{"title":"Fibroblasts take center stage in brain repair.","authors":"Lidia Garcia-Bonilla,Josef Anrather,Costantino Iadecola","doi":"10.1038/s41590-025-02310-8","DOIUrl":"https://doi.org/10.1038/s41590-025-02310-8","url":null,"abstract":"","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"9 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145296133","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}
Nature ImmunologyPub Date : 2025-10-15DOI: 10.1038/s41590-025-02298-1
James E Vince,Nadia M Davidson,Maria C Tanzer
{"title":"Necroptotic cell death consequences and disease relevance.","authors":"James E Vince,Nadia M Davidson,Maria C Tanzer","doi":"10.1038/s41590-025-02298-1","DOIUrl":"https://doi.org/10.1038/s41590-025-02298-1","url":null,"abstract":"Arguably one of the most surprising revelations in the field of cell death research was the discovery that cellular necrosis, a lytic and inherently messy cell death with far-reaching consequences for human physiology, can be genetically encoded. There is no single necrotic pathway either, as compelling evidence exists for distinct necrotic modalities such as pyroptosis, necroptosis and ferroptosis. The recent momentum of molecular, structural and disease-relevant findings has opened the door to targeting necrotic machinery to prevent collateral tissue damage and inflammatory diseases. In this Review, we evaluate the case for targeting the necrotic cell death pathway called necroptosis. We examine the organs and cell types where the human necroptotic machinery is expressed, identifying a lymphocytic ZBP1, RIPK1, RIPK3 and MLKL signature, review knowledge into the immunogenic consequences of necroptotic signaling and highlight building evidence that necroptosis is engaged in humans and can be triggered by ischemic injuries. Finally, we note several limitations of mouse studies due to fundamental differences with the human necroptotic apparatus and critically appraise the evidence for necroptosis being a disease-driving factor that, if successfully targeted, could be of clinical benefit.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"11 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145296313","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}
Nature ImmunologyPub Date : 2025-10-15DOI: 10.1038/s41590-025-02300-w
Camilla Panetti,Rahel Daetwyler,Anja Moncsek,Nikolaos Patikas,Andreas Agrafiotis,Adelynn Tang,Francesco Andreata,Valeria Fumagalli,Jean De Lima,Lifen Wen,Carolyn G King,Ajithkumar Vasanthakumar,Matteo Iannacone,Axel Kallies,Alexander Yermanos,Martin Hemberg,Nicole Joller
{"title":"The co-inhibitory receptor TIGIT promotes tissue-protective functions in T cells.","authors":"Camilla Panetti,Rahel Daetwyler,Anja Moncsek,Nikolaos Patikas,Andreas Agrafiotis,Adelynn Tang,Francesco Andreata,Valeria Fumagalli,Jean De Lima,Lifen Wen,Carolyn G King,Ajithkumar Vasanthakumar,Matteo Iannacone,Axel Kallies,Alexander Yermanos,Martin Hemberg,Nicole Joller","doi":"10.1038/s41590-025-02300-w","DOIUrl":"https://doi.org/10.1038/s41590-025-02300-w","url":null,"abstract":"The co-inhibitory receptor TIGIT suppresses excessive immune responses in autoimmune conditions while also restraining antitumor immunity. In viral infections, TIGIT alone does not affect viral control but has been shown to limit tissue pathology. However, the underlying mechanisms are incompletely understood. Here we found TIGIT+ T cells to express not only an immunoregulatory gene signature but also a tissue repair gene signature. Specifically, after viral infection, TIGIT directly drives expression of the tissue growth factor amphiregulin (Areg), which is strongly reduced in the absence of TIGIT. We identified regulatory T (Treg) cells, but not CD8+ T cells, as the critical T cell subset mediating these tissue-protective effects. In Treg cells, TIGIT engagement after T cell antigen receptor stimulation induces the transcription factor Blimp-1, which then promotes Areg production and tissue repair. Thus, we uncovered a nonclassical function of the co-inhibitory receptor TIGIT, wherein it not only limits immune pathology by suppressing the immune response but also actively fosters tissue regeneration by inducing the tissue growth factor Areg in T cells.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"1 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145296136","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}
