Nature Immunology最新文献

{"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}

{"title":"The epitranscriptional factor PCIF1 orchestrates CD8+ T cell ferroptosis and activation to control antitumor immunity","authors":"Bolin Xiang, Meiling Zhang, Kai Li, Zijian Zhang, Yutong Liu, Minling Gao, Xiyong Wang, Xiangling Xiao, Yishuang Sun, Chuan He, Jie Shi, Hongzeng Fan, Xixin Xing, Gaoshan Xu, Yingmeng Yao, Gang Chen, Haichuan Zhu, Chengqi Yi, Jinfang Zhang","doi":"10.1038/s41590-024-02047-w","DOIUrl":"10.1038/s41590-024-02047-w","url":null,"abstract":"T cell-based immunotherapies have revolutionized cancer treatment, yet durable responses remain elusive. Here we show that PCIF1, an RNA N6 2′-O-dimethyladenosine (m6Am) methyltransferase, negatively regulates CD8+ T cell antitumor responses. Whole-body or T cell-specific Pcif1 knockout (KO) reduced tumor growth in mice. Single-cell RNA sequencing shows an increase in the number of tumor-infiltrating cytotoxic CD8+ T cells in Pcif1-deficient mice. Mechanistically, proteomic and m6Am-sequencing analyses pinpoint that Pcif1 KO elevates m6Am-modified targets, specifically ferroptosis suppressor genes (Fth1, Slc3a2), and the T cell activation gene Cd69, imparting resistance to ferroptosis and enhancing CD8+ T cell activation. Of note, Pcif1-deficient mice had enhanced responses to anti-PD-1 immunotherapy, and Pcif1 KO chimeric antigen receptor T cells improved tumor control. Clinically, cancer patients with low PCIF1 expression in T cells have enhanced responses to immunotherapies. These findings suggest that PCIF1 suppresses CD8+ T cell activation and targeting PCIF1 is a promising strategy to boost antitumor immunity. Here the authors show that PCIF1 can regulate CD8+ T cell antitumor responses in mice and use this information to enhance chimeric antigen receptor T cell design.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 2","pages":"252-264"},"PeriodicalIF":27.7,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142929719","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":"Innate immune barrier against oncogenic transformation","authors":"","doi":"10.1038/s41590-024-02043-0","DOIUrl":"10.1038/s41590-024-02043-0","url":null,"abstract":"In a mouse model of lymphoma, inflammasome dysfunction increases hematopoietic stem cell turnover and accelerates lymphomagenesis. Our data show that inflammasome function, through the NLRP3–ASC–caspase 1–GSDMD axis, in bone marrow stromal cells controls the rate of hematopoietic stem cell proliferation and thereby reduces premalignant to malignant transformation.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 1","pages":"13-14"},"PeriodicalIF":27.7,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913070","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":"System vaccinology analysis of predictors and mechanisms of antibody response durability to multiple vaccines in humans","authors":"Mario Cortese, Thomas Hagan, Nadine Rouphael, Sheng-Yang Wu, Xia Xie, Dmitri Kazmin, Florian Wimmers, Shakti Gupta, Robbert van der Most, Margherita Coccia, Prabhu S. Aranuchalam, Helder I. Nakaya, Yating Wang, Elizabeth Coyle, Shu Horiuchi, Hanchih Wu, Mary Bower, Aneesh Mehta, Clifford Gunthel, Steve E. Bosinger, Yuri Kotliarov, Foo Cheung, Pamela L. Schwartzberg, Ronald N. Germain, John Tsang, Shuzhao Li, Randy Albrecht, Hideki Ueno, Shankar Subramaniam, Mark J. Mulligan, Surender Khurana, Hana Golding, Bali Pulendran","doi":"10.1038/s41590-024-02036-z","DOIUrl":"10.1038/s41590-024-02036-z","url":null,"abstract":"We performed a systems vaccinology analysis to investigate immune responses in humans to an H5N1 influenza vaccine, with and without the AS03 adjuvant, to identify factors influencing antibody response magnitude and durability. Our findings revealed a platelet and adhesion-related blood transcriptional signature on day 7 that predicted the longevity of the antibody response, suggesting a potential role for platelets in modulating antibody response durability. As platelets originate from megakaryocytes, we explored the effect of thrombopoietin (TPO)-mediated megakaryocyte activation on antibody response longevity. We found that TPO administration enhanced the durability of vaccine-induced antibody responses. TPO-activated megakaryocytes also promoted survival of human bone-marrow plasma cells through integrin β1/β2-mediated cell–cell interactions, along with survival factors APRIL and the MIF–CD74 axis. Using machine learning, we developed a classifier based on this platelet-associated signature, which predicted antibody response longevity across six vaccines from seven independent trials, highlighting a conserved mechanism for vaccine durability. Pulendran and colleagues define a molecular signature that can be used to predict the durability of antibody responses to vaccination and reveal important insights into the mechanisms by which vaccines induce durable immunity.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 1","pages":"116-130"},"PeriodicalIF":27.7,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913063","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 stromal inflammasome Ras safeguard against Myc-driven lymphomagenesis","authors":"Andrew Kent, Kristel Joy Yee Mon, Zachary Hutchins, Gregory Putzel, Dmitry Zhigarev, Alexander Grier, Baosen Jia, Roderik M. Kortlever, Gaetan Barbet, Gerard I. Evan, J. Magarian Blander","doi":"10.1038/s41590-024-02028-z","DOIUrl":"10.1038/s41590-024-02028-z","url":null,"abstract":"The inflammasome plays multifaceted roles in cancer, but less is known about its function during premalignancy upon initial cell transformation. We report a homeostatic function of the inflammasome in suppressing malignant transformation through Ras inhibition. We identified increased hematopoietic stem cell (HSC) proliferation within the bone marrow of inflammasome-deficient mice. HSCs within an inflammasome-deficient stroma expressed a Ras signature associated with increased Ras pathway- and cancer-related transcripts and heightened levels of cytokine, chemokine and growth factor receptors. Stromal inflammasome deficiency established a poised Ras-dependent mitogenic state within HSCs, which fueled progeny B cell lymphomagenesis upon Myc deregulation in a spontaneous model of B cell lymphoma, and shortened its premalignant stage leading to faster onset of malignancy. Thus, the stromal inflammasome preserves tissue balance by restraining Ras to disrupt the most common oncogenic Myc–Ras cooperation and establish a natural defense against transition to malignancy. These findings should inform preventative therapies against hematological malignancies. Blander and colleagues report a homeostatic regulatory effect played by inflammasomes in the bone marrow stromal compartment that suppresses premalignant stages of lymphomagenesis.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 1","pages":"53-67"},"PeriodicalIF":27.7,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913061","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}