Nature Immunology最新文献

{"title":"A novel CAF population coordinates hyper-suppressive regulatory T cell recruitment and localization in lung cancer","authors":"Olivia R. Ringham, Monica Rivera, Lucas F. Loffredo, Melih Arda Ozsoy, Christina M. Healy, Maye F. Cheng, Yinuo Jin, Noah Chen, Kenia de los Santos-Alexis, Elham Azizi, Anjali Saqi, Matthew B. Buechler, Carla P. Concepcion-Crisol, Nicholas Arpaia","doi":"10.1038/s41590-026-02607-2","DOIUrl":"10.1038/s41590-026-02607-2","url":null,"abstract":"Across many solid tumor types, cancer-associated fibroblasts (CAFs) are abundant and heterogeneous, with distinct subpopulations exerting immunomodulatory functions. Here we identify a novel population of immunomodulatory CAFs (imCAFs) in primary lung adenocarcinoma and pulmonary metastases, characterized by cell adhesion molecule L1-like (CHL1) expression and enriched in immune regulation and chemokine signaling programs. Through single-cell and spatial transcriptomics, we demonstrate that imCAFs are spatially colocalized with CXCR3+ regulatory T (Treg) cells, a hyper-suppressive subset accumulating at the tumor border. imCAFs produce CXCL9, driving CXCR3+ Treg cell recruitment and promoting an immunosuppressive microenvironment. CXCR3+ Treg cells display enhanced proliferative and suppressive capacity and are transcriptionally distinct from CXCR3− counterparts. Genetic ablation of Cxcr3 in Treg cells or Cxcl9 in stromal cells reduces Treg cell accumulation, enhances CD8+ T cell activation and decreases tumor burden. Analogous CHL1+ imCAF-like fibroblasts in human non-small cell lung cancer colocalize with Treg cells, and elevated CHL1 expression is associated with reduced cytotoxicity and decreased progression-free survival, highlighting the imCAF–CXCL9–CXCR3+ Treg axis as a promising therapeutic target. Ringham et al. identify immunomodulatory cancer-associated fibroblasts that influence regulatory T cell dynamics in lung cancer.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"27 9","pages":"1899-1912"},"PeriodicalIF":26.5,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41590-026-02607-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148713338","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss of cellular RNA homeostasis contributes to MDA5 activation during virus infection","authors":"Natália G. Sampaio, Tanja Davis, Linden J. Gearing, Antonio G. Dias Junior, Lise Chauveau, Georgie Wray-McCann, Valerie Odon, Vladyslava Liudkovska, Alexandra L. McAllan, Chiara Cursi, Alice Mayer, Madara Ratnadiwakara, Minna-Liisa Änkö, Maciej Cieśla, Paul J. Hertzog, Jan Rehwinkel","doi":"10.1038/s41590-026-02614-3","DOIUrl":"10.1038/s41590-026-02614-3","url":null,"abstract":"MDA5 is an innate immune RNA sensor that senses infection with a range of viruses and other pathogens. MDA5’s RNA agonists are not well defined. Here we used single-nucleotide resolution crosslinking and immunoprecipitation (iCLIP) to study its ligands. Of note, upon infection with SARS-CoV-2 or encephalomyocarditis virus, MDA5 bound overwhelmingly to cellular RNAs. Many binding sites were intronic and proximal to Alu elements and to potentially base-paired structures. Concomitantly, cytoplasmic levels of aberrant transcripts and intron-containing unspliced transcripts increased in infected cells and displayed enrichment of MDA5 iCLIP peaks. Moreover, overexpression of the splicing factor SRSF3 reduced aberrant transcription and abrogated MDA5 activation. Taken together, we propose that MDA5 surveys RNA processing fidelity and can detect infections by sensing perturbations of post-transcriptional events such as splicing. MDA5 detects double-stranded RNA during viral infections. This work shows that MDA5 binds aberrant host RNA induced during viral infection. Rescue of aberrant cytoplasmic RNA during infection abrogated MDA5 activation.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"27 9","pages":"1815-1828"},"PeriodicalIF":26.5,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41590-026-02614-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148713270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TIF1γ regulates stability of regulatory T cells during inflammation","authors":"Eugenio Contreras-Castillo, Jesús Daniel Zambrano-Romero, Hober Nelson Núñez-Martínez, Ma. Cleofas Marcial-Medina, Javier Orozco-Cordoba, Diana Ríos-Ramírez, Ofelia Muñoz-Paleta, Diego Pérez-Vázquez, Andrés Felipe Sáenz-Cabezas, María Guadalupe García-Patiño, José Luis Ramos-Balderas, Gustavo Tapia-Urzúa, Luis Tenorio-Hernández, Georgina Guerrero, Nallely Cano-Domínguez, Diego Delgado-Zaldívar, Aurora Candelario-Martínez, Isaac Martínez-Racine, Ileana Licona-Limón, Iris Madera-Salcedo, Florencia Rosetti, José C. Crispín, Lilia G. Noriega, Porfirio Nava, Araceli