Nature Immunology最新文献

{"title":"AMBRA1 allosterically activates NLRP3 by releasing its autoinhibition","authors":"Minghui Pan, Jie Zhou, Shuo Fu, Yuluan Tang, Gonglu Zou, Pilong Li, Zhengfan Jiang","doi":"10.1038/s41590-026-02644-x","DOIUrl":"10.1038/s41590-026-02644-x","url":null,"abstract":"Nod-like receptor family pyrin domain-containing 3 (NLRP3) is activated by many stimuli, and its dysfunction is involved in various inflammatory diseases. Activation of NLRP3 is thought to happen via a multistep process involving phase separation, conformational opening and oligomerization. However, how NLRP3 is released from its autorepressed conformation remains elusive. Here we report that activating molecule in Beclin1-regulated autophagy protein 1 (AMBRA1), previously known for its role in autophagy, bound NLRP3 to scaffold and allosterically activate NLRP3. AMBRA1 engaged the leucine-rich repeat and helical domain 2 subdomains of NLRP3 through its β-propeller domain and destabilized the closed, inactive conformation of NLRP3, facilitating adenosine triphosphate binding and transition of NLRP3 to the active state. AMBRA1 deficiency in monocytes or macrophages impaired NLRP3 activation and reduced inflammatory responses in mouse models of endotoxic shock, colitis and sepsis. Nanobodies blocking the interaction between AMBRA1 and NLRP3 inhibited NLRP3 activation, underscoring the therapeutic potential of targeting this interaction. Our study revealed the role of AMBRA1 in NLRP3 inflammasome assembly and activation, offering potential pharmacological targets for related diseases. Jiang and colleagues show that the adaptor protein AMBRA1 binds NLRP3 to destabilize the closed, inactive conformation of NLRP3 and facilitate binding of ATP and transition to the active state of NLRP3.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"27 10","pages":"2017-2028"},"PeriodicalIF":26.5,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148920670","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":"Microbial adhesion promotes Piezo1 activation to initiate innate immunity.","authors":"Giulia Stucchi, Marco Galli, Stefano Cozzi, Anna Celant, Laura Marongiu, Giuseppe Rocca, Francesca Colnaghi, Maria Rita Chelazzi, Alessandra Polissi, Alessandra Maria Martorana, Giampiero Pietrocola, Marina Vai, Ivan Orlandi, Renato Ostuni, Simona Barresi, Angelo Lombardo, Metello Innocenti, Francesca Granucci","doi":"10.1038/s41590-026-02643-y","DOIUrl":"https://doi.org/10.1038/s41590-026-02643-y","url":null,"abstract":"<p><p>How mammals mount an effective immune response against infectious agents remains unresolved. Here we identify microbial adhesion to myeloid cells as a critical initiating event that precedes pattern recognition receptor (PRR) engagement. Using a skin infection model with pathogenic bacteria and fungi, we demonstrate that neutrophil recruitment occurs in two sequential phases. The early phase is PRR-independent and instead driven by microbial adhesion, which engages the mechanosensitive ion channel Piezo1 to promote leukotriene (LT)B₄ production. Together with interleukin-1α, LTB₄ induces CXCL1 release, triggering neutrophil infiltration via the same circuit at play during sterile inflammation. By contrast, the late phase is toll-like receptor (TLR)- and CXCL2-dependent, marking a transition to the canonical, pathogen-driven response. Our findings uncover microbial adhesion as a previously unrecognized danger signal that activates innate immunity via mechanotransduction, revealing a paradigm of how immune responses to infection are initiated.