Xiaoye Liu, Ryan Huang, Zhiqiang Ku, Jingjing Xie, Heyu Chen, Yubo He, Qi Lou, Chengcheng Zhang, Xing Yang, Cheryl Lewis, Jade Homsi, Ankit Gupta, Lei Dong, Kenian Chen, Annabel Tu, Liming Du, Hailong Yu, Qing Hu, Meng Fang, Bufan Li, A. E. M. Adan Khan, Caroline Simith, Samuel John, Lin Xu, Ningyan Zhang, Zhiqiang An, Cheng Cheng Zhang
{"title":"Claudins interact with LILRB immune inhibitory receptors to promote myeloid immunosuppression in cancer","authors":"Xiaoye Liu, Ryan Huang, Zhiqiang Ku, Jingjing Xie, Heyu Chen, Yubo He, Qi Lou, Chengcheng Zhang, Xing Yang, Cheryl Lewis, Jade Homsi, Ankit Gupta, Lei Dong, Kenian Chen, Annabel Tu, Liming Du, Hailong Yu, Qing Hu, Meng Fang, Bufan Li, A. E. M. Adan Khan, Caroline Simith, Samuel John, Lin Xu, Ningyan Zhang, Zhiqiang An, Cheng Cheng Zhang","doi":"10.1126/sciimmunol.adt7832","DOIUrl":"10.1126/sciimmunol.adt7832","url":null,"abstract":"<div >The mechanisms underlying tumor cell–myeloid cell interactions in the tumor microenvironment (TME) remain unclear, and predictive biomarkers for patient response to myeloid checkpoint blockade are lacking. This study identified specific binding between tight junction claudins (CLDNs) and leukocyte immunoglobulin-like receptor subfamily B2 (LILRB2) and LILRB5. In multiple human cancer cohorts, the spatial proximity of LILRB2-positive macrophages to CLDN-expressing cancer cells correlated with clinical outcomes, highlighting this spatial relationship as a potential biomarker. In syngeneic LILRB2-transgenic and humanized mouse models, CLDN18.2-LILRB2 interactions triggered bidirectional signaling, enhanced the immunosuppressive activity of myeloid cells, and accelerated tumor progression. These effects were reversed by LILRB2 blockade. The CLDN-LILRB2 axis sustained immunosuppression by regulating NF-κB and STAT signaling pathways. Our findings reveal a mechanism of myeloid cell regulation by tight junction proteins in the TME, offering a rationale for targeting this pathway in cancer therapy.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 118","pages":""},"PeriodicalIF":16.3,"publicationDate":"2026-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147599610","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}
Biao Ma, Wenxin Lyu, John Rizk, Xiaoyue Han, Majken Kjær, Vinnycius Pereira Almeida, Malin Jessen, Max Benjamin Sauerland, Carol Sze Ki Leung, Benoit J. Van den Eynde, Xin Lu, Mads Gyrd-Hansen
{"title":"Upstream ORFs control TNFR1 abundance and tissue tolerance to TNF","authors":"Biao Ma, Wenxin Lyu, John Rizk, Xiaoyue Han, Majken Kjær, Vinnycius Pereira Almeida, Malin Jessen, Max Benjamin Sauerland, Carol Sze Ki Leung, Benoit J. Van den Eynde, Xin Lu, Mads Gyrd-Hansen","doi":"10.1126/sciimmunol.aeb6484","DOIUrl":"10.1126/sciimmunol.aeb6484","url":null,"abstract":"<div >Tumor necrosis factor (TNF) orchestrates immune responses but can also drive inflammation-associated tissue damage. However, the mechanisms governing tissue tolerance to TNF remain poorly understood. Here, we reveal that TNF receptor 1 (TNFR1) abundance is regulated by two upstream open reading frames (uORFs) in the 5′ untranslated region of <i>TNFRSF1A</i> and demonstrate that this is a key determinant of TNF tolerance. uORF2 dominantly limits TNFR1 translation, and its disruption increases TNFR1 levels, leading to excessive TNF-induced gene activation and cell death in cell culture. By contrast, uORF1 dynamically regulates TNFR1 levels in response to inflammatory and stress signals. In mice, uORF2 protects against TNF-driven systemic inflammatory response syndrome and liver pathology. We additionally report that the translation of other immune receptor messenger RNAs, including <i>TLR4</i>, <i>IFNAR1</i>, and <i>IFNGR2</i>, is also controlled by uORFs. Thus, regulation of TNFR1 levels and possibly of other immune receptors emerges as a mechanism safeguarding against excessive immune responses and tissue damage.