Pub Date : 2026-09-04DOI: 10.1126/sciimmunol.aea1426
Mathieu Deygas, Mathilde Bernard, Pierre Nivoit, Henry De Belly, Alexandre Deslys, Theresa Jakuszeit, Damien Cuvelier, Moira Garcia-Gomez, Lucie Barbier, Li Wang, Mathieu Maurin, Emmanuel Tejerina, Oumaima Baaziz, Emmanuel Terriac, Rafaele Attia, Anna Kniazeva, Serge Garbay, Marina Ortega-Zapero, Angela Saez, Raquel Gomez-Bris, Pilar Gonzalo, Jose M. Gonzalez-Granado, Vicente Andrés, Orion D. Weiner, Ana-Maria Lennon-Duménil, Guillaume Duménil, Matthieu Piel, Pablo Vargas
To reach inflamed tissues, neutrophils must traverse capillaries as narrow as 2 micrometers. However, how they do so without compromising blood flow or capillary function has remained unclear. By combining intravital live-cell imaging with biomimetic microdevices, we show that neutrophils maintain migration speed in capillaries across increasing levels of confinement. This behavior was not shared by other leukocytes and was independent of nuclear properties. Instead, confinement rapidly engaged Rho-dependent actomyosin contractility at the cell rear, thereby offsetting the increased mechanical resistance imposed by confinement. Disrupting this adaptive response caused neutrophil jamming and eventual occlusion of confined capillary-like networks. These findings identify a neutrophil-intrinsic mechanism that couples capillary confinement to rapid migratory adaptation, helping preserve vascular patency and potentially limiting tissue dysfunction during inflammation.
{"title":"Adaptive motility enables neutrophils to rapidly navigate confined capillaries","authors":"Mathieu Deygas, Mathilde Bernard, Pierre Nivoit, Henry De Belly, Alexandre Deslys, Theresa Jakuszeit, Damien Cuvelier, Moira Garcia-Gomez, Lucie Barbier, Li Wang, Mathieu Maurin, Emmanuel Tejerina, Oumaima Baaziz, Emmanuel Terriac, Rafaele Attia, Anna Kniazeva, Serge Garbay, Marina Ortega-Zapero, Angela Saez, Raquel Gomez-Bris, Pilar Gonzalo, Jose M. Gonzalez-Granado, Vicente Andrés, Orion D. Weiner, Ana-Maria Lennon-Duménil, Guillaume Duménil, Matthieu Piel, Pablo Vargas","doi":"10.1126/sciimmunol.aea1426","DOIUrl":"https://doi.org/10.1126/sciimmunol.aea1426","url":null,"abstract":"To reach inflamed tissues, neutrophils must traverse capillaries as narrow as 2 micrometers. However, how they do so without compromising blood flow or capillary function has remained unclear. By combining intravital live-cell imaging with biomimetic microdevices, we show that neutrophils maintain migration speed in capillaries across increasing levels of confinement. This behavior was not shared by other leukocytes and was independent of nuclear properties. Instead, confinement rapidly engaged Rho-dependent actomyosin contractility at the cell rear, thereby offsetting the increased mechanical resistance imposed by confinement. Disrupting this adaptive response caused neutrophil jamming and eventual occlusion of confined capillary-like networks. These findings identify a neutrophil-intrinsic mechanism that couples capillary confinement to rapid migratory adaptation, helping preserve vascular patency and potentially limiting tissue dysfunction during inflammation.","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"7 1","pages":""},"PeriodicalIF":24.8,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148890199","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 : 2026-09-04DOI: 10.1126/sciimmunol.ael7920
Lauren B Rodda
Both memory and de novo antibody clones neutralize SARS-CoV-2 variants, but with distinct origins and targets.
记忆抗体和新生抗体克隆都能中和SARS-CoV-2变体，但它们的起源和目标不同。
{"title":"Old dog with new tricks: SARS-CoV-2 variant-specific B cells complement imprinted memory.","authors":"Lauren B Rodda","doi":"10.1126/sciimmunol.ael7920","DOIUrl":"https://doi.org/10.1126/sciimmunol.ael7920","url":null,"abstract":"<p><p>Both memory and de novo antibody clones neutralize SARS-CoV-2 variants, but with distinct origins and targets.</p>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 123","pages":"eael7920"},"PeriodicalIF":16.4,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148892363","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 : 2026-09-04DOI: 10.1126/sciimmunol.ael7921
Oluwagbemiga A Ojo, Stephanie C Eisenbarth
Germinal center-experienced IgM memory B cells require BCL6 but not TFH cells.
