Nature ImmunologyPub Date : 2025-09-08DOI: 10.1038/s41590-025-02263-y
Emma C. Erlich, Quazim A. Alayo, Ayoung Kim, Jichang Han, Rachel L. Mintz, Christopher G. Huckstep, Heather S. Ruiz, Rachael L. Field, Taylor J. Dunning, Leila S. Saleh, Mark H. Hoofnagle, Alexei V. Tumanov, Farshid Guilak, Jonathan R. Brestoff, Rafael S. Czepielewski, Gwendalyn J. Randolph
{"title":"Distinct roles for B cell-derived LTα3 and LTα1β2 in TNF-mediated ileitis","authors":"Emma C. Erlich, Quazim A. Alayo, Ayoung Kim, Jichang Han, Rachel L. Mintz, Christopher G. Huckstep, Heather S. Ruiz, Rachael L. Field, Taylor J. Dunning, Leila S. Saleh, Mark H. Hoofnagle, Alexei V. Tumanov, Farshid Guilak, Jonathan R. Brestoff, Rafael S. Czepielewski, Gwendalyn J. Randolph","doi":"10.1038/s41590-025-02263-y","DOIUrl":"10.1038/s41590-025-02263-y","url":null,"abstract":"Crohn’s disease pathology is modeled in TNFΔARE+/− mice that overproduce tumor necrosis factor (TNF) to drive disease through TNF receptors. An alternative ligand for TNF receptors, soluble LTα3, is produced by B cells, but has received scarce attention because LTα also partners with LTβ to generate membrane-tethered LTαβ2 that promotes tertiary lymphoid tissue—another feature of Crohn’s disease. We hypothesized that B cell-derived LTαβ2 would critically affect ileitis in TNFΔARE+/− mice. However, whereas deleting LTβ in B cells was essential for tertiary lymphoid tissue, disease pathology was minimally affected. By contrast, loss of B cell-derived LTα increased intestinal permeability, shrunk the pool of IgA+ ileal plasma cells, elevated cytokines and prompted weight loss, including loss of muscle mass—a systemic feature of Crohn’s disease. Neutralizing antibodies to LTα3 strongly augmented the cachexic-like effects of TNF. Thus, B cell-produced LTαβ2 and LTα3 have distinct roles in ileitis, with the role of LTα3 unexpectedly protective through counterbalancing TNF. Erlich et al. show that soluble LTα and membrane-bound LTα1β2 lymphotoxins expressed by B cells play distinct roles to attenuate the pathology observed in ileitis.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 10","pages":"1781-1793"},"PeriodicalIF":27.6,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41590-025-02263-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145009042","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}
Nature ImmunologyPub Date : 2025-09-05DOI: 10.1038/s41590-025-02293-6
Rebeca Arroyo Hornero, Raul A. Maqueda-Alfaro, Miguel A. Solís-Barbosa, Rebecca A. Leylek, Olin Medina Chavez, Olivia M. Martinez, Andres Gottfried-Blackmore, Juliana Idoyaga
{"title":"Publisher Correction: TNF and type I interferon crosstalk controls the fate and function of plasmacytoid dendritic cells","authors":"Rebeca Arroyo Hornero, Raul A. Maqueda-Alfaro, Miguel A. Solís-Barbosa, Rebecca A. Leylek, Olin Medina Chavez, Olivia M. Martinez, Andres Gottfried-Blackmore, Juliana Idoyaga","doi":"10.1038/s41590-025-02293-6","DOIUrl":"https://doi.org/10.1038/s41590-025-02293-6","url":null,"abstract":"<p>Correction to: <i>Nature Immunology</i> https://doi.org/10.1038/s41590-025-02234-3, published online 12 August 2025.</p>","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"35 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145002991","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 : 2025-09-05DOI: 10.1038/s41590-025-02277-6
Nanyang Xiao, Airi Kogishi, Lisa Radochonski, Yuchong Lei, Jueqi Chen
