Prlic
Clinical and therapeutic innovation relies on our understanding of the human immune system. Here, investigators discuss current and developing methodologies to study human immunity, and the importance of thoughtful experimental design and sample collection for advancing the frontier of immunology research.
{"title":"Approaches toward understanding human immunity","authors":"Petter Brodin, Feng Wang, Bo Zhu, Timothy Hammond, Catherine P. Lu, Florian Wimmers, Alexandra Zhernakova, Wanlu Liu, Kari Nadeau, Martin Prlic","doi":"10.1016/j.immuni.2025.08.011","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.08.011","url":null,"abstract":"Clinical and therapeutic innovation relies on our understanding of the human immune system. Here, investigators discuss current and developing methodologies to study human immunity, and the importance of thoughtful experimental design and sample collection for advancing the frontier of immunology research.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"72 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145018081","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 : 2025-09-09DOI: 10.1016/j.immuni.2025.08.013
Carolyn A. Thomson, Kathy D. McCoy
The immune system of wildlings—mice with a wild-derived microbiota—has features similar to that in adult humans. In this issue of Immunity, Oh et al. demonstrate the long-term stability of wildling microbiota and immune traits, establishing these mice as an accessible, transferable model for immunology research.
{"title":"Born to be wild: Wildings stay the course","authors":"Carolyn A. Thomson, Kathy D. McCoy","doi":"10.1016/j.immuni.2025.08.013","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.08.013","url":null,"abstract":"The immune system of wildlings—mice with a wild-derived microbiota—has features similar to that in adult humans. In this issue of <em>Immunity</em>, Oh et al. demonstrate the long-term stability of wildling microbiota and immune traits, establishing these mice as an accessible, transferable model for immunology research.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"14 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145018085","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}
The persistence of tissue-specific chronic inflammation results from an interplay of genetic and environmental factors. How these factors coordinate to sustain pathology in chronic conditions like psoriasis is not well resolved. Using a Card14E138A/+ murine model of psoriasis, we found that spontaneous skin inflammation reshaped not only the immune architecture in the skin but also systemic metabolites. We identified indole-producing microbiota in the gut—but not the skin—as drivers of psoriatic inflammation. Mechanistically, indole-producing intestinal microbes promoted host indoxyl sulfate (I3S) biosynthesis via a metabolic relay. I3S signaled through the aryl hydrocarbon receptor (AHR) in skin T helper (Th) 17 cells to modulate chromatin accessibility, which potentiated skin inflammation. In human psoriasis cohorts, serum I3S levels correlated with disease severity. In summary, our study uncovers a mechanistic link between gut microbial factors and skin inflammation, highlighting microbiota and metabolites as potential therapeutic targets for psoriasis.
{"title":"Gut microbe-derived metabolites drive psoriatic inflammation via modulation of skin Th17 cells","authors":"Chenliang Wang, Shangzhi Dai, Shanshan Zhang, Zheyu Zheng, Zhixiao Zhou, Zhuojing Chen, Mingchao Wang, Yumei Gao, Yan Xin, Weihang Xiong, Sihan Xiong, Xiaowen Wang, Aiping Wang, Xueqiang Zhao, Hang Li, Xin Lin","doi":"10.1016/j.immuni.2025.08.006","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.08.006","url":null,"abstract":"The persistence of tissue-specific chronic inflammation results from an interplay of genetic and environmental factors. How these factors coordinate to sustain pathology in chronic conditions like psoriasis is not well resolved. Using a <em>Card14</em><sup>E138A/+</sup> murine model of psoriasis, we found that spontaneous skin inflammation reshaped not only the immune architecture in the skin but also systemic metabolites. We identified indole-producing microbiota in the gut—but not the skin—as drivers of psoriatic inflammation. Mechanistically, indole-producing intestinal microbes promoted host indoxyl sulfate (I3S) biosynthesis via a metabolic relay. I3S signaled through the aryl hydrocarbon receptor (AHR) in skin T helper (Th) 17 cells to modulate chromatin accessibility, which potentiated skin inflammation. In human psoriasis cohorts, serum I3S levels correlated with disease severity. In summary, our study uncovers a mechanistic link between gut microbial factors and skin inflammation, highlighting microbiota and metabolites as potential therapeutic targets for psoriasis.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"14 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145018087","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 : 2025-09-09DOI: 10.1016/j.immuni.2025.07.021
Zhengxu Ren, Chenqi Xu
In this issue of Immunity, Lv et al. develop a new CAR-T cell culture system that uses integrin mechanical signaling to boost CAR-T proliferation while preserving stemness, pointing out a new direction of CAR-T manufacturing.
