Nature ImmunologyPub Date : 2024-07-02DOI: 10.1038/s41590-024-01884-z
Herman Netskar, Aline Pfefferle, Jodie P. Goodridge, Ebba Sohlberg, Olli Dufva, Sarah A. Teichmann, Demi Brownlie, Jakob Michaëlsson, Nicole Marquardt, Trevor Clancy, Amir Horowitz, Karl-Johan Malmberg
{"title":"Pan-cancer profiling of tumor-infiltrating natural killer cells through transcriptional reference mapping","authors":"Herman Netskar, Aline Pfefferle, Jodie P. Goodridge, Ebba Sohlberg, Olli Dufva, Sarah A. Teichmann, Demi Brownlie, Jakob Michaëlsson, Nicole Marquardt, Trevor Clancy, Amir Horowitz, Karl-Johan Malmberg","doi":"10.1038/s41590-024-01884-z","DOIUrl":"10.1038/s41590-024-01884-z","url":null,"abstract":"The functional diversity of natural killer (NK) cell repertoires stems from differentiation, homeostatic, receptor–ligand interactions and adaptive-like responses to viral infections. In the present study, we generated a single-cell transcriptional reference map of healthy human blood- and tissue-derived NK cells, with temporal resolution and fate-specific expression of gene-regulatory networks defining NK cell differentiation. Transfer learning facilitated incorporation of tumor-infiltrating NK cell transcriptomes (39 datasets, 7 solid tumors, 427 patients) into the reference map to analyze tumor microenvironment (TME)-induced perturbations. Of the six functionally distinct NK cell states identified, a dysfunctional stressed CD56bright state susceptible to TME-induced immunosuppression and a cytotoxic TME-resistant effector CD56dim state were commonly enriched across tumor types, the ratio of which was predictive of patient outcome in malignant melanoma and osteosarcoma. This resource may inform the design of new NK cell therapies and can be extended through transfer learning to interrogate new datasets from experimental perturbations or disease conditions. Malmberg and colleagues generated a single-cell transcriptional reference map to investigate pan-cancer profiles of tumor-infiltrating natural killer cells.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":null,"pages":null},"PeriodicalIF":27.7,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41590-024-01884-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141489207","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 : 2024-07-02DOI: 10.1038/s41590-024-01883-0
Lucas Rebuffet, Janine E. Melsen, Bertrand Escalière, Daniela Basurto-Lozada, Avinash Bhandoola, Niklas K. Björkström, Yenan T. Bryceson, Roberta Castriconi, Frank Cichocki, Marco Colonna, Daniel M. Davis, Andreas Diefenbach, Yi Ding, Muzlifah Haniffa, Amir Horowitz, Lewis L. Lanier, Karl-Johan Malmberg, Jeffrey S. Miller, Lorenzo Moretta, Emilie Narni-Mancinelli, Luke A. J. O’Neill, Chiara Romagnani, Dylan G. Ryan, Simona Sivori, Dan Sun, Constance Vagne, Eric Vivier
{"title":"High-dimensional single-cell analysis of human natural killer cell heterogeneity","authors":"Lucas Rebuffet, Janine E. Melsen, Bertrand Escalière, Daniela Basurto-Lozada, Avinash Bhandoola, Niklas K. Björkström, Yenan T. Bryceson, Roberta Castriconi, Frank Cichocki, Marco Colonna, Daniel M. Davis, Andreas Diefenbach, Yi Ding, Muzlifah Haniffa, Amir Horowitz, Lewis L. Lanier, Karl-Johan Malmberg, Jeffrey S. Miller, Lorenzo Moretta, Emilie Narni-Mancinelli, Luke A. J. O’Neill, Chiara Romagnani, Dylan G. Ryan, Simona Sivori, Dan Sun, Constance Vagne, Eric Vivier","doi":"10.1038/s41590-024-01883-0","DOIUrl":"10.1038/s41590-024-01883-0","url":null,"abstract":"Natural killer (NK) cells are innate lymphoid cells (ILCs) contributing to immune responses to microbes and tumors. Historically, their classification hinged on a limited array of surface protein markers. Here, we used single-cell RNA sequencing (scRNA-seq) and cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) to dissect the heterogeneity of NK cells. We identified three prominent NK cell subsets in healthy human blood: NK1, NK2 and NK3, further differentiated into six distinct subgroups. Our findings delineate the molecular characteristics, key transcription factors, biological functions, metabolic traits and cytokine responses of each subgroup. These data also suggest two separate ontogenetic origins for NK cells, leading to divergent transcriptional trajectories. Furthermore, we analyzed the distribution of NK cell subsets in the lung, tonsils and intraepithelial lymphocytes isolated from healthy individuals and in 22 tumor types. This standardized terminology aims at fostering clarity and consistency in future research, thereby improving cross-study comparisons. Single-cell technologies have unveiled a complex understanding of NK cells that has led to variations in nomenclature and inconsistencies across the scientific literature. Here, Vivier and colleagues used these technologies to dissect the heterogeneity of NK cells, revealing three prominent NK cell subsets in healthy human blood.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":null,"pages":null},"PeriodicalIF":27.7,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41590-024-01883-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141489436","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 : 2024-07-01DOI: 10.1038/s41590-024-01870-5