{"title":"Type A cholesterol-dependent cytolysins translocate to the trans-Golgi network for NLRP3 inflammasome activation","authors":"Nanyang Xiao, Airi Kogishi, Lisa Radochonski, Yuchong Lei, Jueqi Chen","doi":"10.1038/s41590-025-02277-6","DOIUrl":"10.1038/s41590-025-02277-6","url":null,"abstract":"Cholesterol-dependent cytolysins (CDCs) constitute the largest group of pore-forming toxins and serve as critical virulence factors for diverse pathogenic bacteria. Several CDCs are known to activate the NLRP3 inflammasome, although the mechanisms are unclear. Here we discovered that multiple CDCs, which we referred to as type A CDCs, were internalized and translocated to the trans-Golgi network (TGN) to remodel it into a platform for NLRP3 activation through a unique peeling membrane mechanism. Potassium efflux was dispensable for CDC-mediated TGN remodeling and NLRP3 recruitment, but was required for the recruitment of the downstream adaptor ASC. In contrast, desulfolysin, which we referred to as type B CDC, was not internalized or translocated to the TGN due to its distinct C-terminal domain 4, despite potent pore formation on the plasma membrane, and hence could not activate NLRP3. Our discoveries uncovered the ability of CDCs to directly remodel an intracellular organelle for inflammatory response. Chen and colleagues show that type A cholesterol-dependent cytolysins, a group of bacteria pore-forming toxins, translocate to the trans-Golgi network to remodel it into a platform for NLRP3 activation.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 10","pages":"1673-1685"},"PeriodicalIF":27.6,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144995783","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 : 2025-09-05DOI: 10.1038/s41590-025-02269-6
Aliza Rosen, Iannis Aifantis
{"title":"The pre-T cell receptor as a tumor immunotherapy target in T cell leukemia","authors":"Aliza Rosen, Iannis Aifantis","doi":"10.1038/s41590-025-02269-6","DOIUrl":"10.1038/s41590-025-02269-6","url":null,"abstract":"The pre-T cell receptor is essential for T cell development. It is also an emerging immunotherapy target.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 10","pages":"1635-1636"},"PeriodicalIF":27.6,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144995782","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 : 2025-08-29DOI: 10.1038/s41590-025-02274-9
Nicholas J. Bernard
{"title":"T cells in space and time","authors":"Nicholas J. Bernard","doi":"10.1038/s41590-025-02274-9","DOIUrl":"10.1038/s41590-025-02274-9","url":null,"abstract":"","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 9","pages":"1425-1425"},"PeriodicalIF":27.6,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144915582","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 : 2025-08-29DOI: 10.1038/s41590-025-02273-w
Laurie A. Dempsey
{"title":"Humanized mice for MS studies","authors":"Laurie A. Dempsey","doi":"10.1038/s41590-025-02273-w","DOIUrl":"10.1038/s41590-025-02273-w","url":null,"abstract":"","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 9","pages":"1425-1425"},"PeriodicalIF":27.6,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144915584","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 : 2025-08-27DOI: 10.1038/s41590-025-02252-1
Maria Stadheim Eggebø, Julia Heinzelbecker, Heyilimu Palashati, Nicholas Chandler, Trung The Tran, Yingqian Li, Weiwen Yang, Maarja Laos, Isaac Blaas, Even Holth Rustad, Ravi Chand Bollineni, Marina Delic-Sarac, Fridtjof Lund-Johansen, Morten Milek Nielsen, Johanna Olweus
{"title":"TCR-engineered T cells targeting a shared β-catenin mutation eradicate solid tumors","authors":"Maria Stadheim Eggebø, Julia Heinzelbecker, Heyilimu Palashati, Nicholas Chandler, Trung The Tran, Yingqian Li, Weiwen Yang, Maarja Laos, Isaac Blaas, Even Holth Rustad, Ravi Chand Bollineni, Marina Delic-Sarac, Fridtjof Lund-Johansen, Morten Milek Nielsen, Johanna Olweus","doi":"10.1038/s41590-025-02252-1","DOIUrl":"10.1038/s41590-025-02252-1","url":null,"abstract":"HLA-bound peptides encoded by recurrent driver mutations are candidate targets for T cell-directed immunotherapy. Here we identify two neopeptides encoded by the CTNNB1S37F mutation presented on the frequent HLA-A*02:01 and HLA-A*24:02 molecules in cell lines naturally expressing the mutation and HLA alleles. This mutation leads to a gain of function in β-catenin and is estimated to occur in >7,000 new cancer cases annually in the United States. T cell receptors (TCRs) that specifically recognize the mutant peptides were isolated from naive healthy donor T cells. T cells redirected with CTNNB1-S37F TCRs efficiently killed