Nature ImmunologyPub Date : 2025-10-15DOI: 10.1038/s41590-025-02309-1
Akil Akhtar,Tiffany M Styles,Chunyang Gu,André Nicolás León,Gregory K Tharp,Kasey Stokdyk,Anass Abbad,Cora Hirst,Shirin Strohmeier,Gabriele Neumann,Sara T Richey,James A Ferguson,Uchurappa Mala,Hasan Ahmed,Julianna Han,Juan Manuel Carreño,Carl W Davis,Rustom Antia,Peter Palese,Andrew B Ward,Yoshihiro Kawaoka,Florian Krammer,Rafi Ahmed,Rama R Amara
{"title":"Influenza vaccine based on AS03-adjuvanted chimeric HA induces long-lived stalk-specific plasma cells in bone marrow and lymph nodes of nonhuman primates.","authors":"Akil Akhtar,Tiffany M Styles,Chunyang Gu,André Nicolás León,Gregory K Tharp,Kasey Stokdyk,Anass Abbad,Cora Hirst,Shirin Strohmeier,Gabriele Neumann,Sara T Richey,James A Ferguson,Uchurappa Mala,Hasan Ahmed,Julianna Han,Juan Manuel Carreño,Carl W Davis,Rustom Antia,Peter Palese,Andrew B Ward,Yoshihiro Kawaoka,Florian Krammer,Rafi Ahmed,Rama R Amara","doi":"10.1038/s41590-025-02309-1","DOIUrl":"https://doi.org/10.1038/s41590-025-02309-1","url":null,"abstract":"Current influenza vaccines face challenges due to antigenic evolution of the circulating virus and waning immunity in humans. Here we investigated the durability of humoral immunity induced by an influenza vaccine based on AS03-adjuvanted chimeric hemagglutinin (cHA) in nonhuman primates (NHPs). Two groups of NHPs received two doses of a seasonal quadrivalent influenza vaccine, followed by sequential immunization with split virus cHA vaccines cH8/1N1, and cH5/1N1. One group received cHA immunizations with AS03 adjuvant. We monitored serum antibodies and long-lived plasma cells in bone marrow for nearly 2 years after the final vaccination. cHA vaccines induced stalk-specific antibody responses. The addition of AS03 enhanced both the magnitude and durability of humoral immunity by establishing long-lived plasma cells in the bone marrow and lymph nodes for nearly 2 years. Passive transfer of NHP serum provided protection against challenge with heterologous influenza A virus strains in mice. This study highlights the potential of the AS03-adjuvanted chimeric HA vaccine strategy to provide durable and broadly protective humoral immunity.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"28 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145296130","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}
Nature ImmunologyPub Date : 2025-10-14DOI: 10.1038/s41590-025-02279-4
Joseph N Pucella,Raul A Maqueda-Alfaro,Hai Ni,Fernando Bandeira Sulczewski,Anna Eichinger,Eduardo Esteva,Ai C Ra,Annesa Das,Oriana A Perez,Jue Feng,Marlon Stoeckius,Peter Smibert,Alireza Khodadadi-Jamayran,Igor Dolgalev,Ellie Ivanova,Stela Sota,Ken Cadwell,Sergei B Koralov,Judy Zhong,Chetna Soni,Daniel B Stetson,Stuart P Weisberg,Donna L Farber,Juliana Idoyaga,Boris Reizis
{"title":"Tonic type I interferon signaling optimizes the antiviral function of plasmacytoid dendritic cells.","authors":"Joseph N Pucella,Raul A Maqueda-Alfaro,Hai Ni,Fernando Bandeira Sulczewski,Anna Eichinger,Eduardo Esteva,Ai C Ra,Annesa Das,Oriana A Perez,Jue Feng,Marlon Stoeckius,Peter Smibert,Alireza Khodadadi-Jamayran,Igor Dolgalev,Ellie Ivanova,Stela Sota,Ken Cadwell,Sergei B Koralov,Judy Zhong,Chetna Soni,Daniel B Stetson,Stuart P Weisberg,Donna L Farber,Juliana Idoyaga,Boris Reizis","doi":"10.1038/s41590-025-02279-4","DOIUrl":"https://doi.org/10.1038/s41590-025-02279-4","url":null,"abstract":"Plasmacytoid dendritic cells (pDCs) mount powerful antiviral type I interferon (IFN-I) responses, yet only a fraction of pDCs produces high levels of IFN-I. Here we report that peripheral pDCs in naive mice comprise three subsets (termed A, B and C) that represent progressive differentiation stages. This heterogeneity was generated by tonic IFN-I signaling elicited in part by the cGAS/STING and TLR9 DNA-sensing pathways. A small 'IFN-I-naive' subset (pDC-A) could give rise to other subsets; it was expanded in STING deficiency or after the IFN-I receptor blockade, but was abolished by exogenous IFN-I. In response to RNA viruses, pDC-A showed increased Bcl2-dependent survival and superior IFN-I responses, but was susceptible to virus infection. Conversely, the majority of pDCs comprised the 'IFN-I-primed' subsets (pDC-B/C) that showed lower IFN-I responses and poor survival, but did not support virus replication. Thus, tonic IFN-I signaling decreases the cytokine-producing capacity and survival of pDCs but increases their virus resistance, facilitating optimal antiviral responses.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"1 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145288402","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}