生发中心经历IgM记忆的B细胞需要BCL6而不需要TFH细胞。
{"title":"The many roads to B cell memory.","authors":"Oluwagbemiga A Ojo, Stephanie C Eisenbarth","doi":"10.1126/sciimmunol.ael7921","DOIUrl":"https://doi.org/10.1126/sciimmunol.ael7921","url":null,"abstract":"<p><p>Germinal center-experienced IgM memory B cells require BCL6 but not T<sub>FH</sub> cells.</p>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 123","pages":"eael7921"},"PeriodicalIF":16.4,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148892411","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 : 2026-09-04DOI: 10.1126/sciimmunol.aeb9244
Laura Pena-Couso, Jon Sicilia, Sofía Vieto, Roberto Silva-Rojas, María Sánchez-Díaz, Enrique Calvo, Rafael Romero-Becerra, Cintia Folgueira, Leticia Herrera-Melle, Raquel Justo-Méndez, Xiaotong Hong, Silvia Campanario, Juan A. López, Georgiana Crainiciuc, María Gil, Sandra Martín-Salamanca, Vera Lukesova, Jessica Segalés, Antonio L. Serrano, Iván Ballesteros, Marta León, Macarena de Andrés-Laguillo, Sebastian A. Stifter, Lorena Esteban-Martínez, Joan Isern, Jorge Alegre-Cebollada, Miguel Torres, Melanie Greter, Jesús Vázquez, José A. Enríquez, Guadalupe Sabio-Buzo, Pura Muñoz-Cánoves, Andrés Hidalgo, José A. Nicolás-Ávila
Removal of cellular waste from the extracellular space is fundamental for tissue health. Because the rate of material ejected by parenchymal cells varies across tissues, we searched for mechanisms that couple waste production and removal. Here, we show that the uptake of parenchyma-released mitochondria by macrophages is prominent across organs that rely on oxidative respiration—including heart, skeletal muscle, and brown adipose tissue—and that macrophage numbers closely align with the mitochondrial activity of each of these organs. We found that the mitochondrial activity of myofibers dictates the abundance of macrophages by modulating colony-stimulating factor 1 (CSF1) availability and the number of CSF1-producing fibroblasts in the tissue. Consequently, inhibition of CSF1–CSF1 receptor (CSF1R) signaling depleted macrophages and collapsed the mitochondrial activity of skeletal muscles. We propose that, by coupling macrophage abundance to the mitochondrial activity of their parenchyma, tissues ensure efficient waste disposal and fitness.
{"title":"Tissue mitochondrial activity dictates the macrophage pool size","authors":"Laura Pena-Couso, Jon Sicilia, Sofía Vieto, Roberto Silva-Rojas, María Sánchez-Díaz, Enrique Calvo, Rafael Romero-Becerra, Cintia Folgueira, Leticia Herrera-Melle, Raquel Justo-Méndez, Xiaotong Hong, Silvia Campanario, Juan A. López, Georgiana Crainiciuc, María Gil, Sandra Martín-Salamanca, Vera Lukesova, Jessica Segalés, Antonio L. Serrano, Iván Ballesteros, Marta León, Macarena de Andrés-Laguillo, Sebastian A. Stifter, Lorena Esteban-Martínez, Joan Isern, Jorge Alegre-Cebollada, Miguel Torres, Melanie Greter, Jesús Vázquez, José A. Enríquez, Guadalupe Sabio-Buzo, Pura Muñoz-Cánoves, Andrés Hidalgo, José A. Nicolás-Ávila","doi":"10.1126/sciimmunol.aeb9244","DOIUrl":"https://doi.org/10.1126/sciimmunol.aeb9244","url":null,"abstract":"Removal of cellular waste from the extracellular space is fundamental for tissue health. Because the rate of material ejected by parenchymal cells varies across tissues, we searched for mechanisms that couple waste production and removal. Here, we show that the uptake of parenchyma-released mitochondria by macrophages is prominent across organs that rely on oxidative respiration—including heart, skeletal muscle, and brown adipose tissue—and that macrophage numbers closely align with the mitochondrial activity of each of these organs. We found that the mitochondrial activity of myofibers dictates the abundance of macrophages by modulating colony-stimulating factor 1 (CSF1) availability and the number of CSF1-producing fibroblasts in the tissue. Consequently, inhibition of CSF1–CSF1 receptor (CSF1R) signaling depleted macrophages and collapsed the mitochondrial activity of skeletal muscles. We propose that, by coupling macrophage abundance to the mitochondrial activity of their parenchyma, tissues ensure efficient waste disposal and fitness.","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"212 1","pages":""},"PeriodicalIF":24.8,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148890217","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 : 2026-09-04DOI: 10.1126/sciimmunol.aee8841
