Nature Immunology最新文献

Cholesterol mobilization regulates dendritic cell maturation and the immunogenic response to cancer

IF 30.5 1区医学

Nature Immunology Pub Date : 2025-01-21 DOI: 10.1038/s41590-024-02065-8

Meriem Belabed, Matthew D. Park, Cédric M. Blouin, Sreekumar Balan, Chang Y. Moon, Grace Freed, Miguel Quijada-Álamo, Ante Peros, Raphaël Mattiuz, Amanda M. Reid, Nader Yatim, Jesse Boumelha, Camillia S. Azimi, Nelson M. LaMarche, Leanna Troncoso, Angelo Amabile, Jessica Le Berichel, Steven T. Chen, C. Matthias Wilk, Brian D. Brown, Kristen J. Radford, Sourav Ghosh, Carla V. Rothlin, Laurent Yvan-Charvet, Thomas U. Marron, Daniel J. Puleston, Elvin Wagenblast, Nina Bhardwaj, Christophe Lamaze, Miriam Merad

{"title":"Cholesterol mobilization regulates dendritic cell maturation and the immunogenic response to cancer","authors":"Meriem Belabed, Matthew D. Park, Cédric M. Blouin, Sreekumar Balan, Chang Y. Moon, Grace Freed, Miguel Quijada-Álamo, Ante Peros, Raphaël Mattiuz, Amanda M. Reid, Nader Yatim, Jesse Boumelha, Camillia S. Azimi, Nelson M. LaMarche, Leanna Troncoso, Angelo Amabile, Jessica Le Berichel, Steven T. Chen, C. Matthias Wilk, Brian D. Brown, Kristen J. Radford, Sourav Ghosh, Carla V. Rothlin, Laurent Yvan-Charvet, Thomas U. Marron, Daniel J. Puleston, Elvin Wagenblast, Nina Bhardwaj, Christophe Lamaze, Miriam Merad","doi":"10.1038/s41590-024-02065-8","DOIUrl":"https://doi.org/10.1038/s41590-024-02065-8","url":null,"abstract":"Maturation of conventional dendritic cells (cDCs) is crucial for maintaining tolerogenic safeguards against auto-immunity and for promoting immunogenic responses to pathogens and cancer. The subcellular mechanism for cDC maturation remains poorly defined. We show that cDCs mature by leveraging an internal reservoir of cholesterol (harnessed from extracellular cell debris and generated by de novo synthesis) to assemble lipid nanodomains on cell surfaces of maturing cDCs, enhance expression of maturation markers and stabilize immune receptor signaling. This process is dependent on cholesterol transport through Niemann–Pick disease type C1 (NPC1) and mediates homeostatic and Toll-like receptor (TLR)-induced maturation. Importantly, we identified the receptor tyrosine kinase AXL as a regulator of the NPC1-dependent construction of lipid nanodomains. Deleting AXL from cDCs enhances their maturation, thus improving anti-tumor immunity. Altogether, our study presents new insights into cholesterol mobilization as a fundamental basis for cDC maturation and highlights AXL as a therapeutic target for modulating cDCs.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"9 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142990660","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}

引用次数: 0

Variants and vaccines impact nasal immunity over three waves of SARS-CoV-2

IF 30.5 1区医学

Nature Immunology Pub Date : 2025-01-20 DOI: 10.1038/s41590-024-02052-z

Jaclyn M. L. Walsh, Vincent N. Miao, Anna H. Owings, Ying Tang, Joshua D. Bromley, Samuel W. Kazer, Kyle Kimler, Chelsea Asare, Carly G. K. Ziegler, Samira Ibrahim, Tasneem Jivanjee, Micayla George, Andrew W. Navia, Riley S. Drake, Adam Parker, Benjamin C. Billingsley, Paul Dotherow, Spurthi Tarugu, Sai K. Kota, Hannah Laird, T. Grant Wichman, Yesenia T. Davis, Neha S. Dhaliwal, Yilianys Pride, Yanglin Guo, Michal Senitko, Jessie Harvey, John T. Bates, Gill Diamond, Michael R. Garrett, D. Ashley Robinson, I. J. Frame, Jonathan J. Lyons, Tanya O. Robinson, Alex K. Shalek, Bruce H. Horwitz, Sarah C. Glover, Jose Ordovas-Montanes