</p>","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":" ","pages":""},"PeriodicalIF":26.5,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148920708","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":"Neutrophil-hybrid CAR-macrophages bring double trouble to tumors","authors":"Marie Siwicki,&nbsp;Paul Kubes","doi":"10.1038/s41590-026-02650-z","DOIUrl":"10.1038/s41590-026-02650-z","url":null,"abstract":"Chimeric antigen receptors (CARs) have revolutionized engineered cell therapies for cancer. Impressive anti-tumor effects have now been achieved by fitting CARs onto fused macrophage–neutrophil hybrid syncytial, with a promising outlook for stand-alone and combination therapies.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"27 10","pages":"1975-1976"},"PeriodicalIF":26.5,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148912991","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":"Intratumoral T cell activation kills tumors regardless of T cell specificity","authors":"Olivia C. Ghirardelli Smith,&nbsp;Tyler T. Dao,&nbsp;Noah V. Gavil,&nbsp;Stephen D. O’Flanagan,&nbsp;Adam J. Rubin,&nbsp;Son Nguyen,&nbsp;Matthew B. Watowich,&nbsp;Nuo Liu,&nbsp;Eyob Weyu,&nbsp;Clare F. Quarnstrom,&nbsp;Andrew G. Soerens,&nbsp;Vineet Joag,&nbsp;Pamela C. Rosato,&nbsp;Matthew F. Krummel,&nbsp;Melissa A. Geller,&nbsp;Jeffrey S. Miller,&nbsp;Alessio Giubellino,&nbsp;Vaiva Vezys,&nbsp;Alex K. Shalek,&nbsp;David Masopust","doi":"10.1038/s41590-026-02642-z","DOIUrl":"10.1038/s41590-026-02642-z","url":null,"abstract":"Immunotherapies putatively require tumor-specific T cells. Here we show how T cells can eliminate tumors without tumor specificity via paracrine signaling. Activating unexhausted bystander non-tumor-specific T cells within tumors resulted in tumor elimination without conventional recognition-dependent mechanisms and in the absence of any tumor-specific T cell receptor (TCR)αβ+ T cells. Robust T cell activation recruited immune cells, used innate leukocytes and triggered a tumoricidal combination of effector molecules and panoptotic pathways. Mechanistically, interferon-γ, tumor necrosis factor and nitric oxide induced caspase-dependent death, recapitulating melanoma clearance in mice or human melanoma cell death in vitro. Gene expression signatures associated with this response in mice were predictive of survival among human patients with melanoma. Thus, triggering productive T cell activation within tumors can be sufficient for immunotherapy, without needing to induce or rescue cancer-specific responses. Here the authors show that T cell activation within tumors triggers tumor clearance that is independent of tumor antigen recognition and occurs via a paracrine mechanism involving effector cytokines, nitric oxide, leukocyte recruitment and innate immune cells.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"27 10","pages":"2134-2142"},"PeriodicalIF":26.5,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148912931","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":"New frontiers in pathogen immunity","authors":"Mauro Gaya,&nbsp;Mads Gyrd-Hansen,&nbsp;Anna Kajaste-Rudnitski,&nbsp;Matteo Iannacone,&nbsp;Nicolas Manel,&nbsp;Jonathan N. Pruneda,&nbsp;Jan Rehwinkel,&nbsp;Annemarthe G. van der Veen","doi":"10.1038/s41590-026-02657-6","DOIUrl":"10.1038/s41590-026-02657-6","url":null,"abstract":"The EMBO workshop ‘Pathogen Immunity and Signaling’ was held from 8 to 11 June 2026 in Leiden, the Netherlands, bringing together 175 participants from 25 countries to discuss the latest advances in antimicrobial immune defense.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"27 10","pages":"1986-1989"},"PeriodicalIF":26.5,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148912993","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":"ID2 orchestrates the final ‘E-scape’ from the −165-kb Zeb2 enhancer for cDC1 specification","authors":"Jingjing Yan,&nbsp;Yugu Zhang,&nbsp;Michaël Chopin","doi":"10.1038/s41590-026-02659-4","DOIUrl":"10.1038/s41590-026-02659-4","url":null,"abstract":"The Zeb2 −165-kb enhancer is not a simple genetic switch but a regulatory crossroads where transcription factors compete to calibrate lineage decisions and shape immune cell diversity.