ImmunityPub Date : 2026-08-03DOI: 10.1016/j.immuni.2026.07.008
Christopher D. Balak,Johannes C.M. Schlachetzki,Addison J. Lana,Elizabeth West,Christine Hong,Jordan DuGal,Yi Zhou,Benjamin Li,Nathanael J. Spann,Payam Saisan,Vishal Sarsani,Kilian L. Kleemann,Xiaoming Zhang,Martina P. Pasillas,Sydney O’Brien,Juliette A. Bokor,Philip L.S.M. Gordts,Oleg Butovsky,Beth Stevens,Fredrik Kamme,Christopher K. Glass
{"title":"Lysosomal dysfunction drives a transcriptional and epigenetic signature found in disease-associated microglia in neurodegenerative diseases","authors":"Christopher D. Balak,Johannes C.M. Schlachetzki,Addison J. Lana,Elizabeth West,Christine Hong,Jordan DuGal,Yi Zhou,Benjamin Li,Nathanael J. Spann,Payam Saisan,Vishal Sarsani,Kilian L. Kleemann,Xiaoming Zhang,Martina P. Pasillas,Sydney O’Brien,Juliette A. Bokor,Philip L.S.M. Gordts,Oleg Butovsky,Beth Stevens,Fredrik Kamme,Christopher K. Glass","doi":"10.1016/j.immuni.2026.07.008","DOIUrl":"https://doi.org/10.1016/j.immuni.2026.07.008","url":null,"abstract":"Lysosomal dysfunction is causally linked to neurodegeneration in many lysosomal storage disorders and is associated with various age-related neurodegenerative diseases. Here, we investigated the question of underlying mechanisms using a mouse model of mucopolysaccharidosis type IIIA caused by deficiency of the lysosomal hydrolase SGSH. Systematic imaging and transcriptomic and epigenetic studies revealed microglia to be the most profoundly impacted cell type in brains of Sgsh-deficient mice. Further investigation identified dominant and context-dependent roles of members of the MITF/TFE family as major drivers of microglia-specific epigenetic and transcriptional changes resulting from lysosomal stress that are dependent on collaborative interactions with AP-1/ATF, C/EBP, and PU.1/ETS transcription factors. Features of the transcriptomic and epigenetic alterations observed in murine Sgsh deficiency were also observed in microglia derived from mouse models of age-related neurodegeneration and in human Alzheimer’s disease patients. These findings reveal common and disease-specific transcriptional mechanisms associated with disease-associated microglia phenotypes.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"55 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148666057","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}
ImmunityPub Date : 2026-08-03DOI: 10.1016/j.immuni.2026.07.009
Leon Tejwani,Catherine M. Heffner,Christopher Balak,Lukas L. Skuja,David Tatarakis,Anil Rana,Seungyoon B. Yu,Gabriel A. Fitzgerald,Connie Ha,Gabrielly Lunkes de Melo,Elizabeth W. Sun,Matthew J. Simon,Jason C. Dugas,Johann Chow,Elliot Thomsen,Lily Sarrafha,Eric Liang,Neal Gould,Jung Suh,Thomas Sandmann,Christopher K. Glass,Gilbert Di Paolo
{"title":"Progranulin deficiency-induced lysosomal dysfunction drives maladaptive myeloid cell states through the MITF/TFE transcription factors","authors":"Leon Tejwani,Catherine M. Heffner,Christopher Balak,Lukas L. Skuja,David Tatarakis,Anil Rana,Seungyoon B. Yu,Gabriel A. Fitzgerald,Connie Ha,Gabrielly Lunkes de Melo,Elizabeth W. Sun,Matthew J. Simon,Jason C. Dugas,Johann Chow,Elliot Thomsen,Lily Sarrafha,Eric Liang,Neal Gould,Jung Suh,Thomas Sandmann,Christopher K. Glass,Gilbert Di Paolo","doi":"10.1016/j.immuni.2026.07.009","DOIUrl":"https://doi.org/10.1016/j.immuni.2026.07.009","url":null,"abstract":"Lysosomal dysfunction in myeloid cells is increasingly implicated in neurodegenerative diseases. To examine the interplay between lysosomal health and cellular state, we performed multi-omic profiling of myeloid cells from brains of aged mice lacking progranulin (Grn−/− mice), a lysosomal protein linked to neurodegeneration. Single-cell RNA sequencing identified a microglial