{"title":"Touch of youth: Mechanosensing expands stem-like CAR-T cells","authors":"Zhengxu Ren, Chenqi Xu","doi":"10.1016/j.immuni.2025.07.021","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.07.021","url":null,"abstract":"In this issue of <em>Immunity</em>, Lv et al. develop a new CAR-T cell culture system that uses integrin mechanical signaling to boost CAR-T proliferation while preserving stemness, pointing out a new direction of CAR-T manufacturing.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"18 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145018084","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 : 2025-09-09Epub Date: 2025-08-18DOI: 10.1016/j.immuni.2025.07.020
Hanne Andersen, Malika Aid, Jonathan J Stone, Claire E Lyons, Autumn Berlied, Joseph Nkolola, Ninaad Lasrado, Max Peterson, Laurent Pessaint, Christopher Kitajewski, Jake Yalley-Ogunro, Maciel Porto, Rebecca Stone, Mehtap Cabus, Daniel Valentin, Alex Van Ry, Brandon Narvaez, Tatyana Orekov, Swagata Kar, Elyse Teow, Katelyn Kouneski, Abismel Ferreira, Jason Velasco, Robert Campbell, Colin Henderson, Wilfred Beah, Grishma Patel, Brad Finneyfrock, Anthony Cook, Soumen Paul, Joost Haasnoot, Lisbeth Ramirez-Carvajal, Martin H Koldijk, Sagrario Arias Rivas, Clarissa M Koch, Jaap Goudsmit, Mark G Lewis, Amanda J Martinot, Dan H Barouch
The H5N1 avian influenza virus clade 2.3.4.4b outbreak represents a major pandemic threat for humans, with some reported cases of severe and fatal respiratory illness. A key unanswered question is the pathogenesis of severe H5N1 disease following respiratory infection. In this study, we explored mechanisms of pathogenesis of severe H5N1 disease in cynomolgus and rhesus macaques following infection with the H5N1 isolate A/Texas/37/2024 (huTX37-H5N1). Cynomolgus macaques developed severe pneumonia that was lethal in 100% of macaques by 7 days post-infection. By contrast, rhesus macaques demonstrated dose-dependent mortality, and surviving animals showed protective immunity against high-dose re-challenge. A multi-omics analysis demonstrated that H5N1 infection was characterized by robust induction of proinflammatory cytokines, innate immune cells, complement, coagulation, apoptosis, and immune exhaustion pathways. Taken together, our data indicate inflammation and immune dysregulation as key mechanisms of H5N1 pathogenesis in nonhuman primates.
{"title":"Immunopathogenesis of lethal H5N1 avian influenza virus clade 2.3.4.4b infection in macaques.","authors":"Hanne Andersen, Malika Aid, Jonathan J Stone, Claire E Lyons, Autumn Berlied, Joseph Nkolola, Ninaad Lasrado, Max Peterson, Laurent Pessaint, Christopher Kitajewski, Jake Yalley-Ogunro, Maciel Porto, Rebecca Stone, Mehtap Cabus, Daniel Valentin, Alex Van Ry, Brandon Narvaez, Tatyana Orekov, Swagata Kar, Elyse Teow, Katelyn Kouneski, Abismel Ferreira, Jason Velasco, Robert Campbell, Colin Henderson, Wilfred Beah, Grishma Patel, Brad Finneyfrock, Anthony Cook, Soumen Paul, Joost Haasnoot, Lisbeth Ramirez-Carvajal, Martin H Koldijk, Sagrario Arias Rivas, Clarissa M Koch, Jaap Goudsmit, Mark G Lewis, Amanda J Martinot, Dan H Barouch","doi":"10.1016/j.immuni.2025.07.020","DOIUrl":"10.1016/j.immuni.2025.07.020","url":null,"abstract":"<p><p>The H5N1 avian influenza virus clade 2.3.4.4b outbreak represents a major pandemic threat for humans, with some reported cases of severe and fatal respiratory illness. A key unanswered question is the pathogenesis of severe H5N1 disease following respiratory infection. In this study, we explored mechanisms of pathogenesis of severe H5N1 disease in cynomolgus and rhesus macaques following infection with the H5N1 isolate A/Texas/37/2024 (huTX37-H5N1). Cynomolgus macaques developed severe pneumonia that was lethal in 100% of macaques by 7 days post-infection. By contrast, rhesus macaques demonstrated dose-dependent mortality, and surviving animals showed protective immunity against high-dose re-challenge. A multi-omics analysis demonstrated that H5N1 infection was characterized by robust induction of proinflammatory cytokines, innate immune cells, complement, coagulation, apoptosis, and immune exhaustion pathways. Taken together, our data indicate inflammation and immune dysregulation as key mechanisms of H5N1 pathogenesis in nonhuman primates.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":" ","pages":"2157-2165.e5"},"PeriodicalIF":26.3,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144882735","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 : 2025-09-09DOI: 10.1016/j.immuni.2025.08.010
Guillem Estivill, Anna C. Obenauf
In a recent issue of Nature, Adrover et al. report a neutrophil subset that induces pleomorphic tumor necrosis through neutrophil extracellular trap (NET)-mediated vascular occlusion. This process drives epithelial-to-mesenchymal transition (EMT) and metastasis of perinecrotic cancer cells, reframing necrosis as an active process and uncovering targetable mechanisms to combat cancer dissemination.