Nature ImmunologyPub Date : 2025-10-14DOI: 10.1038/s41590-025-02327-z
Margarita Dominguez-Villar,Anne-Sophie Gautron,Marine de Marcken,Marla J Keller,David A Hafler
{"title":"Author Correction: TLR7 induces anergy in human CD4+ T cells.","authors":"Margarita Dominguez-Villar,Anne-Sophie Gautron,Marine de Marcken,Marla J Keller,David A Hafler","doi":"10.1038/s41590-025-02327-z","DOIUrl":"https://doi.org/10.1038/s41590-025-02327-z","url":null,"abstract":"","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"95 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145288400","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}
Nature ImmunologyPub Date : 2025-10-14DOI: 10.1038/s41590-025-02290-9
Annika Niehrs,Laura Hertwig,Marcus Buggert,Isabella Nordström,Maura Statzu,M Betina Pampena,Sadia Samer,James J Knox,Benedikt Strunz,Dan Sun,Son Nguyen,Claudia Janoschka,Yafei Xing,Vincent H Wu,Ernesto Sparrelid,Arlisa Alisjahbana,Yu Gao,Natalie Sleiers,Otto Strauss,Iva Filipovic,Andrea Ponzetta,Itzel Medina-Andrade,Vera Nilsén,Carl Jorns,Martin Cornillet,Christopher Maucourant,Christoph Ziegenhain,Julia Hengst,George Tweet,Kyle Kroll,Gregory J Golden,Heiner Wedemeyer,Murat Kürtüncü,Yoav Dori,Maxim G Itkin,Luisa Klotz,Marie Schaffer,Bo-Göran Ericzon,Martin A Ivarsson,Mirko Paiardini,Greg Nowak,Tim Willinger,R Keith Reeves,Michael R Betts,Niklas K Björkström
{"title":"Transient tissue residency and lymphatic egress define human CD56bright NK cell homeostasis.","authors":"Annika Niehrs,Laura Hertwig,Marcus Buggert,Isabella Nordström,Maura Statzu,M Betina Pampena,Sadia Samer,James J Knox,Benedikt Strunz,Dan Sun,Son Nguyen,Claudia Janoschka,Yafei Xing,Vincent H Wu,Ernesto Sparrelid,Arlisa Alisjahbana,Yu Gao,Natalie Sleiers,Otto Strauss,Iva Filipovic,Andrea Ponzetta,Itzel Medina-Andrade,Vera Nilsén,Carl Jorns,Martin Cornillet,Christopher Maucourant,Christoph Ziegenhain,Julia Hengst,George Tweet,Kyle Kroll,Gregory J Golden,Heiner Wedemeyer,Murat Kürtüncü,Yoav Dori,Maxim G Itkin,Luisa Klotz,Marie Schaffer,Bo-Göran Ericzon,Martin A Ivarsson,Mirko Paiardini,Greg Nowak,Tim Willinger,R Keith Reeves,Michael R Betts,Niklas K Björkström","doi":"10.1038/s41590-025-02290-9","DOIUrl":"https://doi.org/10.1038/s41590-025-02290-9","url":null,"abstract":"Human tissue-resident (TR) CD56bright natural killer (NK) cells can be identified by expression of integrins and chemokine receptors inferred from murine studies, but many aspects of their homeostasis are unclear. Here we used an integrated approach of dynamic human, humanized mouse and non-human primate models and sampling of efferent lymph fluid to determine recirculation and TR patterns of human NK cells. By intravascular labeling, we showed that CD56bright NK cells access tissue niches at steady state. Furthermore, in human liver transplantation, donor-derived CD56bright NK cells represent the dominant TR NK cell population early after transplantation, but are replaced over time by infiltrating recipient NK cells that establish TR traits, a process partly regulated by Runx3. Transient TR CD56bright NK cells recirculated via lymphatics, displaying a consistent phenotype detectable in draining lymph nodes and efferent lymph fluid, and waned from peripheral blood on lymph node egress blockade. Finally, CD56dim NK cells, constrained to vasculature at steady state, entered lymph nodes upon inflammation. This study provides a mechanistic framework for the transient tissue residency and recirculation pattern of human NK cell populations.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"83 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145288477","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}
Nature ImmunologyPub Date : 2025-10-14DOI: 10.1038/s41590-025-02314-4
{"title":"Glomerular cross-talk in the progression of autoimmune kidney disease.","authors":"","doi":"10.1038/s41590-025-02314-4","DOIUrl":"https://doi.org/10.1038/s41590-025-02314-4","url":null,"abstract":"","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"42 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145288403","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}