subpopulation defined by GPNMB expression, which displays hallmarks of lysosomal stress, including altered lysosomal protein expression, lipofuscinosis, and metabolic and lipid dysregulation. Epigenetic profiling of Grn−/− microglia revealed an enrichment of MITF/TFE transcription factor motifs at active enhancers, and deletion of these factors reversed the Grn−/−-specific myeloid cell transcriptional signature. Diverse lysosomal perturbations drove a common transcriptional and functional signature, with conditions that induce lysosomal deacidification closely phenocopying progranulin deficiency. Finally, compensatory GPNMB induction in Grn−/− myeloid cells promoted lysosomal acidification, and loss of myeloid cell GPNMB exacerbated neurotoxicity. Our findings link lysosomal health with epigenetic, transcriptional, and functional myeloid cell states associated with neurodegeneration.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"78 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148666056","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}
ImmunityPub Date : 2026-07-14Epub Date: 2026-05-13DOI: 10.1016/j.immuni.2026.04.009
Lai Wang, Jiao Jiang, Haoyuan Yin, Junhui Wu, Xiaoyu Su, Lingchang Meng, Lulu Wang, Jingjing Bao, Qilin Li, Yunbo Wei, Zhian Chen, Jialei Gong, Pablo F Cañete, Meiling Zheng, Wenrui Li, Qiongqiong Zhou, Ming Zhao, Di Yu, Qianjin Lu
{"title":"Modulation of the mevalonate pathway by TCR engagement regulates T follicular helper cell generation in homeostasis and autoimmunity.","authors":"Lai Wang, Jiao Jiang, Haoyuan Yin, Junhui Wu, Xiaoyu Su, Lingchang Meng, Lulu Wang, Jingjing Bao, Qilin Li, Yunbo Wei, Zhian Chen, Jialei Gong, Pablo F Cañete, Meiling Zheng, Wenrui Li, Qiongqiong Zhou, Ming Zhao, Di Yu, Qianjin Lu","doi":"10.1016/j.immuni.2026.04.009","DOIUrl":"10.1016/j.immuni.2026.04.009","url":null,"abstract":"<p><p>Surface proteins enable T follicular helper (Tfh) cells' chemotactic migration toward B cells and subsequent functional interactions, underpinning effective humoral immunity. We showed that geranylgeranyl diphosphate (GGPP), a mevalonate (MVA) pathway-derived isoprenoid, was indispensable for Tfh cell function by maintaining surface protein expression. Either pharmacological inhibition or genetic depletion of geranylgeranyl diphosphate synthase (GGPS1), the enzyme responsible for GGPP biosynthesis, impaired Tfh cell generation. Mechanistically, geranylgeranyl transferase Ⅱ (GGTase Ⅱ) utilizes GGPP to geranylgeranylate RAB GTPases for surface protein expression, as exemplified by RAB35-mediated recycling of the chemokine receptor CXCR5 to the cell surface. Notably, the MVA pathway-GGPS1-GGTase Ⅱ-RAB35 axis in Tfh cells was enhanced by T cell receptor signaling and hyperactivated in autoimmunity. Conversely, the potent statin pitavastatin inhibited this axis to suppress pathogenic Tfh cells and alleviate autoimmunity. Thus, GGPP links the MVA pathway to T cell function via surface protein regulation, revealing a therapeutic target for autoimmune diseases.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":" ","pages":"1911-1927.e12"},"PeriodicalIF":30.6,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147941258","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}
ImmunityPub Date : 2026-07-14Epub Date: 2026-06-25DOI: 10.1016/j.immuni.2026.06.019
Paloma Navarro Negredo, Justin You, Max Hauptschein, Adam B Schroer, Daniel J Richard, Gita C Abhiraman, Andy P Tsai, Eric D Sun, Giulia Notarangelo, Julliana Ramirez-Matias, Olivia Y Zhou, Matthew T Buckley, Karen E Malacon, Lucy Xu, Juliana Sucharov, Eduardo Ramirez Lopez, Lora Picton, Tony Wyss-Coray, Robert A Saxton, Ricardo A Fernandes, Saul A Villeda, K Christopher Garcia, Anne Brunet