{"title":"Trio fatale: Neutrophils, NETs, and necrosis","authors":"Guillem Estivill, Anna C. Obenauf","doi":"10.1016/j.immuni.2025.08.010","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.08.010","url":null,"abstract":"In a recent issue of <em>Nature</em>, Adrover et al. report a neutrophil subset that induces pleomorphic tumor necrosis through neutrophil extracellular trap (NET)-mediated vascular occlusion. This process drives epithelial-to-mesenchymal transition (EMT) and metastasis of perinecrotic cancer cells, reframing necrosis as an active process and uncovering targetable mechanisms to combat cancer dissemination.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"14 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145018086","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 : 2025-09-09DOI: 10.1016/j.immuni.2025.08.008
Dayana B. Rivadeneira, Sanjana Thosar, Kevin Quann, William G. Gunn, Victoria G. Dean, Bingxian Xie, Angelina Parise, Andrew C. McGovern, Kellie Spahr, Konstantinos Lontos, Ryan P. Barnes, Marcel P. Bruchez, Patricia L. Opresko, Greg M. Delgoffe
The tumor microenvironment (TME) imposes immunologic and metabolic stresses sufficient to deviate immune cell differentiation into dysfunctional states. Oxidative stress originating in the mitochondria can induce DNA damage, most notably telomeres. Here, we show that dysfunctional T cells in cancer did not harbor short telomeres indicative of replicative senescence but rather harbored damaged telomeres, which we hypothesized arose from oxidative stress. Chemo-optogenetic induction of highly localized mitochondrial or telomeric reactive oxygen species (ROS) using a photosensitizer caused the accumulation of DNA damage at telomeres, driving telomere fragility. Telomeric damage was sufficient to drive a dysfunctional state in T cells, showing a diminished capability for cytokine production. Localizing the ROS scavenger GPX1 directly to telomeres reduced telomere fragility in tumors and improved the function of therapeutic T cells. Protecting telomeres through expression of a telomere-targeted antioxidant may preserve T cell function in the TME and drive superior responses to cell therapies.
{"title":"Oxidative-stress-induced telomere instability drives T cell dysfunction in cancer","authors":"Dayana B. Rivadeneira, Sanjana Thosar, Kevin Quann, William G. Gunn, Victoria G. Dean, Bingxian Xie, Angelina Parise, Andrew C. McGovern, Kellie Spahr, Konstantinos Lontos, Ryan P. Barnes, Marcel P. Bruchez, Patricia L. Opresko, Greg M. Delgoffe","doi":"10.1016/j.immuni.2025.08.008","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.08.008","url":null,"abstract":"The tumor microenvironment (TME) imposes immunologic and metabolic stresses sufficient to deviate immune cell differentiation into dysfunctional states. Oxidative stress originating in the mitochondria can induce DNA damage, most notably telomeres. Here, we show that dysfunctional T cells in cancer did not harbor short telomeres indicative of replicative senescence but rather harbored damaged telomeres, which we hypothesized arose from oxidative stress. Chemo-optogenetic induction of highly localized mitochondrial or telomeric reactive oxygen species (ROS) using a photosensitizer caused the accumulation of DNA damage at telomeres, driving telomere fragility. Telomeric damage was sufficient to drive a dysfunctional state in T cells, showing a diminished capability for cytokine production. Localizing the ROS scavenger GPX1 directly to telomeres reduced telomere fragility in tumors and improved the function of therapeutic T cells. Protecting telomeres through expression of a telomere-targeted antioxidant may preserve T cell function in the TME and drive superior responses to cell therapies.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"13 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145018080","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 : 2025-09-09DOI: 10.1016/j.immuni.2025.07.025
Paola Brescia, Maria Rescigno
The small intestine coordinates nutrient absorption and immune defense, but the epithelial signaling mechanisms bridging these functions are unclear. In this issue of Immunity, Yu et al. reveal a gasdermin-D-driven circuit that links lipid uptake and enterocyte metabolism to γδ T cell maintenance and barrier protection.
{"title":"Gut instincts: Gasdermin D feeds while it fights","authors":"Paola Brescia, Maria Rescigno","doi":"10.1016/j.immuni.2025.07.025","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.07.025","url":null,"abstract":"The small intestine coordinates nutrient absorption and immune defense, but the epithelial signaling mechanisms bridging these functions are unclear. In this issue of <em>Immunity</em>, Yu et al. reveal a gasdermin-D-driven circuit that links lipid uptake and enterocyte metabolism to γδ T cell maintenance and barrier protection.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"11 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145018083","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}
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