{"title":"Transcriptomic analysis of celiac disease treatment with transglutaminase 2 inhibitor","authors":"","doi":"10.1038/s41590-024-01870-5","DOIUrl":"10.1038/s41590-024-01870-5","url":null,"abstract":"The molecular basis for the efficacy of ZED1227 — a transglutaminase 2 inhibitor — in celiac disease is unknown. We show that orally administered ZED1227 effectively prevented gluten-induced intestinal damage and inflammation at the transcriptome level, and that individuals with high-risk HLA class II celiac disease consistently display a more ‘deteriorated’ molecular phenotype.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":null,"pages":null},"PeriodicalIF":27.7,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141477005","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":"Reciprocal regulation of T follicular helper cells and dendritic cells drives colitis development","authors":"Xue Bai, Sijie Chen, Xinxin Chi, Bowen Xie, Xinyi Guo, Han Feng, Peng Wei, Di Zhang, Shan Xie, Tian Xie, Yongzhen Chen, Mengting Gou, Qin Qiao, Xinwei Liu, Wei Jin, Wei Xu, Zixuan Zhao, Qi Xing, Xiaohu Wang, Xuegong Zhang, Chen Dong","doi":"10.1038/s41590-024-01882-1","DOIUrl":"10.1038/s41590-024-01882-1","url":null,"abstract":"The immunological mechanisms underlying chronic colitis are poorly understood. T follicular helper (TFH) cells are critical in helping B cells during germinal center reactions. In a T cell transfer colitis model, a lymphoid structure composed of mature dendritic cells (DCs) and TFH cells was found within T cell zones of colonic lymphoid follicles. TFH cells were required for mature DC accumulation, the formation of DC–T cell clusters and colitis development. Moreover, DCs promoted TFH cell differentiation, contributing to colitis development. A lineage-tracing analysis showed that, following migration to the lamina propria, TFH cells transdifferentiated into long-lived pathogenic TH1 cells, promoting colitis development. Our findings have therefore demonstrated the reciprocal regulation of TFH cells and DCs in colonic lymphoid follicles, which is critical in chronic colitis pathogenesis. Dong and colleagues describe how TFH cells initially interact with dendritic cells in colonic lymphoid follicles and further differentiate into long-lived pathogenic TH1 cells, promoting the progression of colitis.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":null,"pages":null},"PeriodicalIF":27.7,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141462619","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 : 2024-06-25DOI: 10.1038/s41590-024-01869-y
{"title":"Vaccination prevents cognitive impairment after breakthrough infection with SARS-CoV-2","authors":"","doi":"10.1038/s41590-024-01869-y","DOIUrl":"10.1038/s41590-024-01869-y","url":null,"abstract":"IL-1R1 signaling in neural stem cells reduces hippocampal neurogenesis in adult mice, potentially affecting learning and memory. Using a new mouse model, we report that IL-1β drives cognitive impairment after infection with SARS-CoV-2, and that IL-1β-driven cognitive impairment can be prevented by vaccination, even in cases of breakthrough infection.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":null,"pages":null},"PeriodicalIF":27.7,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141448293","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 : 2024-06-25DOI: 10.1038/s41590-024-01880-3
Daniel P. Chupp, Carlos E. Rivera, Yulai Zhou, Yijiang Xu, Patrick S. Ramsey, Zhenming Xu, Hong Zan, Paolo Casali
{"title":"A humanized mouse that mounts mature class-switched, hypermutated and neutralizing antibody responses","authors":"Daniel P. Chupp, Carlos E. Rivera, Yulai Zhou, Yijiang Xu, Patrick S. Ramsey, Zhenming Xu, Hong Zan, Paolo Casali","doi":"10.1038/s41590-024-01880-3","DOIUrl":"10.1038/s41590-024-01880-3","url":null,"abstract":"Humanized mice are limited in terms of modeling human immunity, particularly with regards to antibody responses. Here we constructed a humanized (THX) mouse by grafting non-γ-irradiated, genetically myeloablated KitW-41J mutant immunodeficient pups with human cord blood CD34+ cells, followed by 17β-estradiol conditioning to promote immune cell differentiation. THX mice reconstitute a human lymphoid and myeloid immune system, including marginal zone B cells, germinal center B cells, follicular helper T cells and neutrophils, and develop well-formed lymph nodes and intestinal lymphoid tissue, including Peyer’s patches, and human thymic epithelial cells. These mice have diverse human B cell and T cell antigen receptor repertoires and can mount mature T cell-dependent and T cell-independent antibody responses, entailing somatic hypermutation, class-switch recombination, and plasma cell and memory B cell differentiation. Upon flagellin or a Pfizer-BioNTech coronavirus disease 2019 (COVID-19) mRNA vaccination, THX mice mount neutralizing antibody responses to Salmonella or severe acute respiratory syndrome coronavirus 2 Spike S1 receptor-binding domain, with blood incretion of human cytokines, including APRIL, BAFF, TGF-β, IL-4 and IFN-γ, all at physiological levels. These mice can also develop lupus autoimmunity after pristane injection. By leveraging estrogen activity to support human immune cell differentiation and maturation of antibody responses, THX mice provide a platform to study the human immune system and to develop human vaccines and therapeutics. Humanized mice have been a valuable tool for modeling human immunology but are limited in their ability to model human antibody responses. Here the authors present their THX humanized mouse that does model human antibody responses and test its suitability for vaccination and autoimmunity studies.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":null,"pages":null},"PeriodicalIF":27.7,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41590-024-01880-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141448344","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 : 2024-06-25DOI: 10.1038/s41590-024-01889-8
{"title":"Lymphoid TCF1+CD39+CD8+ T cells maintain stem-like features and contribute to viral control","authors":"","doi":"10.1038/s41590-024-01889-8","DOIUrl":"10.1038/s41590-024-01889-8","url":null,"abstract":"Improved understanding of CD8+ T cell function during HIV infection is vital to designing an HIV cure. We have identified a subset of lymph node CD8+ T cells that demonstrate simultaneous stem-like and effector properties and are strongly associated with viral control during SIV and HIV infection.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":null,"pages":null},"PeriodicalIF":27.7,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141448211","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}