{"title":"Targeting immune cells in the aged brain reveals that engineered cytokine IL-10 enhances neurogenesis and improves cognition.","authors":"Paloma Navarro Negredo, Justin You, Max Hauptschein, Adam B Schroer, Daniel J Richard, Gita C Abhiraman, Andy P Tsai, Eric D Sun, Giulia Notarangelo, Julliana Ramirez-Matias, Olivia Y Zhou, Matthew T Buckley, Karen E Malacon, Lucy Xu, Juliana Sucharov, Eduardo Ramirez Lopez, Lora Picton, Tony Wyss-Coray, Robert A Saxton, Ricardo A Fernandes, Saul A Villeda, K Christopher Garcia, Anne Brunet","doi":"10.1016/j.immuni.2026.06.019","DOIUrl":"10.1016/j.immuni.2026.06.019","url":null,"abstract":"","PeriodicalId":13269,"journal":{"name":"Immunity","volume":" ","pages":"2053-2054"},"PeriodicalIF":30.6,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13440024/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148329156","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}
ImmunityPub Date : 2026-07-14Epub Date: 2026-05-29DOI: 10.1016/j.immuni.2026.04.018
Jingfei Yao, Yuting Wang, Yi Zhang
{"title":"Activating an interleukin 4-FLT3-STAT6 axis in multipotent progenitors restores lymphopoiesis in inflammation and aging.","authors":"Jingfei Yao, Yuting Wang, Yi Zhang","doi":"10.1016/j.immuni.2026.04.018","DOIUrl":"10.1016/j.immuni.2026.04.018","url":null,"abstract":"<p><p>Chronic inflammation and aging skew hematopoiesis toward myelopoiesis at the expense of lymphoid output. We screened type 2 and anti-inflammatory cytokines to identify extrinsic signals capable of restoring lymphoid lineage commitment in hematopoietic stem and progenitor cells (HSPCs). Interleukin 4 (IL-4) specifically inhibited inflammation-induced myelopoiesis and shifted multipotent progenitor (MPP) differentiation toward the lymphoid lineage. IL-4 activated a signal transducer and activator of transcription 6 (STAT6)-dependent transcriptional program in MPPs, increasing the expression of lymphoid-specific genes. Mechanistically, the receptor tyrosine kinase FMS-like tyrosine kinase 3 (FLT3), which is highly expressed in MPPs, interacted with IL-4Rα to facilitate STAT6 activation. In vivo, IL-4 reversed inflammation-induced hematopoietic imbalance and accelerated lymphoid recovery. In aged mice, IL-4 administration shifted the MPP composition toward a lymphoid bias and restored B and T lymphocyte output. Long-term IL-4 treatment in aged mice improved immune, metabolic, physical, and cognitive functions; these rejuvenating effects were recapitulated by transplantation of IL-4-treated HSPCs. Promoting IL-4 signaling in MPPs may enable correction of hematopoietic dysregulation in inflammatory and aging-related conditions.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":" ","pages":"1843-1859.e7"},"PeriodicalIF":30.6,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13404287/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148054249","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}
ImmunityPub Date : 2026-07-14Epub Date: 2026-07-03DOI: 10.1016/j.immuni.2026.06.002
Yange Gu, Lulu Zhang, Jianhua Li, Ensi Ma, Weiwei Hu, Yun Liu, Xiaocheng Du, Feifei Zhang, Tiange Yang, Linyue Bian, Wenfeng Li, Yitian Jin, Yinghua Wang, Zihan Ning, Chune Yu, Dun Li, Jing Zhao, Chenqi Xu, Zhengxin Wang, Guangchuan Wang
