Nature ImmunologyPub Date : 2025-10-24DOI: 10.1038/s41590-025-02315-3
Kazuko Shibuya,Akira Shibuya
{"title":"A co-stimulatory signal via the coinhibitory TIGIT.","authors":"Kazuko Shibuya,Akira Shibuya","doi":"10.1038/s41590-025-02315-3","DOIUrl":"https://doi.org/10.1038/s41590-025-02315-3","url":null,"abstract":"","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"119 3 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145357638","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 : 2025-10-22DOI: 10.1038/s41590-025-02313-5
Ryan J Rahman,Mariko L Bennett
{"title":"Microglial MEF2C is a uniquely human bridge between neurodevelopment and neurodegeneration.","authors":"Ryan J Rahman,Mariko L Bennett","doi":"10.1038/s41590-025-02313-5","DOIUrl":"https://doi.org/10.1038/s41590-025-02313-5","url":null,"abstract":"","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"43 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145339029","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 : 2025-10-22DOI: 10.1038/s41590-025-02299-0
Celina Nguyen,Emily H Broersma,Anna S Warden,Cristina Mora,Claudia Z Han,Zahara Keulen,Nathanael Spann,Jing Wang,Gabriela Ramirez,Samantha Mak,Samantha Trescott,Mohammadparsa Khakpour,Avalon Johnson,Fatir Qureshi,Michael R La Frano,Kiana Mohajeri,Michael E Talkowski,Olivia Corradin,Marie-Ève Tremblay,Christopher K Glass,Nicole G Coufal
{"title":"Transcriptional and epigenetic targets of MEF2C in human microglia contribute to cellular functions related to autism risk and age-related disease.","authors":"Celina Nguyen,Emily H Broersma,Anna S Warden,Cristina Mora,Claudia Z Han,Zahara Keulen,Nathanael Spann,Jing Wang,Gabriela Ramirez,Samantha Mak,Samantha Trescott,Mohammadparsa Khakpour,Avalon Johnson,Fatir Qureshi,Michael R La Frano,Kiana Mohajeri,Michael E Talkowski,Olivia Corradin,Marie-Ève Tremblay,Christopher K Glass,Nicole G Coufal","doi":"10.1038/s41590-025-02299-0","DOIUrl":"https://doi.org/10.1038/s41590-025-02299-0","url":null,"abstract":"MEF2C encodes a transcription factor that is critical in nervous system development. Here, to examine disease-associated functions of MEF2C in human microglia, we profiled microglia differentiated from isogenic MEF2C-haploinsufficient and MEF2C-knockout induced pluripotent stem cell lines. Complementary transcriptomic and functional analyses revealed that loss of MEF2C led to a hyperinflammatory phenotype with broad phagocytic impairment, lipid accumulation, lysosomal dysfunction and elevated basal inflammatory cytokine secretion. Genome-wide profiling of MEF2C-bound sites coupled with the active regulatory landscape enabled inference of its transcriptional functions and potential mechanisms for MEF2C-associated cellular functions. Transcriptomic and epigenetic approaches identified substantial overlap with idiopathic autism datasets, suggesting a broader role of human microglial MEF2C dysregulation in idiopathic autism. In a mouse xenotransplantation model, loss of MEF2C led to morphological, lysosomal and lipid abnormalities in human microglia in vivo. Together, these studies reveal mechanisms by which reduced microglial MEF2C could contribute to the development of neurological diseases.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"101 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145339028","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 : 2025-10-22DOI: 10.1038/s41590-025-02307-3
Kyle Ferchen,Xuan Zhang,Kairavee Thakkar,Guangyuan Li,David Bernardicius,Sidharth Sen,Priyanka Rawat,Andre Olsson,Sierra N Bennett,Crystal Potter,Fred D Finkelman,Josh Croteau,Samantha Morris,Harinder Singh,Nathan Salomonis,H Leighton Grimes
{"title":"A unified multimodal single-cell framework reveals a discrete state model of hematopoiesis in mice.","authors":"Kyle Ferchen,Xuan Zhang,Kairavee Thakkar,Guangyuan Li,David Bernardicius,Sidharth Sen,Priyanka Rawat,Andre Olsson,Sierra N Bennett,Crystal Potter,Fred D Finkelman,Josh Croteau,Samantha Morris,Harinder Singh,Nathan Salomonis,H Leighton Grimes","doi":"10.1038/s41590-025-02307-3","DOIUrl":"https://doi.org/10.1038/s41590-025-02307-3","url":null,"abstract":"Large-scale, unbiased single-cell genomics studies of complex developmental compartments, such as hematopoiesis, have inferred novel cell states and trajectories; however, further characterization has been hampered by difficulty isolating cells corresponding to discrete genomic states. To address this, we present a framework that integrates multimodal single-cell analyses (RNA, surface protein and chromatin) with high-dimensional flow cytometry and enables semiautomated enrichment and functional characterization of diverse cell states. Our approach combines transcription factor expression with chromatin activity to uncover hierarchical gene regulatory networks driving these states. We delineated and isolated rare bone marrow Lin-Sca-CD117+CD27+ multilineage cell states ('MultiLin'), validated predicted lineage trajectories and mapped differentiation potentials. Additionally, we used transcription factor activity on chromatin to trace and isolate multilineage progenitors undergoing multipotent to oligopotent lineage restriction. In the proposed model of steady-state hematopoiesis, discrete states governed developmental trajectories. This framework provides a scalable solution for isolating and characterizing novel cell states across different biological systems.