CTNNB1S37F+ cell lines and patient-derived organoids in vitro and eradicated established tumors in a melanoma cell line mouse model and a patient-derived xenograft model of endometrial adenocarcinoma naturally expressing the mutation and the restricting HLA. We propose that TCR-T cells targeting CTNNB1-S37F can serve as a basis for solid cancer immunotherapy. TCR-T cells are T cells engineered to express a specific T cell receptor. Here the authors present a TCR-T cell that targets CTNNB1-S37F, corresponding to a shared cancer driver mutation. This immunotherapy killed solid tumors when applied to a patient-derived xenograft model in mice.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 10","pages":"1726-1736"},"PeriodicalIF":27.6,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41590-025-02252-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144906041","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}
Nature ImmunologyPub Date : 2025-08-22DOI: 10.1038/s41590-025-02257-w
Siying Lin, Hongshen Niu, Yuqi Zhang, Kexin Gai, Ryan Brown, Ashley Brown, Jian Shen, Ziyang Xu, Ravi K. Shah, Jessica L. Schmeling, Marlenny Vargas-Cortes, Anthony E. Zamora, Terumi Kohwi-Shigematsu, Jie Fan, Bin Zhang, Weiguo Cui
{"title":"SATB1 is a key regulator of quiescence in stem-like CD8+ T cells","authors":"Siying Lin, Hongshen Niu, Yuqi Zhang, Kexin Gai, Ryan Brown, Ashley Brown, Jian Shen, Ziyang Xu, Ravi K. Shah, Jessica L. Schmeling, Marlenny Vargas-Cortes, Anthony E. Zamora, Terumi Kohwi-Shigematsu, Jie Fan, Bin Zhang, Weiguo Cui","doi":"10.1038/s41590-025-02257-w","DOIUrl":"10.1038/s41590-025-02257-w","url":null,"abstract":"Stem-like progenitor CD8+ T (TPRO) cells sustain cytotoxic immunity during chronic infection and cancer through quiescence, multipotency and self-renewal, hallmarks shared with memory T cells. However, how these properties are maintained under persistent antigen stimulation remains unclear. Here we identify the genomic organizer SATB1 as selectively enriched in both TPRO and memory CD8+ T cells. Given its role in promoting quiescence in hematopoietic stem cells, we hypothesized that SATB1 supports CD8+ T cell stemness. Using CD8+ T cell-specific CRISPR deletion of the Satb1 gene, we show that SATB1 is essential for maintaining TPRO cells during chronic lymphocytic choriomeningitis virus infection and for memory CD8+ T cell formation during acute infection. Multi-omic profiling revealed that SATB1 regulates the chromatin accessibility, transcriptional activity and genome architecture of stemness-associated genes including Tcf7, Bach2 and Myb. These findings reveal a critical role for SATB1 in preserving the transcriptional and epigenetic programs that sustain the stem-like state of antigen-specific CD8+ T cells. Cui and colleagues identify the chromatin organizer protein SATB1 as a critical regulator of quiescence in stem-like progenitor CD8+ T cells that arise during chronic viral infection and cancer.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 10","pages":"1737-1751"},"PeriodicalIF":27.6,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144900339","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 : 2025-08-20DOI: 10.1038/s41590-025-02264-x
Stella Maris Ranuncolo, Jose M Polo, Jamil Dierov, Michael Singer, Tracy Kuo, John Greally, Roland Green, Martin Carroll, Ari Melnick
{"title":"Editorial Expression of Concern: Bcl-6 mediates the germinal center B cell phenotype and lymphomagenesis through transcriptional repression of the DNA-damage sensor ATR","authors":"Stella Maris Ranuncolo, Jose M Polo, Jamil Dierov, Michael Singer, Tracy Kuo, John Greally, Roland Green, Martin Carroll, Ari Melnick","doi":"10.1038/s41590-025-02264-x","DOIUrl":"10.1038/s41590-025-02264-x","url":null,"abstract":"","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 10","pages":"1837-1837"},"PeriodicalIF":27.6,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41590-025-02264-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144900342","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}