{"title":"Targeting cholesterol esterification sensitizes liver cancer to CD8<sup>+</sup> T cell attack by impairing metabolic and redox resilience.","authors":"Yange Gu, Lulu Zhang, Jianhua Li, Ensi Ma, Weiwei Hu, Yun Liu, Xiaocheng Du, Feifei Zhang, Tiange Yang, Linyue Bian, Wenfeng Li, Yitian Jin, Yinghua Wang, Zihan Ning, Chune Yu, Dun Li, Jing Zhao, Chenqi Xu, Zhengxin Wang, Guangchuan Wang","doi":"10.1016/j.immuni.2026.06.002","DOIUrl":"10.1016/j.immuni.2026.06.002","url":null,"abstract":"<p><p>Recurrence after tumor resection and liver transplantation remains a major clinical challenge in hepatocellular carcinoma (HCC). We examined tumor samples from HCC liver transplant patients to identify drivers of disease recurrence. Integration of proteomic profiling of human HCC samples with or without recurrence and T cell killing assays linked the cholesterol esterification enzyme SOAT1 to immune evasion and cancer recurrence. Genetic or pharmacological inhibition of SOAT1 sensitized liver cancer cells to CD8<sup>+</sup> T cell-mediated immunosurveillance, anti-programmed cell death 1 (anti-PD-1) therapy, and chimeric antigen receptor (CAR)-T cell therapy and increased intratumoral CD8<sup>+</sup> T cell infiltration. Mechanistically, the inhibition of SOAT1-mediated cholesterol esterification disrupted intratumoral cholesterol and lipid metabolism and reduced unsaturated fatty acids and prostaglandin E2 production; this impaired the antioxidant capacity and metabolic resilience of cancer cells under immune attack. Accordingly, SOAT1 inhibition enhanced immunotherapy efficacy in obesity-associated tumors and under immunosuppressant-induced conditions. Thus, cholesterol esterification supports redox fitness and cancer cell resilience upon immune attack, suggesting a strategy to prevent recurrence and improve immunotherapy outcomes.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":" ","pages":"1948-1963.e11"},"PeriodicalIF":30.6,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148382040","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}
ImmunityPub Date : 2026-07-14Epub Date: 2026-06-24DOI: 10.1016/j.immuni.2026.05.018
Arantxa Agesta, Chloé Ferrand, Anne-Louise Le Dorze, Cindy Peillex, Nadège Carrié, Rebecca Barascud, Arthur Palak, Lucie Esteban, Tanguy Bernal, Emeline Joulia, Céline Colacios, Tania Margarido Pereira, Romain Peroceschi, Andrea Pichler, Adeline Chaubet, Margot Zahm, Abdelhadi Saoudi, Hicham El Costa, Veronique Adoue, Benjamin Y Lu, Liliana E Lucca, Ludovic Martinet, Anne S Dejean
{"title":"The transcription factor Eomes drives a stemness program in CD4<sup>+</sup> T cells that promotes anti-tumor immunity in response to immunotherapy.","authors":"Arantxa Agesta, Chloé Ferrand, Anne-Louise Le Dorze, Cindy Peillex, Nadège Carrié, Rebecca Barascud, Arthur Palak, Lucie Esteban, Tanguy Bernal, Emeline Joulia, Céline Colacios, Tania Margarido Pereira, Romain Peroceschi, Andrea Pichler, Adeline Chaubet, Margot Zahm, Abdelhadi Saoudi, Hicham El Costa, Veronique Adoue, Benjamin Y Lu, Liliana E Lucca, Ludovic Martinet, Anne S Dejean","doi":"10.1016/j.immuni.2026.05.018","DOIUrl":"10.1016/j.immuni.2026.05.018","url":null,"abstract":"<p><p>CD4<sup>+</sup> T helper (Th) cells contribute to tumor immunity, yet the subsets and differentiation programs involved remain unclear. Here, we show that the transcription factor Eomesodermin (Eomes) is essential for Th-mediated anti-tumor immunity. Eomes orchestrated the differentiation and maintenance of an exhausted-like Th cell lineage, transcriptionally and functionally distinct from conventional effector or memory Th subsets. This Eomes-dependent program was enhanced by 4-1BB stimulation and promoted effective Th-cell-mediated tumor control. The progenitor subset of this lineage (pTh) expressed stemness-associated transcription factors, displayed self-renewal capacity, and seeded effector subsets capable of controlling tumor growth. At the transcriptional level, Eomes supported the survival, metabolic fitness, and apoptotic resistance of this lineage. Eomes⁺ pTh cells exhibited conserved transcriptional features in humans across multiple tumor types. As the most expanded Th cell population upon immune checkpoint inhibitor therapy, targeting these cells has potential to improve current immunotherapies.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":" ","pages":"1876-1893.e7"},"PeriodicalIF":30.6,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148316984","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}