Yuki Tai, Takuya Koike, Hiromi Yamamoto, Kyoko Shida, Niklas Engels, Takeshi Inoue, Wataru Ise, Jürgen Wienands, Tomohiro Kurosaki
During a primary immune response, B cells can undergo isotype switching from an immunoglobulin M (IgM) B cell receptor (BCR) to an IgG BCR. B cells that have switched to IgG give rise to more bone marrow long-lived plasma cells (PCs) compared with those expressing IgM, but how BCR isotype–driven bias occurs remains unclear. Here, we found that IgG1-expressing germinal center B cells presented higher levels of antigen to T follicular helper cells, resulting in greater proliferation of IgG1 PCs than IgM PCs. BCR signaling through IgM induced more Bim-dependent apoptosis in IgM PCs, together leading to the predominance of IgG1 PCs in secondary lymphoid tissues. In addition, IgG1 PCs were more prone to migrating to bone marrow. Hence, our findings suggest that isotype-specific differences in antigen presentation and BCR signaling contribute to the enrichment of IgG1 PCs in the bone marrow long-lived PC compartment.
{"title":"Positive selection of IgG over IgM plasma cells through BCR isotype–specific antigen presentation and signaling","authors":"Yuki Tai, Takuya Koike, Hiromi Yamamoto, Kyoko Shida, Niklas Engels, Takeshi Inoue, Wataru Ise, Jürgen Wienands, Tomohiro Kurosaki","doi":"10.1126/sciimmunol.aee8841","DOIUrl":"https://doi.org/10.1126/sciimmunol.aee8841","url":null,"abstract":"During a primary immune response, B cells can undergo isotype switching from an immunoglobulin M (IgM) B cell receptor (BCR) to an IgG BCR. B cells that have switched to IgG give rise to more bone marrow long-lived plasma cells (PCs) compared with those expressing IgM, but how BCR isotype–driven bias occurs remains unclear. Here, we found that IgG1-expressing germinal center B cells presented higher levels of antigen to T follicular helper cells, resulting in greater proliferation of IgG1 PCs than IgM PCs. BCR signaling through IgM induced more Bim-dependent apoptosis in IgM PCs, together leading to the predominance of IgG1 PCs in secondary lymphoid tissues. In addition, IgG1 PCs were more prone to migrating to bone marrow. Hence, our findings suggest that isotype-specific differences in antigen presentation and BCR signaling contribute to the enrichment of IgG1 PCs in the bone marrow long-lived PC compartment.","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"14 1","pages":""},"PeriodicalIF":24.8,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148890208","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 : 2026-08-28DOI: 10.1126/sciimmunol.aec9853
Davide Marotta, Chiara Perucchini, Marta Grillo, Valeria Fumagalli, Pietro Di Lucia, Jordan Rixon, Micol Ravà, Leonardo Giustini, Chiara Malpighi, Giulia D’Uonnolo, Mariangela Scavone, Violette Mouro, Caitlin Abbott, Natalia Stachura-Chyla, Francesco Andreata, Erica Scalambrino, Marigrazia Clerici, Lorena Donnici, Marika Longo Minnolo, Donato Inverso, Raffaele De Francesco, Mauro Gaya, Zaverio M. Ruggeri, Armando Tripodi, Gian Marco Podda, Luca G. Guidotti, Matteo Iannacone, Marco De Giovanni
Elderly individuals affected by COVID-19 are vulnerable to severe respiratory failure for reasons that have remained poorly defined. Here, we show that platelet-released serotonin drives lung pathology in a mouse model of age-associated disease severity after SARS-CoV-2 infection. In middle-aged mice and aged human healthy donors, platelet serotonin release upon activation was enhanced, and increased morbidity with respiratory dysfunction was associated with activated platelets aggregating and promoting fibrin deposition in the lung microvasculature. Pharmacologic or genetic disruption of serotonin uptake, or blockade of serotonin-dependent signaling, attenuated platelet activation and protected against respiratory distress, independently of viral replication and immune responses. Inhibition of fibrin formation similarly reduced disease severity, implicating serotonin-driven platelet procoagulant activity as a key contributor to age-related lung dysfunction. Thus, serotonin-mediated platelet procoagulant activity is a major contributor to respiratory insufficiency during SARS-CoV-2 infection and a potential therapeutic target for preserving pulmonary function, particularly in the elderly.
