Nature Immunology最新文献

{"title":"Intestinal microbiome metabolites control sepsis outcome","authors":"Carolina M. Polonio, Francisco J. Quintana","doi":"10.1038/s41590-024-02050-1","DOIUrl":"10.1038/s41590-024-02050-1","url":null,"abstract":"Sepsis results from a dysregulated immune response to infection. A study now shows that gut microbiota-derived metabolites prevent infection-triggered immunopathology by activating the aryl hydrocarbon receptor; pathogens inhibit this protective mechanism.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 2","pages":"155-156"},"PeriodicalIF":27.7,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987477","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 cocktail of kinase inhibitors that enhance the antitumor effects of CAR-T cell therapy","authors":"","doi":"10.1038/s41590-024-02049-8","DOIUrl":"10.1038/s41590-024-02049-8","url":null,"abstract":"In an unbiased high-throughput screen of 800 kinase inhibitors, we identified a cocktail of kinase inhibitors that increase the frequency of T memory stem cells for CAR-T cell therapy, resulting in improved antitumor effects both in vitro and in mouse models.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 2","pages":"170-171"},"PeriodicalIF":27.7,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142986806","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: Dual blockade of IL-10 and PD-1 leads to control of SIV viral rebound following analytical treatment interruption","authors":"Susan Pereira Ribeiro, Zachary Strongin, Hugo Soudeyns, Felipe ten-Caten, Khader Ghneim, Gabriela Pacheco Sanchez, Giuliana Xavier de Medeiros, Perla Mariana Del Rio Estrada, Adam-Nicolas Pelletier, Timothy Hoang, Kevin Nguyen, Justin Harper, Sherrie Jean, Chelsea Wallace, Robert Balderas, Jeffrey D. Lifson, Gopalan Raghunathan, Eric Rimmer, Cinthia V. Pastuskovas, Guoxin Wu, Luca Micci, Ruy M. Ribeiro, Chi Ngai Chan, Jacob D. Estes, Guido Silvestri, Daniel M. Gorman, Bonnie J. Howell, Daria J. Hazuda, Mirko Paiardini, Rafick P. Sekaly","doi":"10.1038/s41590-025-02079-w","DOIUrl":"10.1038/s41590-025-02079-w","url":null,"abstract":"","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 3","pages":"524-524"},"PeriodicalIF":27.7,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41590-025-02079-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142986805","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":"Differential roles of human CD4+ and CD8+ regulatory T cells in controlling self-reactive immune responses","authors":"Xin Chen, Mustafa Ghanizada, Vamsee Mallajosyula, Elsa Sola, Robson Capasso, Karan Raj Kathuria, Mark M. Davis","doi":"10.1038/s41590-024-02062-x","DOIUrl":"10.1038/s41590-024-02062-x","url":null,"abstract":"Here we analyzed the relative contributions of CD4+ regulatory T cells expressing Forkhead box protein P3 (FOXP3) and CD8+ regulatory T cells expressing killer cell immunoglobulin-like receptors to the control of autoreactive T and B lymphocytes in human tonsil-derived immune organoids. FOXP3 and GZMB respectively encode proteins FOXP3 and granzyme B, which are critical to the suppressive functions of CD4+ and CD8+ regulatory T cells. Using CRISPR–Cas9 gene editing, we were able to achieve a reduction of ~90–95% in the expression of these genes. FOXP3 knockout in tonsil T cells led to production of antibodies against a variety of autoantigens and increased the affinity of influenza-specific antibodies. By contrast, GZMB knockout resulted in an increase in follicular helper T cells, consistent with the ablation of CD8+ regulatory T cells observed in mouse models, and a marked expansion of autoreactive CD8+ and CD4+ T cells. These findings highlight the distinct yet complementary roles of CD8+ and CD4+ regulatory T cells in regulating cellular and humoral responses to prevent autoimmunity. Here the authors use a tonsil organoid culture model system to investigate the roles of human CD4+ and CD8+ regulatory T cells in controlling self-reactive immune responses. CD4+ regulatory T cells were stronger regulators of autoreactive B cells, autoantibodies and antigen-specific antibody affinity, whereas CD8+ regulatory T cells predominantly controlled expansion of follicular helper cells and autoreactive CD4+ and CD8+ T cells.