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"27 10","pages":"1-3"},"PeriodicalIF":26.5,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148912986","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":"The dual roles of uterine monocytes in regulation of tissue homeostasis throughout reproductive cycles in health and disease","authors":"Abdullah Shahzad,&nbsp;Olivia Moran,&nbsp;Yousef Alebrahim,&nbsp;Stefano Colombo,&nbsp;Livia Lacerda Mariano,&nbsp;Olivia Shorthouse,&nbsp;Hannah Morgan,&nbsp;Daxina Bhatt,&nbsp;Nicholas Scott,&nbsp;Felicity K. Hunter,&nbsp;Catriona Laverty,&nbsp;Peter Ruane,&nbsp;Gerard Graham,&nbsp;Isabel Paterson,&nbsp;Navneet Kaur,&nbsp;Zohra Amin,&nbsp;Mariam Lokman,&nbsp;I-Hsuan Lin,&nbsp;Syed Murtuza-Baker,&nbsp;Michael Haley,&nbsp;Ian J. Donaldson,&nbsp;Jenny Myers,&nbsp;Daniel R. Brison,&nbsp;John D. Aplin,&nbsp;Molly A. Ingersoll,&nbsp;Laurence Pearmain,&nbsp;Lamiya Mohiyiddeen,&nbsp;Elizabeth R. Mann","doi":"10.1038/s41590-026-02651-y","DOIUrl":"10.1038/s41590-026-02651-y","url":null,"abstract":"Inflammation occurs during the recurring cycles of tissue degradation, repair and remodeling in the uterus, but the mechanisms by which the immune system contributes to uterine tissue integrity are unclear. We reveal that uterine monocytes have dual roles in both tissue remodeling and inflammation, depending on the reproductive cycle stage. Circulating inflammatory monocytes infiltrated the uterus before their differentiation into proinflammatory or pro-repair macrophages, depending on interferon-γ and transforming growth factor-β, respectively. Human monocyte numbers peaked before the window of implantation, when an inflammatory environment is required for embryo implantation. Uterine monocytes exhibited cytotoxic properties, regulating epithelial cell apoptosis. Bioinformatic analyses of receptor–ligand interactions indicated that monocytes dominated interactions between myeloid cells and fibroblasts. These pathways were disrupted in uterine fibrosis, marked by excess inflammatory monocytes or macrophages and a loss of rhythmicity through reproductive cycles. These data reveal a key role for monocytes and their progeny in the regulation of uterine tissue homeostasis. Mann and colleagues reveal key roles for monocytes in replenishing the subsets of uterine macrophages involved in tissue remodeling and inflammation. These processes maintain tissue homeostasis in healthy reproductive cycles, but are disrupted in reproductive disease.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"27 10","pages":"2058-2073"},"PeriodicalIF":26.5,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41590-026-02651-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148912929","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: Peyer’s patch M cells organize an epithelial niche that sustains group 3 innate lymphoid cells and IL-22","authors":"Wang H. J. Cao,&nbsp;Yue You,&nbsp;Nancy Wang,&nbsp;M. Zeeshan Chaudhry,&nbsp;Huiyang Yu,&nbsp;Peter T. Bell,&nbsp;Ellesandra C. Noye,&nbsp;Renae Denman,&nbsp;Byungchul Lee,&nbsp;Abbey Waddington,&nbsp;Junpeng Ye,&nbsp;Jaring Schreuder,&nbsp;Qiutong Huang,&nbsp;Julie Tellier,&nbsp;Sophie Curio,&nbsp;James Santiago,&nbsp;Daniela Amann-Zalcenstein,&nbsp;Nicolas Jacquelot,&nbsp;Peter Hickey,&nbsp;Stephen L. Nutt,&nbsp;Cyril Seillet,&nbsp;Philip M. Hansbro,&nbsp;Verena C. Wimmer,&nbsp;Richard A. Strugnell,&nbsp;Zewen Kelvin Tuong,&nbsp;Matthew E. Ritchie,&nbsp;Gabrielle T. Belz","doi":"10.1038/s41590-026-02669-2","DOIUrl":"10.1038/s41590-026-02669-2","url":null,"abstract":"","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"27 