{"title":"Platelet-derived serotonin drives age-related lung pathology in SARS-CoV-2 infection","authors":"Davide Marotta, Chiara Perucchini, Marta Grillo, Valeria Fumagalli, Pietro Di Lucia, Jordan Rixon, Micol Ravà, Leonardo Giustini, Chiara Malpighi, Giulia D’Uonnolo, Mariangela Scavone, Violette Mouro, Caitlin Abbott, Natalia Stachura-Chyla, Francesco Andreata, Erica Scalambrino, Marigrazia Clerici, Lorena Donnici, Marika Longo Minnolo, Donato Inverso, Raffaele De Francesco, Mauro Gaya, Zaverio M. Ruggeri, Armando Tripodi, Gian Marco Podda, Luca G. Guidotti, Matteo Iannacone, Marco De Giovanni","doi":"10.1126/sciimmunol.aec9853","DOIUrl":"10.1126/sciimmunol.aec9853","url":null,"abstract":"<div >Elderly individuals affected by COVID-19 are vulnerable to severe respiratory failure for reasons that have remained poorly defined. Here, we show that platelet-released serotonin drives lung pathology in a mouse model of age-associated disease severity after SARS-CoV-2 infection. In middle-aged mice and aged human healthy donors, platelet serotonin release upon activation was enhanced, and increased morbidity with respiratory dysfunction was associated with activated platelets aggregating and promoting fibrin deposition in the lung microvasculature. Pharmacologic or genetic disruption of serotonin uptake, or blockade of serotonin-dependent signaling, attenuated platelet activation and protected against respiratory distress, independently of viral replication and immune responses. Inhibition of fibrin formation similarly reduced disease severity, implicating serotonin-driven platelet procoagulant activity as a key contributor to age-related lung dysfunction. Thus, serotonin-mediated platelet procoagulant activity is a major contributor to respiratory insufficiency during SARS-CoV-2 infection and a potential therapeutic target for preserving pulmonary function, particularly in the elderly.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 122","pages":""},"PeriodicalIF":16.4,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.aec9853","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148838457","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}
Pub Date : 2026-08-28DOI: 10.1126/sciimmunol.aeh4719
Kelly Wemyss, Lauren M. Webb, Hayley M. Bridgeman, Ian E. Prise, Rufus H. Daw, Verena Kästele, Tovah N. Shaw, Sabrina Tamburrano, Seona Thompson, Elia D. Tait Wojno, Pedro H. Papotto, Richard K. Grencis, Andrew S. MacDonald, Jennifer S. Cavet, Joanne E. Konkel, Kathryn J. Else, John R. Grainger
Alterations to monocyte output and function occur during infections driving T helper 1 (TH1)–type inflammation. The degree to which monocytes respond to infections initiating alternative types of responses is poorly understood. Here, we describe a distinct state of the monocyte compartment associated with type 2–polarizing intestinal helminths. Unexpectedly, the adapted monocyte state in a type 2 setting was associated with acquisition of an interferon (IFN) signature. This IFN-induced state provided helminth-infected animals with systemic protection against secondary bacterial infection and allowed for the development of effective type 2 immunity. This pathway of monocyte education was distinct from that in TH1 settings and involved an endogenous bacteria–mediated induction of type I IFN that led to adaptive lymphocyte–dependent IFN-γ priming of monocytes. These findings reveal an IFN-driven mechanism of monocyte education that enables the host to be simultaneously protected against type 2 infections at barrier sites and type 1 infections in the circulation.