Pérez-López, José Luis Maravillas-Montero, Félix Recillas-Targa, Victor Julián Valdés, Marina Macías-Silva, Martha Robles-Flores, Mayra Furlan-Magaril, Vesa Kaartinen, Jorge Henao-Mejía, Richard Flavell, Paula Licona-Limón","doi":"10.1038/s41590-026-02603-6","DOIUrl":"10.1038/s41590-026-02603-6","url":null,"abstract":"Regulatory T (Treg) cells are essential for controlling inflammation and maintaining tissue homeostasis. Transcriptional intermediary factor 1-γ (TIF1γ) has been implicated in noncanonical TGFβ–Smad signaling in hematopoietic stem cells, but its role in Treg cell function has not been explored. Here we show that TIF1γ-deficient Treg cells lose Foxp3 expression and acquire effector phenotypes in a cell-intrinsic manner upon inflammatory challenge. In vivo, TIF1γ-deficient Treg cells adopt type 1 helper T cell-like or pro-inflammatory ex-Treg cell states in autoimmune settings and display type 2 helper T cell-like features during helminth infection. These cells exhibit transcriptional programs associated with proliferation, T cell activation and T helper differentiation, along with increased chromatin accessibility at regulatory regions enriched for key transcription factors controlling T cell activation and lineage specification. Mechanistically, Treg cell instability in the absence of TIF1γ is largely independent of transforming growth factor beta signaling and instead is driven by activation of the β-catenin pathway. TIF1γ-deficient Treg cells accumulate β-catenin and display enhanced TCF7 activity. Genetic or pharmacological targeting of β-catenin restores Treg cell stability and function. We identify TIF1γ as a critical regulator of Treg cell stability that restrains β-catenin–TCF7 signaling, thereby preserving Foxp3 expression and preventing inflammatory reprogramming. This study identifies TIF1γ as a critical regulator of regulatory T cell stability during inflammation. By restraining β-catenin–TCF7 signaling, TIF1γ preserves Foxp3 expression, prevents inflammatory reprogramming and maintains immune tolerance.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"27 9","pages":"1887-1898"},"PeriodicalIF":26.5,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148713336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Author Correction: Regulatory T cells function in established systemic inflammation and reverse fatal autoimmunity","authors":"Wei Hu, Zhong-Min Wang, Yongqiang Feng, Michail Schizas, Beatrice E. Hoyos, Joris van der Veeken, Jacob G. Verter, Regina Bou-Puerto, Alexander Y. Rudensky","doi":"10.1038/s41590-026-02640-1","DOIUrl":"10.1038/s41590-026-02640-1","url":null,"abstract":"","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"27 9","pages":"1970-1970"},"PeriodicalIF":26.5,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41590-026-02640-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148707396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Author Correction: The kinase MST4 limits inflammatory responses through direct phosphorylation of the adaptor TRAF6","authors":"Shi Jiao, Zhen Zhang, Chuanchuan Li, Min Huang, Zhubing Shi, Yanyan Wang, Xiaomin Song, Heng Liu, Chunyang Li, Min Chen, Wenjia Wang, Yun Zhao, Zhengfan Jiang, Hongyan Wang, Catherine C. L. Wong, Chen Wang, Zhaocai Zhou","doi":"10.1038/s41590-026-02634-z","DOIUrl":"10.1038/s41590-026-02634-z","url":null,"abstract":"","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"27 9","pages":"1970-1970"},"PeriodicalIF":26.5,"publicationDate":"2026-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41590-026-02634-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148689715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Author Correction: 2B or not 2B is the question in DC ontogeny","authors":"Venetia Bigley, Matthew Collin","doi":"10.1038/s41590-026-02633-0","DOIUrl":"10.1038/s41590-026-02633-0","url":null,"abstract":"","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"27 9","pages":"1969-1969"},"PeriodicalIF":26.5,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41590-026-02633-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148669632","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tissue-resident immune cells drive genetic risk in autoimmune and lung diseases","authors":"Benjamin J. Schmiedel, Cristian Gonzalez-Colin, Vicente Fajardo-Rosas, Job Rocha, Hayley Simon, Johannes Ottensmeier, Ignacio E. Ramírez-Bernabé, April Cano, Angel De la Cruz Castillo, Elizabeth Márquez-Gómez, Brendan Ha, Jason A. Greenbaum, Lindsey Chudley, Judith Cave, Aiman Alzetani, Edwin Woo, Michael Shackcloth, Serena J. Chee, Vivek Chandra, Mitchell Kronenberg, Bjoern Peters, Christian H. Ottensmeier, Anusha-Preethi Ganesan, Pandurangan Vijayanand","doi":"10.1038/s41590-026-02596-2","DOIUrl":"10.1038/s41590-026-02596-2","url":null,"abstract":"Common