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"27 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145339027","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":"Single-cell RNA profiling of blood CD4+ T cells identifies distinct helper and dysfunctional regulatory clusters in children with SLE.","authors":"Preetha Balasubramanian,Uthra Balaji,Marina Silva Santos,Jeanine Baisch,Cynthia Smitherman,Lynnette Walters,Paola Sparagana,Lorien Nassi,Katie Stewart,Julie Fuller,Terry Means,Virginia Savova,Jacques F Banchereau,Tracey Wright,Virginia Pascual,Jinghua Gu,Simone Caielli","doi":"10.1038/s41590-025-02297-2","DOIUrl":"https://doi.org/10.1038/s41590-025-02297-2","url":null,"abstract":"To characterize the complexity of the CD4⁺ T cell compartment in patients with systemic lupus erythematosus (SLE), we performed single-cell RNA sequencing of sorted blood CD4⁺ T cells from pediatric patients and healthy donors. We identified naive, memory, regulatory T (Treg) cell, proliferative and interferon-stimulated gene-high (ISG-high) clusters. Within the memory compartment, both follicular and peripheral helper cells were expanded in patients with lupus nephritis and/or high disease activity. Cytotoxic signatures were enriched in effector memory T cells re-expressing CD45RA (TEMRA), as well as in two memory subclusters, one of which overlapped with T helper 10-like cells (TH10). Notably, we observed an expansion of dysfunctional Treg cells in patients with lupus nephritis, along with upregulation of TLR5 and FCRL3 in SLE-naive Treg cells, suggesting a potential link with mucosal microbial dysbiosis. These findings highlight distinct CD4⁺ T cell subsets that may contribute to aberrant antibody responses and impaired immune regulation in SLE.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"58 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145338604","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 : 2025-10-21DOI: 10.1038/s41590-025-02312-6
Nan Shen,Betty P Tsao
{"title":"Charting new territory for T cells in pediatric lupus.","authors":"Nan Shen,Betty P Tsao","doi":"10.1038/s41590-025-02312-6","DOIUrl":"https://doi.org/10.1038/s41590-025-02312-6","url":null,"abstract":"","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"56 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145338603","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 : 2025-10-20DOI: 10.1038/s41590-025-02322-4
{"title":"Unexpected redundancy or harmfulness of plasmacytoid dendritic cells in viral infections.","authors":"","doi":"10.1038/s41590-025-02322-4","DOIUrl":"https://doi.org/10.1038/s41590-025-02322-4","url":null,"abstract":"","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"53 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145331639","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 : 2025-10-17DOI: 10.1038/s41590-025-02320-6
Tilman L B Hoelting,Tyler Park,Chrysothemis C Brown
{"title":"Antigen-presenting cells as arbiters of mucosal tolerance and immunity.","authors":"Tilman L B Hoelting,Tyler Park,Chrysothemis C Brown","doi":"10.1038/s41590-025-02320-6","DOIUrl":"https://doi.org/10.1038/s41590-025-02320-6","url":null,"abstract":"Within the intestine, the immune system encounters a vast array of microbial antigens, as well as dietary components. Antigen-presenting cells (APCs) play a critical role in tailoring an appropriate immune response, ensuring both tolerance to innocuous antigens and protection from pathogens. An explosion of single-cell transcriptomic studies has revealed new subsets of APCs within mucosal tissues and lymph nodes, most notably within the gut. Harnessing their full potential to elicit protective immunity during oral vaccination or restoration of tolerance in inflammatory or allergic diseases requires an in-depth understanding of their unique functional roles and differentiation programs. Here we review the growing understanding of APC heterogeneity and discuss how balance and cooperation between distinct subsets shape mucosal immunity, inflammation and tolerance.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"25 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145311459","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 : 2025-10-16DOI: 10.1038/s41590-025-02308-2
Samir N Khleif,Seema Gupta
{"title":"Cancer vaccines as enablers of immunotherapy.","authors":"Samir N Khleif,Seema Gupta","doi":"10.1038/s41590-025-02308-2","DOIUrl":"https://doi.org/10.1038/s41590-025-02308-2","url":null,"abstract":"Immunotherapy has transformed cancer care, but most patients do not respond and ultimately develop resistance. A central barrier to durable efficacy is the absence of robust, tumor-specific T cell responses, particularly in tumors characterized by low antigenicity and an immunosuppressive tumor microenvironment. Cancer vaccines, long explored with limited clinical success as monotherapies, are emerging as enablers of immunotherapy by restoring T cell priming, broadening neoantigen-specific repertoires and converting tumors from 'cold' to 'hot'. Advances in genomics and computational neoantigen prediction have reinvigorated the field. In this Review, we synthesize current knowledge on the immunobiology of T cell priming in cancer, define how cancer vaccines can address the multifaceted mechanisms of immune evasion, and outline principles for designing next-generation vaccine-based combinations. We also propose that integration of vaccines into immunotherapy regimens, guided by tumor-specific immune contexture, antigen selection and treatment sequencing, might expand the benefit of immunotherapy to a broader patient population.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"11 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145305591","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}