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 118","pages":""},"PeriodicalIF":16.3,"publicationDate":"2026-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147599611","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":"Copper supports regulatory T cell energetic state to sustain peripheral immune tolerance","authors":"Yage Zhang, Fan Shi, Haoyu Tang, Tianyi Wang, Hui Zhao, Jie Chang, Chengyao Zhu, Wei Xu, Zhenli Zhu, Jing-wen Lin, Yanfang Wang, Xiangguang Shi, Jiucun Wang, Junxia Min, Fudi Wang, Qian Wu, Songmin Ying","doi":"10.1126/sciimmunol.aec2573","DOIUrl":"10.1126/sciimmunol.aec2573","url":null,"abstract":"<div >Fine-tuning of energy metabolism is essential for the survival and suppressive function of regulatory T cells (T<sub>reg</sub> cells). Here, we show that T<sub>reg</sub> cells with a high energetic state display enhanced functional capacity. Using a screen of mitochondrial inhibitors, we identified copper chelators and ionophores as modulators of T<sub>reg</sub> cell energetic state. T cell receptor (TCR) stimulation in vitro and human autoimmune conditions increased the labile copper pool in T<sub>reg</sub> cells. In murine T<sub>reg</sub> cells, we characterized Slc31a1 as a major copper transporter that supports oxidative phosphorylation, sustains nicotinamide adenine dinucleotide/reduced NAD<sup>+</sup> (NAD<sup>+</sup>/NADH) homeostasis, and promotes histone acetylation at loci encoding core T<sub>reg</sub> cell functional molecules. These mechanisms collectively ensured energy production and T<sub>reg</sub> cell functionality, which were indispensable for peripheral immune tolerance but could be rescued by the copper ionophore elesclomol. Together, our findings identify copper metabolism as a critical regulator of T<sub>reg</sub> cell functionality and suggest potential therapeutic avenues for autoimmune diseases.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 118","pages":""},"PeriodicalIF":16.3,"publicationDate":"2026-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147599628","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}
Shohei Suzuki, Kentaro Miyamoto, Anna Tojo, Yusuke Yoshimatsu, Toshiaki Teratani, Hitoshi Uchida, Yasuhiro Nemoto, Ryuichi Okamoto, Andreas Michael Sihombing, Toshiro Sato, Jin Nakahara, Takanori Kanai, Tomohisa Sujino
{"title":"Intestinal epithelial MHC class II induces encephalitogenic CD4 T cells and initiates central nervous system autoimmunity","authors":"Shohei Suzuki, Kentaro Miyamoto, Anna Tojo, Yusuke Yoshimatsu, Toshiaki Teratani, Hitoshi Uchida, Yasuhiro Nemoto, Ryuichi Okamoto, Andreas Michael Sihombing, Toshiro Sato, Jin Nakahara, Takanori Kanai, Tomohisa Sujino","doi":"10.1126/sciimmunol.aec1627","DOIUrl":"10.1126/sciimmunol.aec1627","url":null,"abstract":"<div >The intestinal epithelium plays a critical role in immune-microbiota interactions, yet its contribution to systemic autoimmunity remains unclear. Here, we identify intestinal epithelial cells (IECs) as initiators of experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS). In both EAE mice and patients with MS, IECs up-regulate antigen presentation pathways and are associated with increased intestinal T helper 17 (T<sub>H</sub>17) cell accumulation. Epithelial major histocompatibility complex class II (MHC II) was highly expressed during EAE, particularly in the ileum, and its conditional deletion reduced pathogenic T<sub>H</sub>17 cell generation and disease severity. Using parabiosis and photoconversion models, we demonstrate that T<sub>H</sub>17 cells induced in the intestinal lamina propria migrate to the spinal cord. Functional coculture assays showed that IEC organoids with cognate myelin oligodendrocyte glycoprotein antigen induce RORγt<sup>+</sup>CD4<sup>+</sup> T cell differentiation in an MHC II–dependent manner. These findings uncover a conserved gut–central nervous system axis in autoimmunity and position epithelial antigen presentation as a key initiator of neuroinflammation.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 117","pages":""},"PeriodicalIF":16.3,"publicationDate":"2026-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147523906","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}
Silvia Tiberti, Sara Gennari, Martina Romeo, Ilir Sheraj, Mohamed Faisal Kassir, Juan Fernández-García, Carina B. Nava Lauson, Roberta Noberini, Carlotta Catozzi, Tiziano Dallavilla, Mattia Ballerini, Alessia Loffreda, Simona G. Codreanu, Stacy D. Sherrod, Katrina L. Leaptrot, Alexandra C. Schrimpe-Rutledge, John A. McLean, Martin H. Schaefer, Simona Rodighiero, Tiziana Bonaldi, Sarah-Maria Fendt, Besim Ogretmen, Sara Sdelci, Luigi Nezi, Teresa Manzo