genetic variants are associated with risk of lung and autoimmune diseases. However, we have a limited understanding of the pathological effects of these disease variants, specifically in tissue-resident immune cells at the frontier of infection and disease in the lung. To address this, we performed single-cell expression quantitative trait locus (eQTL) analysis across 29 distinct immune cell subsets isolated from lung tissue. Colocalization analysis of lung immune cell eQTLs with genome-wide association study (GWAS) signals from lung diseases, and infectious and autoimmune diseases, implicate disease-associated variants and their target genes functioning in a single or restricted group of cell types. Several genes, including ZFP57, showed significant colocalization between lung immune cell eQTLs and GWAS signals from multiple systemic and organ-restricted autoimmune diseases, highlighting shared genetic mechanisms underlying the risk of disease. Overall, our study shows that disease-associated variants from a wide range of autoimmune diseases impact gene expression in tissue-resident immune cell types ( https://lung.dice-database.org ). Schmiedel et al. present a human lung immune cell atlas linking disease-associated genetic variants to gene expression in tissue-resident immune cells.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"27 9","pages":"1942-1953"},"PeriodicalIF":26.5,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41590-026-02596-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148669668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Author Correction: Mitochondrial DNA oxidation propagates autoimmunity by enabling plasmacytoid dendritic cells to induce TFH differentiation","authors":"Hongxu Xian, Kosuke Watari, Masafumi Ohira, Jonathan S. Brito, Peng He, Janset Onyuru, Elina I. Zuniga, Hal M. Hoffman, Michael Karin","doi":"10.1038/s41590-026-02630-3","DOIUrl":"10.1038/s41590-026-02630-3","url":null,"abstract":"","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"27 9","pages":"1969-1969"},"PeriodicalIF":26.5,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41590-026-02630-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148648812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BCAT2 links branched-chain amino acids metabolism to interferon signaling to sustain macrophage inflammation","authors":"Xiaohui Meng, Haihui Han, Wulin You, Pengfei Xin, Ya Ju, Liangyu Cai, Lamei Zhou, Sheng Zhong, Zhuoyi Hu, Zhiyu Chen, Wenlei Qin, Yanhao Ge, Wei Yao, Lianbo Xiao, Yafeng Zhang","doi":"10.1038/s41590-026-02604-5","DOIUrl":"10.1038/s41590-026-02604-5","url":null,"abstract":"The mechanisms sustaining chronic inflammation in rheumatoid arthritis (RA) remain incompletely understood. Here we show that branched-chain amino acid (BCAA) catabolism, mediated by the mitochondrial enzyme BCAT2, sustained interferon-driven macrophage activation in autoimmune arthritis. Multi-omics and histological analyses of individuals with active RA or sustained remission revealed that active disease was associated with systemic BCAA depletion, synovial branched-chain ketoacid accumulation and elevated BCAT2 expression in interferon-responsive synovial macrophages. Mechanistically, interferon-γ induced BCAT2 transcription through the transcription factor IRF1 in RA synovial macrophages. In human monocyte-derived macrophages, BCAT2-dependent BCAA catabolism elevated mitochondrial reactive oxygen species, which in turn restrained SHP-1 activity, prolonged STAT1 and STAT2 phosphorylation and drove inflammatory cytokine production. Furthermore, myeloid-specific deletion of Bcat2 ameliorated collagen antibody-induced arthritis in mice. Pharmacological targeting of this pathway with telmisartan suppressed persistent arthritis in methotrexate-treated mice. Together, our findings identified BCAT2-dependent amino acid catabolism as a potentially targetable metabolic pathway in autoimmune arthritis. Zhang and colleagues show that BCAT2-dependent branched-chain amino acid catabolism sustains IFN-driven macrophage activation and chronic inflammation during autoimmune arthritis.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"27 9","pages":"1842-1855"},"PeriodicalIF":26.5,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148648773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A new role for LCs","authors":"Stephanie Houston","doi":"10.1038/s41590-026-02611-6","DOIUrl":"10.1038/s41590-026-02611-6","url":null,"abstract":"","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"27 8","pages":"1531-1531"},"PeriodicalIF":26.5,"publicationDate":"2026-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148605592","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}