10","pages":"1-1"},"PeriodicalIF":26.5,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41590-026-02669-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148875275","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":"Innate immune imprints shape HIV-1 reservoir cell persistence during long-term antiretroviral therapy","authors":"Toong Seng Tan,&nbsp;WeiWei Sun,&nbsp;Ce Gao,&nbsp;Mathias Viard,&nbsp;Lucy C. Walters,&nbsp;Melanie Lancien,&nbsp;Yuko Yuki,&nbsp;Tram N. Van,&nbsp;Carlos Casquero,&nbsp;Xuan Guo,&nbsp;Rebecca Hoh,&nbsp;David W. Haas,&nbsp;Nelson Michael,&nbsp;Gregory D. Kirk,&nbsp;George Yendewa,&nbsp;Rajesh T. Gandhi,&nbsp;Seble G. Kassaye,&nbsp;Phyllis C. Tien,&nbsp;Bruce D. Walker,&nbsp;Michael J. Peluso,&nbsp;Jeffrey M. Jacobson,&nbsp;Steven G. Deeks,&nbsp;Mary Carrington,&nbsp;Xu G. Yu,&nbsp;Mathias Lichterfeld","doi":"10.1038/s41590-026-02637-w","DOIUrl":"10.1038/s41590-026-02637-w","url":null,"abstract":"Host immune responses that can target and eliminate HIV-1 reservoir cells during suppressive antiretroviral therapy are poorly understood. Here, analyzing over 6,000 proviral DNA amplicons from 104 individuals on long-term antiretroviral therapy, we found that carriers of HLA-C2 allotypes, which promote NK cell education via interactions with KIR2DL1, exhibited lower frequencies of intact proviruses. No protective effects of HLA-C2 alleles were observed during untreated infection, suggesting a selective vulnerability of reservoir cells to NK-cell-mediated immune activity under antiretroviral therapy. Supporting this, frequencies of KIR2DL1+ NK cells, particularly those coexpressing the activating HLA-E receptor NKG2C, were inversely correlated with frequencies of intact proviruses. Moreover, viral protein U variants that strongly downregulate HLA-C, increasing a missing-self response by KIR2DL1+ NK cells, were associated with smaller reservoirs in carriers of HLA-C2. Infected cells surviving long-term displayed elevated HLA-C expression, consistent with in vivo selection for resistance to KIR2DL1+ NK-cell-mediated immune clearance. Immune activity of KIR2DL1+ NK cells against viral reservoir cells was enhanced by NKG2C–HLA-E interactions, as sequence variants in HLA-E-restricted HIV-1 epitopes reduced NKG2C-dependent NK cell activation and were associated with higher frequencies of intact proviruses. These findings underscore the critical influence of host and viral genetic variation on reservoir persistence and highlight opportunities for leveraging innate immunity in HIV cure strategies. HIV reservoir cells are traditionally considered invisible to host immune responses due to viral latency. This work challenges this view by demonstrating that HIV persistence during long-term antiretroviral therapy is strongly influenced by KIR2DL1-educated NK cells.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"27 10","pages":"2029-2042"},"PeriodicalIF":26.5,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41590-026-02637-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148875282","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":"Natural killers blast HIV reservoir landscape","authors":"Daniel A. Armendariz,&nbsp;Valter Silva Monteiro,&nbsp;Ya-Chi Ho","doi":"10.1038/s41590-026-02635-y","DOIUrl":"10.1038/s41590-026-02635-y","url":null,"abstract":"Natural killer (NK) cells leave distinct footprints on the HIV reservoir, leading to a smaller HIV reservoir size in individuals carrying the HLA-C2 allele. HIV escapes NK cell-mediated immunity through mutations in the viral proteins Vpu, Gag and Env.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"27 10","pages":"1-3"},"PeriodicalIF":26.5,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148875372","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}