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 2","pages":"230-239"},"PeriodicalIF":27.7,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41590-024-02062-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968272","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":"IRE1α–XBP1 safeguards hematopoietic stem and progenitor cells by restricting pro-leukemogenic gene programs","authors":"Brendan M. Barton, Francheska Son, Akanksha Verma, Saswat Kumar Bal, Qianzi Tang, Rui Wang, Katharine Umphred-Wilson, Rehan Khan, Josephine Trichka, Han Dong, Claudia Lentucci, Xi Chen, Yinghua Chen, Yuning Hong, Cihangir Duy, Olivier Elemento, Ari M. Melnick, Jin Cao, Xi Chen, Laurie H. Glimcher, Stanley Adoro","doi":"10.1038/s41590-024-02063-w","DOIUrl":"10.1038/s41590-024-02063-w","url":null,"abstract":"Hematopoietic stem cells must mitigate myriad stressors throughout their lifetime to ensure normal blood cell generation. Here, we uncover unfolded protein response stress sensor inositol-requiring enzyme-1α (IRE1α) signaling in hematopoietic stem and progenitor cells (HSPCs) as a safeguard against myeloid leukemogenesis. Activated in part by an NADPH oxidase-2 mechanism, IRE1α-induced X-box binding protein-1 (XBP1) mediated repression of pro-leukemogenic programs exemplified by the Wnt–β-catenin pathway. Transcriptome analysis and genome-wide mapping of XBP1 targets in HSPCs identified an ‘18-gene signature’ of XBP1-repressed β-catenin targets that were highly expressed in acute myeloid leukemia (AML) cases with worse prognosis. Accordingly, IRE1α deficiency cooperated with a myeloproliferative oncogene in HSPCs to cause a lethal AML in mice, while genetic induction of XBP1 suppressed the leukemia stem cell program and activity of patient-derived AML cells. Thus, IRE1α–XBP1 signaling safeguards the integrity of the blood system by restricting pro-leukemogenic programs in HSPCs. Adoro and colleagues report the involvement of the IRE1α–XBP1 signaling axis in protecting hematopoietic stem and progenitor cells from proteomic stress and as a safeguard against leukemic transformation.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 2","pages":"200-214"},"PeriodicalIF":27.7,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142937031","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":"Low-avidity T cells drive endogenous tumor immunity in mice and humans","authors":"Summit Singhaviranon, Joseph P. Dempsey, Adam T. Hagymasi, Ion I. Mandoiu, Pramod K. Srivastava","doi":"10.1038/s41590-024-02044-z","DOIUrl":"10.1038/s41590-024-02044-z","url":null,"abstract":"T cells recognize neoepitope peptide-major histocompatibility complex class I on cancer cells. The strength (or avidity) of the T cell receptor–peptide-major histocompatibility complex class I interaction is a critical variable in immune control of cancers. Here, we analyze neoepitope-specific CD8 cells of distinct avidities and show that low-avidity T cells are the sole mediators of cancer control in mice and are solely responsive to checkpoint blockade in mice and humans. High-avidity T cells are ineffective and immune-suppressive. The mechanistic basis of these differences lies in the higher exhaustion status of high-avidity cells. High-avidity T cells have a distinct transcriptomic profile that is used here to calculate an ‘avidity score’, which we then use for in silico identification of low-avidity and high-avidity T cells in mice and humans. Surprisingly, CD8+ T cells with identical T cell receptors exhibit wide variation in avidities, suggesting an additional level of regulation of T cell activity. Aside from providing a better understanding of endogenous T cell responses to cancer, these findings might instruct future immunotherapy strategies. Here the authors show that, in mouse tumors, CD8+ T cells with a low-avidity TCR are the mediators of antitumor and immunotherapy responses, in part because T cells with a high-avidity TCR are more exhausted.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 2","pages":"240-251"},"PeriodicalIF":27.7,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41590-024-02044-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142937028","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":"A multi-kinase inhibitor screen identifies inhibitors preserving stem-cell-like chimeric antigen receptor T cells","authors":"Feifei Song, Ourania Tsahouridis, Simone Stucchi, Tara Walhart, Sophie Mendell, P. Brian Hardy, Matthew Axtman, Shiva K. R. Guduru, Thomas S. K. Gilbert, Lee M. Graves, Laura E. Herring, Barbara Savoldo, Xingcong Ma, Mark Woodcock, Justin J. Milner, Anastasia Ivanova, Kenneth H. Pearce, Yang Xu, Gianpietro Dotti","doi":"10.1038/s41590-024-02042-1","DOIUrl":"10.1038/s41590-024-02042-1","url":null,"abstract":"Chimeric antigen receptor T cells (CAR T cells) with T stem (TSCM) cell-like phenotypic characteristics promote sustained antitumor effects. We performed an unbiased and automated high-throughput screen of a kinase-focused compound set to identify kinase inhibitors (KIs) that preserve human TSCM cell-like CAR T cells. We identified three KIs, UNC10225387B, UNC10225263A and UNC10112761A, that combined in vitro increased the frequency of CD45RA+CCR7+TCF1hi TSCM cell-like CAR T cells from both healthy donors and patients with cancer. KI-treated CAR T cells showed enhanced antitumor effects both in vitro and in vivo in mouse tumor models. The KI cocktail maintains TSCM cell-like phenotype preferentially in CAR T cells originating from naive T cells and causes transcriptomic changes without arresting T cell activation or modulating the chromatin organization. Specific kinases, ITK, ADCK3, MAP3K4 