{"title":"Type I IFN–induced IFN-γ instructs monocyte-mediated systemic bacterial protection during type 2 intestinal helminth infection","authors":"Kelly Wemyss, Lauren M. Webb, Hayley M. Bridgeman, Ian E. Prise, Rufus H. Daw, Verena Kästele, Tovah N. Shaw, Sabrina Tamburrano, Seona Thompson, Elia D. Tait Wojno, Pedro H. Papotto, Richard K. Grencis, Andrew S. MacDonald, Jennifer S. Cavet, Joanne E. Konkel, Kathryn J. Else, John R. Grainger","doi":"10.1126/sciimmunol.aeh4719","DOIUrl":"10.1126/sciimmunol.aeh4719","url":null,"abstract":"<div >Alterations to monocyte output and function occur during infections driving T helper 1 (T<sub>H</sub>1)–type inflammation. The degree to which monocytes respond to infections initiating alternative types of responses is poorly understood. Here, we describe a distinct state of the monocyte compartment associated with type 2–polarizing intestinal helminths. Unexpectedly, the adapted monocyte state in a type 2 setting was associated with acquisition of an interferon (IFN) signature. This IFN-induced state provided helminth-infected animals with systemic protection against secondary bacterial infection and allowed for the development of effective type 2 immunity. This pathway of monocyte education was distinct from that in T<sub>H</sub>1 settings and involved an endogenous bacteria–mediated induction of type I IFN that led to adaptive lymphocyte–dependent IFN-γ priming of monocytes. These findings reveal an IFN-driven mechanism of monocyte education that enables the host to be simultaneously protected against type 2 infections at barrier sites and type 1 infections in the circulation.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 122","pages":""},"PeriodicalIF":16.4,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148838456","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}
Pub Date : 2026-08-21DOI: 10.1126/sciimmunol.aed0186
Xiaofan Tu, Hongjie Chen, Xiaoran Ma, Chantal Donovan, Jing Yang
Sex differences in the rates of asthma onset and remission suggest that sex hormones may play an important role in the pathogenic mechanism underlying certain forms of asthma. Here, we demonstrate that increased endogenous androgen production in male mice can mitigate pulmonary type 2 inflammation after repeated allergen exposures during early life. Building on previous work showing that immune cells can respond to androgen signaling, we report that androgens also promote pulmonary sympathetic innervations, which can dampen type 2 inflammation via the neurotransmitter norepinephrine. Ablation of the androgen signal in sympathetic neurons is sufficient to disturb the establishment of sympathetic structures in the lungs of male mice, thereby amplifying type 2 inflammatory responses to allergens. Thus, an endocrine-neuroimmune axis contributes to the sexual dimorphism of allergic asthma during development.
{"title":"Androgen signaling via sympathetic neurons regulates allergic pulmonary inflammation","authors":"Xiaofan Tu, Hongjie Chen, Xiaoran Ma, Chantal Donovan, Jing Yang","doi":"10.1126/sciimmunol.aed0186","DOIUrl":"10.1126/sciimmunol.aed0186","url":null,"abstract":"<div >Sex differences in the rates of asthma onset and remission suggest that sex hormones may play an important role in the pathogenic mechanism underlying certain forms of asthma. Here, we demonstrate that increased endogenous androgen production in male mice can mitigate pulmonary type 2 inflammation after repeated allergen exposures during early life. Building on previous work showing that immune cells can respond to androgen signaling, we report that androgens also promote pulmonary sympathetic innervations, which can dampen type 2 inflammation via the neurotransmitter norepinephrine. Ablation of the androgen signal in sympathetic neurons is sufficient to disturb the establishment of sympathetic structures in the lungs of male mice, thereby amplifying type 2 inflammatory responses to allergens. Thus, an endocrine-neuroimmune axis contributes to the sexual dimorphism of allergic asthma during development.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 122","pages":""},"PeriodicalIF":16.4,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.aed0186","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148768150","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}
Pub Date : 2026-08-21DOI: 10.1126/sciimmunol.aea6276
Pieter L. Lindenbergh, Theodoros Giavridis, Ophélie Vivier, Michael A. Lopez, Anton Dobrin, Matthias Mack, José L. Cohen, Maria Themeli, Michel Sadelain
Cytokine release syndrome (CRS) is a common and potentially severe toxicity of chimeric antigen receptor (CAR) T cell therapy, characterized by activation of the host myeloid compartment and systemic inflammation. Although downstream effectors such as interleukin-6 (IL-6) and IL-1β are well-characterized, the upstream signals that initiate CRS remain incompletely understood. By selectively disrupting tumor necrosis factor (TNF) signaling in a mouse model of CRS, we show that CAR T cell–derived TNF promotes the accumulation of pro-inflammatory monocyte-derived macrophages at the tumor site and the induction of host-derived cytokines including IL-6 and IL-1β. We further show that TNF is a determinant of CRS severity in humanized xenochimeras, governing the overall disease course including eventual lethality. Our findings thus identify TNF as an upstream regulator of CRS acting at least in part via the host macrophage compartment.
