Nature ImmunologyPub Date : 2024-09-27DOI: 10.1038/s41590-024-01981-z
Stephanie A. Houston
{"title":"Learning from inborn errors","authors":"Stephanie A. Houston","doi":"10.1038/s41590-024-01981-z","DOIUrl":"10.1038/s41590-024-01981-z","url":null,"abstract":"","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":null,"pages":null},"PeriodicalIF":27.7,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142328604","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 : 2024-09-26DOI: 10.1038/s41590-024-01963-1
Geoffrey J. Markowitz, Yi Ban, Diamile A. Tavarez, Liron Yoffe, Enrique Podaza, Yongfeng He, Mitchell T. Martin, Michael J. P. Crowley, Tito A. Sandoval, Dingcheng Gao, M. Laura Martin, Olivier Elemento, Juan R. Cubillos-Ruiz, Timothy E. McGraw, Nasser K. Altorki, Vivek Mittal
{"title":"Deficiency of metabolic regulator PKM2 activates the pentose phosphate pathway and generates TCF1+ progenitor CD8+ T cells to improve immunotherapy","authors":"Geoffrey J. Markowitz, Yi Ban, Diamile A. Tavarez, Liron Yoffe, Enrique Podaza, Yongfeng He, Mitchell T. Martin, Michael J. P. Crowley, Tito A. Sandoval, Dingcheng Gao, M. Laura Martin, Olivier Elemento, Juan R. Cubillos-Ruiz, Timothy E. McGraw, Nasser K. Altorki, Vivek Mittal","doi":"10.1038/s41590-024-01963-1","DOIUrl":"10.1038/s41590-024-01963-1","url":null,"abstract":"TCF1high progenitor CD8+ T cells mediate the efficacy of immunotherapy; however, the mechanisms that govern their generation and maintenance are poorly understood. Here, we show that targeting glycolysis through deletion of pyruvate kinase muscle 2 (PKM2) results in elevated pentose phosphate pathway (PPP) activity, leading to enrichment of a TCF1high progenitor-exhausted-like phenotype and increased responsiveness to PD-1 blockade in vivo. PKM2KO CD8+ T cells showed reduced glycolytic flux, accumulation of glycolytic intermediates and PPP metabolites and increased PPP cycling as determined by 1,2-13C glucose carbon tracing. Small molecule agonism of the PPP without acute glycolytic impairment skewed CD8+ T cells toward a TCF1high population, generated a unique transcriptional landscape and adoptive transfer of agonist-treated CD8+ T cells enhanced tumor control in mice in combination with PD-1 blockade and promoted tumor killing in patient-derived tumor organoids. Our study demonstrates a new metabolic reprogramming that contributes to a progenitor-like T cell state promoting immunotherapy efficacy. TCF1+ progenitor-exhausted CD8+ T cell populations mediate durable antitumor immunity. Upon antigenic stimulation, effector T cells upregulate aerobic glycolysis to support their cytotoxic phenotype. Here, Mittal and colleagues find that loss of metabolic regulator PKM2 enriches for TCF1+ progenitor-exhausted-like cells and improves responsiveness to PD-1 blockade.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":null,"pages":null},"PeriodicalIF":27.7,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142321129","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 : 2024-09-25DOI: 10.1038/s41590-024-01967-x
Kevin Man, Axel Kallies
{"title":"Recreating immune and epithelial interactions in organoids","authors":"Kevin Man, Axel Kallies","doi":"10.1038/s41590-024-01967-x","DOIUrl":"10.1038/s41590-024-01967-x","url":null,"abstract":"A novel method that recreates human intestinal organoids containing viable tissue-resident memory T cells will facilitate the exploration of tissue–immune interactions and clinically relevant immune pathologies.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":null,"pages":null},"PeriodicalIF":27.7,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142317019","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 : 2024-09-23DOI: 10.1038/s41590-024-01962-2
Keita Saeki, Richard Pan, Eunju Lee, Daisuke Kurotaki, Keiko Ozato
{"title":"IRF8 defines the epigenetic landscape in postnatal microglia, thereby directing their transcriptome programs","authors":"Keita Saeki, Richard Pan, Eunju Lee, Daisuke Kurotaki, Keiko Ozato","doi":"10.1038/s41590-024-01962-2","DOIUrl":"10.1038/s41590-024-01962-2","url":null,"abstract":"Microglia are innate immune cells in the brain. Transcription factor IRF8 (interferon regulatory factor 8) is highly expressed in microglia. However, its role in postnatal microglia development is unknown. We demonstrate that IRF8 binds stepwise to enhancer regions of postnatal microglia along with Sall1 and PU.1, reaching a maximum after day 14. IRF8 binding correlated with a stepwise increase in chromatin accessibility, which preceded the initiation of microglia-specific transcriptome. Constitutive and postnatal Irf8 deletion led to a loss of microglia identity and gain of disease-associated microglia (DAM)-like genes. Combined analysis of single-cell (sc)RNA sequencing and single-cell transposase-accessible chromatin with sequencing (scATAC–seq) revealed a correlation between chromatin accessibility and transcriptome at a single-cell level. IRF8 was also required for microglia-specific DNA methylation patterns. Last, in the 5xFAD model, constitutive and postnatal Irf8 deletion reduced the interaction of microglia with amyloidβ plaques and the size of plaques, lessening neuronal loss. Together, IRF8 sets the epigenetic landscape, which is required for postnatal microglia gene expression. Saeki and colleagues show that IRF8 defines the epigenetic landscape in postnatal microglia, thereby directing their transcriptome programs.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":null,"pages":null},"PeriodicalIF":27.7,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142276873","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 : 2024-09-23DOI: 10.1038/s41590-024-01965-z
Maximilian Frosch, Marco Prinz