ImmunityPub Date : 2026-07-14Epub Date: 2026-05-19DOI: 10.1016/j.immuni.2026.04.015
DongUk Lee, Meng-Ping Lu, Priya Rajamanimuthu, Mrinmoy Das, Enxhi Ferraj, Courtney Fisher, Peri Matatia, Chun-Wei Chen, Raif S Geha, Caroline L Sokol, Uthaman Gowthaman
{"title":"Interleukin-4-producing type 2 innate lymphoid cells in the lymph node promote proallergic Tfh13 cell differentiation.","authors":"DongUk Lee, Meng-Ping Lu, Priya Rajamanimuthu, Mrinmoy Das, Enxhi Ferraj, Courtney Fisher, Peri Matatia, Chun-Wei Chen, Raif S Geha, Caroline L Sokol, Uthaman Gowthaman","doi":"10.1016/j.immuni.2026.04.015","DOIUrl":"10.1016/j.immuni.2026.04.015","url":null,"abstract":"<p><p>Proallergic T follicular helper 13 (Tfh13) cells are obligatory for generating high-affinity, anaphylactic immunoglobulin E (IgE) responses to allergens. Unlike Tfh2 cells, which are induced by vaccination and most type 2 immune responses, Tfh13 cells are primarily elicited during allergic disease states. However, the cellular and molecular determinants governing Tfh13 cell differentiation remain unclear. Using orthogonal genetic and bone marrow chimera approaches, we identified a critical role for group 2 innate lymphoid cells (ILC2s) within draining lymph nodes (dLNs) in promoting Tfh13 cell differentiation. During allergen sensitization, ILC2s trafficked into dLNs in a chemokine receptor CCR8-dependent manner and produced interleukin (IL)-4, a factor necessary for Tfh13-but not for Tfh2-cell induction. These findings uncover a mechanism by which ILC2s selectively drive pathogenic Tfh13 responses, underscoring the distinct regulatory requirements for Tfh2 and Tfh13 cell differentiation in allergic immunity.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":" ","pages":"1860-1875.e7"},"PeriodicalIF":30.6,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13244145/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147981671","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}
ImmunityPub Date : 2026-07-14Epub Date: 2026-06-22DOI: 10.1016/j.immuni.2026.05.013
Tomás Cervantes Rincón, Tereza Frckova, Zaria I Contejean, Jasmine Cantergiani, Kevin Groen, Benedetta Cena, Simone G Moro, Filippo Bianchini, Luca Simonelli, David Jarrossay, Silvia Tosolini, Roger Kuratli, Anna R E Robinson, Monika Cizkova, Emily G Niejadlik, Jacques Moritz, Roshan Thakur, Zuzana Krátka, Dragana Mijatović, Jasmina Grujić, Jiri Holoubek, Zorana Budakov-Obradović, Jiri Salat, Václav Hönig, Marija Vraneš, Zvezdana Lojpur, Dajana Lendak, Siniša Sević, Monika Bajči, Lidija Popović-Dragonjić, Biljana Popovska Jovičić, Jagoda Gavrilović, Tania Kapoor, Margaret R MacDonald, Stylianos Bournazos, Luca Varani, Martin Palus, Benjamin G Hale, Pavle Banović, Daniel Ruzek, Christopher O Barnes, Davide F Robbiani
{"title":"Analysis of West Nile disease convalescents identifies human monoclonal antibodies protective against West Nile and related orthoflaviviruses.","authors":"Tomás Cervantes Rincón, Tereza Frckova, Zaria I Contejean, Jasmine Cantergiani, Kevin Groen, Benedetta Cena, Simone G Moro, Filippo Bianchini, Luca Simonelli, David Jarrossay, Silvia Tosolini, Roger Kuratli, Anna R E Robinson, Monika Cizkova, Emily G Niejadlik, Jacques Moritz, Roshan Thakur, Zuzana Krátka, Dragana Mijatović, Jasmina Grujić, Jiri Holoubek, Zorana Budakov-Obradović, Jiri Salat, Václav Hönig, Marija Vraneš, Zvezdana Lojpur, Dajana Lendak, Siniša Sević, Monika Bajči, Lidija Popović-Dragonjić, Biljana Popovska Jovičić, Jagoda Gavrilović, Tania Kapoor, Margaret R MacDonald, Stylianos