{"title":"CAR T cell–derived TNF is an early determinant of cytokine release syndrome severity","authors":"Pieter L. Lindenbergh, Theodoros Giavridis, Ophélie Vivier, Michael A. Lopez, Anton Dobrin, Matthias Mack, José L. Cohen, Maria Themeli, Michel Sadelain","doi":"10.1126/sciimmunol.aea6276","DOIUrl":"10.1126/sciimmunol.aea6276","url":null,"abstract":"<div >Cytokine release syndrome (CRS) is a common and potentially severe toxicity of chimeric antigen receptor (CAR) T cell therapy, characterized by activation of the host myeloid compartment and systemic inflammation. Although downstream effectors such as interleukin-6 (IL-6) and IL-1β are well-characterized, the upstream signals that initiate CRS remain incompletely understood. By selectively disrupting tumor necrosis factor (TNF) signaling in a mouse model of CRS, we show that CAR T cell–derived TNF promotes the accumulation of pro-inflammatory monocyte-derived macrophages at the tumor site and the induction of host-derived cytokines including IL-6 and IL-1β. We further show that TNF is a determinant of CRS severity in humanized xenochimeras, governing the overall disease course including eventual lethality. Our findings thus identify TNF as an upstream regulator of CRS acting at least in part via the host macrophage compartment.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 122","pages":""},"PeriodicalIF":16.4,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148768133","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}
The cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway promotes tumor immunogenicity, but intratumoral STING agonists, despite strong preclinical efficacy, have shown limited clinical efficacy. The mechanisms restricting therapeutic STING activation remain unclear. In mice, intratumoral delivery of the endogenous STING ligand cyclic guanosine monophosphate–adenosine monophosphate (GMP-AMP) (cGAMP) using viruslike particles (VLPs) preferentially activates STING in dendritic cells and primes circulating tumor-specific T cells. Using this system, we investigated mechanisms limiting effective STING-based immunotherapy. STING-induced type I interferon signaling was dispensable for cGAMP-VLP–mediated tumor control. In contrast, dendritic cell autophagy was required for generating circulating antitumor CD8 T cells and for regulating baseline neutrophil levels in lymph nodes. cGAMP-VLP overrode this regulation, inducing neutrophil accumulation in tumors and draining lymph nodes that limited efficacy. Neutrophil depletion enhanced tumor control through mechanisms involving neutrophil elastase and programmed cell death 1 ligand 1. These findings reveal that defective dendritic cell autophagy and neutrophil-mediated immunosuppression, rather than insufficient interferon signaling, hinder the effectiveness of intratumoral STING immunotherapy in preclinical mouse models.
{"title":"A dendritic cell autophagy–neutrophil axis limits intratumoral STING immunotherapy","authors":"Adriana Loverre, Bakhos Jneid, Fabien Delisle, Magali Genest, Chantal Alkhoury, Konstantina Antoniadou, Nicolas Manel","doi":"10.1126/sciimmunol.adw6399","DOIUrl":"10.1126/sciimmunol.adw6399","url":null,"abstract":"<div >The cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway promotes tumor immunogenicity, but intratumoral STING agonists, despite strong preclinical efficacy, have shown limited clinical efficacy. The mechanisms restricting therapeutic STING activation remain unclear. In mice, intratumoral delivery of the endogenous STING ligand cyclic guanosine monophosphate–adenosine monophosphate (GMP-AMP) (cGAMP) using viruslike particles (VLPs) preferentially activates STING in dendritic cells and primes circulating tumor-specific T cells. Using this system, we investigated mechanisms limiting effective STING-based immunotherapy. STING-induced type I interferon signaling was dispensable for cGAMP-VLP–mediated tumor control. In contrast, dendritic cell autophagy was required for generating circulating antitumor CD8 T cells and for regulating baseline neutrophil levels in lymph nodes. cGAMP-VLP overrode this regulation, inducing neutrophil accumulation in tumors and draining lymph nodes that limited efficacy. Neutrophil depletion enhanced tumor control through mechanisms involving neutrophil elastase and programmed cell death 1 ligand 1. These findings reveal that defective dendritic cell autophagy and neutrophil-mediated immunosuppression, rather than insufficient interferon signaling, hinder the effectiveness of intratumoral STING immunotherapy in preclinical mouse models.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 122","pages":""},"PeriodicalIF":16.4,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148728672","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}
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