and CDK13, targeted by the KI cocktail in a dose-dependent manner are directly associated with the preservation of TSCM cell-like CAR T cells. Knockdown of these kinases individually or in combination enriches for TSCM cell-like CAR T cells, but only CAR T cells generated in the presence of the KI cocktail show robust expansion and differentiation on stimulation with tumor cells. Overall, transient pharmacological inhibition of strategically targeted kinases maintains stem-like features in CAR T cells and improves their antitumor activity. Dotti and colleagues performed an unbiased, high-throughput screen of kinase inhibitors to identify a three-kinase inhibitor cocktail capable of preserving a stem-cell-like subset in chimeric antigen receptor T cells.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 2","pages":"279-293"},"PeriodicalIF":27.7,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41590-024-02042-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936114","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":"β-Glucan reprograms neutrophils to promote disease tolerance against influenza A virus","authors":"Nargis Khan, Kim A. Tran, Raphael Chevre, Veronica Locher, Mathis Richter, Sarah Sun, Mina Sadeghi, Erwan Pernet, Andrea Herrero-Cervera, Alexandre Grant, Ahmed Saif, Jeffrey Downey, Eva Kaufmann, Shabaana Abdul Khader, Philippe Joubert, Luis B. Barreiro, Bryan G. Yipp, Oliver Soehnlein, Maziar Divangahi","doi":"10.1038/s41590-024-02041-2","DOIUrl":"10.1038/s41590-024-02041-2","url":null,"abstract":"Disease tolerance is an evolutionarily conserved host defense strategy that preserves tissue integrity and physiology without affecting pathogen load. Unlike host resistance, the mechanisms underlying disease tolerance remain poorly understood. In the present study, we investigated whether an adjuvant (β-glucan) can reprogram innate immunity to provide protection against influenza A virus (IAV) infection. β-Glucan treatment reduces the morbidity and mortality against IAV infection, independent of host resistance. The enhanced survival is the result of increased recruitment of neutrophils via RoRγt+ T cells in the lung tissue. β-Glucan treatment promotes granulopoiesis in a type 1 interferon-dependent manner that leads to the generation of a unique subset of immature neutrophils utilizing a mitochondrial oxidative metabolism and producing interleukin-10. Collectively, our data indicate that β-glucan reprograms hematopoietic stem cells to generate neutrophils with a new ‘regulatory’ function, which is required for promoting disease tolerance and maintaining lung tissue integrity against viral infection. Divangahi and colleagues report that β-glucan pretreatment before influenza A virus challenge can increase survival by inducing long-term reprogramming of neutrophils, promoting disease tolerance irrespective of viral load.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 2","pages":"174-187"},"PeriodicalIF":27.7,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41590-024-02041-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936110","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: Profibrotic monocyte-derived alveolar macrophages are expanded in patients with persistent respiratory symptoms and radiographic abnormalities after COVID-19","authors":"Joseph I. Bailey, Connor H. Puritz, Karolina J. Senkow, Nikolay S. Markov, Estefani Diaz, Emmy Jonasson, Zhan Yu, Suchitra Swaminathan, Ziyan Lu, Samuel Fenske, Rogan A. Grant, Hiam Abdala-Valencia, Ruben J. Mylvaganam, Amy Ludwig, Janet Miller, R. Ian Cumming, Robert M. Tighe, Kymberly M. Gowdy, Ravi Kalhan, Manu Jain, Ankit Bharat, Chitaru Kurihara, Ruben San Jose Estepar, Raul San Jose Estepar, George R. Washko, Ali Shilatifard, Jacob I. Sznajder, Karen M. Ridge, G. R. Scott Budinger, Rosemary Braun, Alexander V. Misharin, Marc A. Sala","doi":"10.1038/s41590-025-02076-z","DOIUrl":"10.1038/s41590-025-02076-z","url":null,"abstract":"","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 2","pages":"323-323"},"PeriodicalIF":27.7,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41590-025-02076-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142934764","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":"Retraction Note: Suppression of inflammation and acute lung injury by Miz1 via repression of C/EBP-δ","authors":"Hanh Chi Do-Umehara, Cong Chen, Daniela Urich, Liang Zhou, Ju Qiu, Samuel Jang, Alia Zander, Margaret A. Baker, Martin Eilers, Peter H. S. Sporn, Karen M. Ridge, Jacob I. Sznajder, G. R. Scott Budinger, Gökhan M. Mutlu, Anning Lin, Jing Liu","doi":"10.1038/s41590-024-02070-x","DOIUrl":"10.1038/s41590-024-02070-x","url":null,"abstract":"","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 2","pages":"324-324"},"PeriodicalIF":27.7,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41590-024-02070-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936111","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}