{"title":"Variants and vaccines impact nasal immunity over three waves of SARS-CoV-2","authors":"Jaclyn M. L. Walsh, Vincent N. Miao, Anna H. Owings, Ying Tang, Joshua D. Bromley, Samuel W. Kazer, Kyle Kimler, Chelsea Asare, Carly G. K. Ziegler, Samira Ibrahim, Tasneem Jivanjee, Micayla George, Andrew W. Navia, Riley S. Drake, Adam Parker, Benjamin C. Billingsley, Paul Dotherow, Spurthi Tarugu, Sai K. Kota, Hannah Laird, T. Grant Wichman, Yesenia T. Davis, Neha S. Dhaliwal, Yilianys Pride, Yanglin Guo, Michal Senitko, Jessie Harvey, John T. Bates, Gill Diamond, Michael R. Garrett, D. Ashley Robinson, I. J. Frame, Jonathan J. Lyons, Tanya O. Robinson, Alex K. Shalek, Bruce H. Horwitz, Sarah C. Glover, Jose Ordovas-Montanes","doi":"10.1038/s41590-024-02052-z","DOIUrl":"https://doi.org/10.1038/s41590-024-02052-z","url":null,"abstract":"Viral variant and host vaccination status impact infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), yet how these factors shift cellular responses in the human nasal mucosa remains uncharacterized. We performed single-cell RNA sequencing (scRNA-seq) on nasopharyngeal swabs from vaccinated and unvaccinated adults with acute Delta and Omicron SARS-CoV-2 infections and integrated with data from acute infections with ancestral SARS-CoV-2. Patients with Delta and Omicron exhibited greater similarity in nasal cell composition driven by myeloid, T cell and SARS-CoV-2hi cell subsets, which was distinct from that of ancestral cases. Delta-infected samples had a marked increase in viral RNA, and a subset of PER2+EGR1+GDF15+ epithelial cells was enriched in SARS-CoV-2 RNA+ cells in all variants. Prior vaccination was associated with increased frequency and activation of nasal macrophages. Expression of interferon-stimulated genes negatively correlated with coronavirus disease 2019 (COVID-19) severity in patients with ancestral and Delta but not Omicron variants. Our study defines nasal cell responses and signatures of disease severity across SARS-CoV-2 variants and vaccination.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"56 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142989762","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}

引用次数: 0

IRE1α–XBP1 moonlighting to restrict leukemia

IF 30.5 1区医学

Nature Immunology Pub Date : 2025-01-17 DOI: 10.1038/s41590-024-02061-y

Stephanie Z. Xie

引用次数: 0

Intestinal microbiome metabolites control sepsis outcome

IF 30.5 1区医学

Nature Immunology Pub Date : 2025-01-17 DOI: 10.1038/s41590-024-02050-1

Carolina M. Polonio, Francisco J. Quintana

引用次数: 0

A cocktail of kinase inhibitors that enhance the antitumor effects of CAR-T cell therapy

IF 30.5 1区医学

Nature Immunology Pub Date : 2025-01-16 DOI: 10.1038/s41590-024-02049-8

引用次数: 0

Author Correction: Dual blockade of IL-10 and PD-1 leads to control of SIV viral rebound following analytical treatment interruption

IF 30.5 1区医学

Nature Immunology Pub Date : 2025-01-16 DOI: 10.1038/s41590-025-02079-w

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

引用次数: 0

Differential roles of human CD4+ and CD8+ regulatory T cells in controlling self-reactive immune responses

IF 30.5 1区医学

Nature Immunology Pub Date : 2025-01-13 DOI: 10.1038/s41590-024-02062-x

Xin Chen, Mustafa Ghanizada, Vamsee Mallajosyula, Elsa Sola, Robson Capasso, Karan Raj Kathuria, Mark M. Davis

{"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":"https://doi.org/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.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"16 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

IRE1α–XBP1 safeguards hematopoietic stem and progenitor cells by restricting pro-leukemogenic gene programs

IF 30.5 1区医学

Nature Immunology Pub Date : 2025-01-09 DOI: 10.1038/s41590-024-02063-w

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

{"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":"https://doi.org/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.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"3 1","pages":""},"PeriodicalIF":30.5,"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}

引用次数: 0

Low-avidity T cells drive endogenous tumor immunity in mice and humans

IF 30.5 1区医学

Nature Immunology Pub Date : 2025-01-09 DOI: 10.1038/s41590-024-02044-z

Summit Singhaviranon, Joseph P. Dempsey, Adam T. Hagymasi, Ion I. Mandoiu, Pramod K. Srivastava

{"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":"https://doi.org/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.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"28 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A multi-kinase inhibitor screen identifies inhibitors preserving stem-cell-like chimeric antigen receptor T cells

IF 30.5 1区医学

Nature Immunology Pub Date : 2025-01-08 DOI: 10.1038/s41590-024-02042-1

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

{"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":"https://doi.org/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.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"77 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0