{"title":"Palmitate-induced mitochondrial damage restricts histone acetylation in CD8 T cells to impair antitumor immunity","authors":"Silvia Tiberti, Sara Gennari, Martina Romeo, Ilir Sheraj, Mohamed Faisal Kassir, Juan Fernández-García, Carina B. Nava Lauson, Roberta Noberini, Carlotta Catozzi, Tiziano Dallavilla, Mattia Ballerini, Alessia Loffreda, Simona G. Codreanu, Stacy D. Sherrod, Katrina L. Leaptrot, Alexandra C. Schrimpe-Rutledge, John A. McLean, Martin H. Schaefer, Simona Rodighiero, Tiziana Bonaldi, Sarah-Maria Fendt, Besim Ogretmen, Sara Sdelci, Luigi Nezi, Teresa Manzo","doi":"10.1126/sciimmunol.aeb1459","DOIUrl":"10.1126/sciimmunol.aeb1459","url":null,"abstract":"<div >Lipid accumulation in the tumor microenvironment is a hallmark of solid tumors, with increased palmitate (PA) availability fostering tumor progression. Although PA’s direct effects on cancer cells are well described, its impact on CD8 T cells [cytotoxic T lymphocytes (CTLs)] remains unclear. Here, we show that PA irreversibly impairs CTL mitochondrial metabolism, leading to the loss of effector functions and compromised antitumor immunity. PA-induced mitochondrial dysfunction reduced histone acetylation and chromatin accessibility, suppressing transcription of genes involved in T cell replication and effector programs. We identified sphingosine kinase 2 (SPHK2) as a key mediator of PA-induced dysfunction, with pharmacological inhibition of SPHK2 restoring mitochondrial fitness, rescuing CTL effector function, and promoting antitumor activity. These findings uncover a distinct mechanism by which PA drives immune evasion in tumors and highlight SPHK2 as a potential therapeutic target to enhance T cell–based immunotherapies.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 117","pages":""},"PeriodicalIF":16.3,"publicationDate":"2026-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147523904","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":"Erratum for the Research Article \"TCRγ constant usage tunes human γδ T cell antigen sensitivity, thymic programming, and peripheral function\".","authors":"","doi":"10.1126/sciimmunol.aeg7865","DOIUrl":"https://doi.org/10.1126/sciimmunol.aeg7865","url":null,"abstract":"","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"197 1","pages":"eaeg7865"},"PeriodicalIF":24.8,"publicationDate":"2026-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147490139","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}
Kumari Anupam, Komal Patel, Pradhnesh Andhare, Brittany Henry, Christopher H. Hanson, Lizzette Pérez-Pérez, Peggy L. Kendall, Brian J. Laidlaw
{"title":"The B cell receptor–mTOR signaling axis restricts the accumulation of lung tissue–resident memory B cells after influenza infection","authors":"Kumari Anupam, Komal Patel, Pradhnesh Andhare, Brittany Henry, Christopher H. Hanson, Lizzette Pérez-Pérez, Peggy L. Kendall, Brian J. Laidlaw","doi":"","DOIUrl":"","url":null,"abstract":"<div >Lung tissue–resident memory B (B<sub>RM</sub>) cells are important in establishing protective immunity against respiratory pathogens. However, the pathways regulating the accumulation of lung B<sub>RM</sub> cells are poorly understood. Here, we show that the transcription factors NFATC1 (nuclear factor of activated T cells 1) and EGR2 (early growth response 2) repress lung B<sub>RM</sub> cell accumulation after influenza infection, whereas IKZF1 (IKAROS family zinc finger 1) enhances it. IKZF1 restrains B cell receptor (BCR) and mTOR (mechanistic target of rapamycin) signaling and is highly expressed in lung B<sub>RM</sub> cells during their development. Lung B<sub>RM</sub> cells display reduced expression of genes associated with BCR and mTOR signaling pathways. Overexpression of a degradation-resistant form of SYK downstream of the BCR restricted lung B<sub>RM</sub> cell accumulation. Conversely, inhibition of mTOR using rapamycin reduced NFATC1 and EGR2 expression and promoted lung B<sub>RM</sub> cell accumulation. These findings establish how the BCR-mTOR signaling axis regulates mucosal B cell responses after influenza infection.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 117","pages":""},"PeriodicalIF":16.3,"publicationDate":"2026-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147570554","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}