Nature ImmunologyPub Date : 2025-10-08DOI: 10.1038/s41590-025-02295-4
Wei Hu, Gabriel A Dolsten, Eric Y Wang, Giorgi Beroshvili, Zhong-Min Wang, Aazam P Ghelani, Lion F K Uhl, Regina Bou-Puerto, Xiao Huang, Anthony J Michaels, Beatrice E Hoyos, Wenjie Jin, Yuri Pritykin, Alexander Y Rudensky
{"title":"Temporal and context-dependent requirements for the transcription factor Foxp3 expression in regulatory T cells.","authors":"Wei Hu, Gabriel A Dolsten, Eric Y Wang, Giorgi Beroshvili, Zhong-Min Wang, Aazam P Ghelani, Lion F K Uhl, Regina Bou-Puerto, Xiao Huang, Anthony J Michaels, Beatrice E Hoyos, Wenjie Jin, Yuri Pritykin, Alexander Y Rudensky","doi":"10.1038/s41590-025-02295-4","DOIUrl":"10.1038/s41590-025-02295-4","url":null,"abstract":"<p><p>Regulatory T (T<sub>reg</sub>) cells, expressing the transcription factor Foxp3, are obligatory gatekeepers of immune responsiveness, yet the mechanisms by which Foxp3 governs the T<sub>reg</sub> transcriptional network remain incompletely understood. Using a novel chemogenetic system of inducible Foxp3 protein degradation in vivo, we found that while Foxp3 was indispensable for the establishment of transcriptional and functional programs of newly generated T<sub>reg</sub> cells, Foxp3 loss in mature T<sub>reg</sub> cells resulted in minimal functional and transcriptional changes under steady state. This resilience of the Foxp3-dependent program in mature T<sub>reg</sub> cells was acquired over an unexpectedly long timescale; however, in settings of severe inflammation, Foxp3 loss led to a pronounced perturbation of T<sub>reg</sub> cell transcriptome and fitness. Furthermore, tumoral T<sub>reg</sub> cells were uniquely sensitive to Foxp3 degradation, which led to impairment in their suppressive function and tumor shrinkage in the absence of pronounced adverse effects. These studies demonstrate a context-dependent differential requirement for Foxp3 for T<sub>reg</sub> transcriptional and functional programs.</p>","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":" ","pages":""},"PeriodicalIF":27.6,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145252091","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}
Nature ImmunologyPub Date : 2025-10-07DOI: 10.1038/s41590-025-02292-7
Brian D Stadinski,Elizabeth A Mills,Preston A Humphries,Sarah B Cleveland,Parker Dow,Koura Murakami,Yue Ru Li,Masaaki Murakami,Masahiro Ono,Byron B Au-Yeung,Gerald P Morris,Juan Carlos Zúñiga-Pflücker,Robert A Campbell,Eric R Griffiths,Eric S Huseby,Wan-Lin Lo
{"title":"Age-dependent Zap70 expression in thymocytes regulates selection of the neonatal regulatory T cell repertoire.","authors":"Brian D Stadinski,Elizabeth A Mills,Preston A Humphries,Sarah B Cleveland,Parker Dow,Koura Murakami,Yue Ru Li,Masaaki Murakami,Masahiro Ono,Byron B Au-Yeung,Gerald P Morris,Juan Carlos Zúñiga-Pflücker,Robert A Campbell,Eric R Griffiths,Eric S Huseby,Wan-Lin Lo","doi":"10.1038/s41590-025-02292-7","DOIUrl":"https://doi.org/10.1038/s41590-025-02292-7","url":null,"abstract":"The Foxp3⁺ regulatory T (Treg) cell repertoire carries age-dependent biases, with neonatal subsets enriched for highly self-reactive clones. However, the thymocyte features distinguishing neonatal from adult Treg selection remain unclear. Here, we show that neonatal double-positive mouse thymocytes, unlike their adult counterparts, fail to upregulate Zap70 during thymic selection, creating a calcium signaling bottleneck. This attenuated Zap70-dependent signaling limits negative selection, allowing highly self-reactive clones to evade deletion. Modulating Zap70 expression alters this balance; reducing Zap70 in adults rescues development of these clones, whereas increasing Zap70 in neonates enforces their deletion. Similarly, enhancing neonatal calcium signaling via increased LAT Y136-mediated PLCγ1 activation promotes clonal deletion. Analysis of pediatric human thymi reveals that ZAP70 expression remains low during the first year of life, aligning with the peak window for thymic Treg cell development. These findings suggest that age-dependent Zap70 expression regulates negative selection and thymic Treg cell development.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"5 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145240875","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}