Bournazos, Luca Varani, Martin Palus, Benjamin G Hale, Pavle Banović, Daniel Ruzek, Christopher O Barnes, Davide F Robbiani","doi":"10.1016/j.immuni.2026.05.013","DOIUrl":"10.1016/j.immuni.2026.05.013","url":null,"abstract":"<p><p>West Nile virus (WNV) is a mosquito-borne pathogen of global concern that can cause fatal neuroinvasive disease, and no specific prophylaxis or treatment exists for infections by WNV and most related orthoflaviviruses. Here, we isolated and characterized antibodies from WNV convalescent individuals and report that neutralizing autoantibodies against type I interferons did not impair antiviral antibody development. Among the monoclonal antibodies with potent neutralizing activity against WNV that were identified, W010 targeted a distinct epitope within the envelope protein domain III (EDIII) and conferred both pre- and post-exposure protection in a murine WNV model, even when interferon signaling was impaired. A second protective antibody, W014, exhibited broad cross-neutralization of other pathogenic orthoflavivirus members, including Japanese encephalitis virus, Murray Valley encephalitis virus, Saint Louis encephalitis virus, and Usutu virus. These findings identify key neutralizing epitopes on WNV EDIII and provide candidates for the development of antibody-based interventions against encephalitic orthoflavivirus infections.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":" ","pages":"2015-2029.e9"},"PeriodicalIF":30.6,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13317730/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148301163","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}
ImmunityPub Date : 2026-07-14Epub Date: 2026-06-24DOI: 10.1016/j.immuni.2026.06.001
Lifen Wen, Chun-Hsi Su, Nikita Potemkin, Lachlan Dryburgh, Lei Qin, Sining Li, Marcela De Lima Moreira, Ashraful Haque, Xiye Sun, Vincenzo Cinella, Jan Schroeder, Carlson Tsui, Axel Kallies
{"title":"Stem-like precursors of exhausted Th cells upheld by a Tox-Myb-Eomes transcriptional hierarchy propagate Th cell responses in chronic infection.","authors":"Lifen Wen, Chun-Hsi Su, Nikita Potemkin, Lachlan Dryburgh, Lei Qin, Sining Li, Marcela De Lima Moreira, Ashraful Haque, Xiye Sun, Vincenzo Cinella, Jan Schroeder, Carlson Tsui, Axel Kallies","doi":"10.1016/j.immuni.2026.06.001","DOIUrl":"10.1016/j.immuni.2026.06.001","url":null,"abstract":"<p><p>CD4<sup>+</sup> T helper (Th) cells are critical drivers of adaptive immunity, but how their responses are maintained during chronic infection remains unclear. Here, we identified a population of CD4<sup>+</sup> T cells that expressed CD62L and the inhibitory receptor PD-1 and exhibited both features of exhaustion and stemness. These cells acted as precursors of T helper (pTh) cells and sustained Th cell immunity during chronic lymphocytic choriomeningitis virus (LCMV) infection, giving rise to type 1 (Th1) and follicular T helper (Tfh) cells and cytotoxic-like T cells. pTh cells developed under conditions of high antigen exposure and depended on exhaustion and stemness-associated transcription factors TOX, EOMES, and MYB. Consequently, the maintenance of mature Th cells was severely compromised when CD4<sup>+</sup> T cells lacked these factors. pTh cells also contributed to Th1 cell expansion upon PD-1 blockade. Overall, our findings reveal a molecular program and cellular hierarchy that preserve long-term CD4<sup>+</sup> Th cell responses during chronic infection and immunotherapy.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":" ","pages":"1894-1910.e5"},"PeriodicalIF":30.6,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148317000","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}
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