Kumari Anupam,Komal Patel,Pradhnesh Andhare,Brittany Henry,Christopher H Hanson,Lizzette Pérez-Pérez,Peggy L Kendall,Brian J Laidlaw
{"title":"The B cell receptor-mTOR signaling axis restricts the accumulation of lung tissue-resident memory B cells after influenza infection.","authors":"Kumari Anupam,Komal Patel,Pradhnesh Andhare,Brittany Henry,Christopher H Hanson,Lizzette Pérez-Pérez,Peggy L Kendall,Brian J Laidlaw","doi":"10.1126/sciimmunol.adw1664","DOIUrl":"https://doi.org/10.1126/sciimmunol.adw1664","url":null,"abstract":"Lung tissue-resident memory B (BRM) cells are important in establishing protective immunity against respiratory pathogens. However, the pathways regulating the accumulation of lung BRM cells are poorly understood. Here, we show that the transcription factors NFATC1 (nuclear factor of activated T cells 1) and EGR2 (early growth response 2) repress lung BRM cell accumulation after influenza infection, whereas IKZF1 (IKAROS family zinc finger 1) enhances it. IKZF1 restrains B cell receptor (BCR) and mTOR (mechanistic target of rapamycin) signaling and is highly expressed in lung BRM cells during their development. Lung BRM cells display reduced expression of genes associated with BCR and mTOR signaling pathways. Overexpression of a degradation-resistant form of SYK downstream of the BCR restricted lung BRM cell accumulation. Conversely, inhibition of mTOR using rapamycin reduced NFATC1 and EGR2 expression and promoted lung BRM cell accumulation. These findings establish how the BCR-mTOR signaling axis regulates mucosal B cell responses after influenza infection.","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"13 1","pages":"eadw1664"},"PeriodicalIF":24.8,"publicationDate":"2026-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147490140","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":"Macrophages restrict tumor immune infiltration by controlling collagen topography.","authors":"Zoé Fusilier,Alexandra Clément,Franck Simon,Isabel Calvente,Roude Jean-Marie,Mathilde Mathieu,Vincent Calmettes,Florence Piastra-Facon,Yazmina Quintana-Perez,Jeyani George Clement,Lou Crestey,Enola Lumineau,Romane Henninger,Mattia Tonani,Valeria Manriquez,Livia Lacerda Mariano,Léa Bensaid,Perrine de Villemagne,Eliane Piaggio,Vincent Semetey,Sylvie Coscoy,Emanuele Martini,Giorgio Scita,Jean-Christophe Gelly,Johanna Ivaska,Hervé Isambert,Christel Goudot,Paolo Pierobon,Ana-Maria Lennon-Duménil,Hélène D Moreau","doi":"10.1126/sciimmunol.adw8291","DOIUrl":"https://doi.org/10.1126/sciimmunol.adw8291","url":null,"abstract":"During tumorigenesis, the extracellular matrix is extensively remodeled. Whereas the impact of such remodeling on tumor growth and invasion is well described, the consequences on immune infiltration are not well understood. Combining tissue imaging and machine learning, we show that immune cell localization in tumors can be predicted by the local topography of fibrillar collagens. Such topographies are dictated by a fibrotic pathway driven by transcription factor 4 (Tcf4) in both cancer and stromal cells, which promotes collagen III deposition and results in intermingled collagen networks that favor intratumor infiltration of T cells and neutrophils. Macrophages inhibit this pathway, highlighting their key structural role in shaping the tumor extracellular matrix. Reanalysis of data from human solid tumors revealed a strong correlation between TCF4, COL3A1, and T cell and neutrophil signatures. Together, our data identify collagen network topographies as a key regulator of tumor-infiltrating immune cells.","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"189 1","pages":"eadw8291"},"PeriodicalIF":24.8,"publicationDate":"2026-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147490141","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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