{"title":"IRF8 as durable architect of the microglial chromatin landscape","authors":"Maximilian Frosch, Marco Prinz","doi":"10.1038/s41590-024-01965-z","DOIUrl":"10.1038/s41590-024-01965-z","url":null,"abstract":"The transcription factor IRF8 has an essential function in microglia during early postnatal development, adulthood and disease.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":null,"pages":null},"PeriodicalIF":27.7,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142276840","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 : 2024-09-17DOI: 10.1038/s41590-024-01961-3
Sarah A. Weiss, Amy Y. Huang, Megan E. Fung, Daniela Martinez, Alex C. Y. Chen, Thomas J. LaSalle, Brian C. Miller, Christopher D. Scharer, Mudra Hegde, Thao H. Nguyen, Jared H. Rowe, Jossef F. Osborn, Dillon G. Patterson, Natalia Sifnugel, C. Mei-An Nolan, Richard A. Davidson, Marc A. Schwartz, Alexander P. R. Bally, Dennis K. Neeld, Martin W. LaFleur, Jeremy M. Boss, John G. Doench, W. Nicholas Haining, Arlene H. Sharpe, Debattama R. Sen
{"title":"Epigenetic tuning of PD-1 expression improves exhausted T cell function and viral control","authors":"Sarah A. Weiss, Amy Y. Huang, Megan E. Fung, Daniela Martinez, Alex C. Y. Chen, Thomas J. LaSalle, Brian C. Miller, Christopher D. Scharer, Mudra Hegde, Thao H. Nguyen, Jared H. Rowe, Jossef F. Osborn, Dillon G. Patterson, Natalia Sifnugel, C. Mei-An Nolan, Richard A. Davidson, Marc A. Schwartz, Alexander P. R. Bally, Dennis K. Neeld, Martin W. LaFleur, Jeremy M. Boss, John G. Doench, W. Nicholas Haining, Arlene H. Sharpe, Debattama R. Sen","doi":"10.1038/s41590-024-01961-3","DOIUrl":"10.1038/s41590-024-01961-3","url":null,"abstract":"PD-1 is a key negative regulator of CD8+ T cell activation and is highly expressed by exhausted T cells in cancer and chronic viral infection. Although PD-1 blockade can improve viral and tumor control, physiological PD-1 expression prevents immunopathology and improves memory formation. The mechanisms driving high PD-1 expression in exhaustion are not well understood and could be critical to disentangling its beneficial and detrimental effects. Here, we functionally interrogated the epigenetic regulation of PD-1 using a mouse model with deletion of an exhaustion-specific PD-1 enhancer. Enhancer deletion exclusively alters PD-1 expression in CD8+ T cells in chronic infection, creating a ‘sweet spot’ of intermediate expression where T cell function is optimized compared to wild-type and Pdcd1-knockout cells. This permits improved control of chronic infection without additional immunopathology. Together, these results demonstrate that tuning PD-1 via epigenetic editing can reduce CD8+ T cell dysfunction while avoiding excess immunopathology. PD-1 is a critical modulator of CD8+ T cell activation and exhaustion. Sen and colleagues show that a cell-state-specific enhancer tunes PD-1 expression exclusively in exhaustion and that deletion of this enhancer improves CD8+ T cell function.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":null,"pages":null},"PeriodicalIF":27.7,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142235043","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 : 2024-09-17DOI: 10.1038/s41590-024-01953-3
{"title":"A B cell receptor variant confers evolutionary protection against pathogens","authors":"","doi":"10.1038/s41590-024-01953-3","DOIUrl":"10.1038/s41590-024-01953-3","url":null,"abstract":"The G396R coding variant in IGHG1, which encodes membrane-bound IgG1 heavy chain, might have arisen within the Southeast Asian population as a potential evolutionary event on an archaic haplotype background. This variant potentiates immune resilience against various life-threatening organisms, illustrating the interplay of human evolution and immune adaptation.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":null,"pages":null},"PeriodicalIF":27.7,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142235041","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 : 2024-09-17DOI: 10.1038/s41590-024-01964-0
{"title":"Genomic map of the cellular composition of the tumor microenvironment","authors":"","doi":"10.1038/s41590-024-01964-0","DOIUrl":"10.1038/s41590-024-01964-0","url":null,"abstract":"We integrated single-cell RNA-sequencing data to provide comprehensive profiles of the cellular composition of the tumor microenvironment and identify their underlying genetic determinants across 23 cancer types. We used this resource to delineate the biological mechanisms by which genetic variants shape the cellular composition of the tumor microenvironment.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":null,"pages":null},"PeriodicalIF":27.7,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142235040","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 : 2024-09-16DOI: 10.1038/s41590-024-01960-4
Nicole M. Haynes, Thomas B. Chadwick, Belinda S. Parker
{"title":"The complexity of immune evasion mechanisms throughout the metastatic cascade","authors":"Nicole M. Haynes, Thomas B. Chadwick, Belinda S. Parker","doi":"10.1038/s41590-024-01960-4","DOIUrl":"10.1038/s41590-024-01960-4","url":null,"abstract":"Metastasis, the spread of cancer from a primary site to distant organs, is an important challenge in oncology. This Review explores the complexities of immune escape mechanisms used throughout the metastatic cascade to promote tumor cell dissemination and affect organotropism. Specifically, we focus on adaptive plasticity of disseminated epithelial tumor cells to understand how they undergo phenotypic transitions to survive microenvironmental conditions encountered during metastasis. The interaction of tumor cells and their microenvironment is analyzed, highlighting the local and systemic effects that innate and adaptive immune systems have in shaping an immunosuppressive milieu to foster aggressive metastatic tumors. Effectively managing metastatic disease demands a multipronged approach to target the parallel and sequential mechanisms that suppress anti-tumor immunity. This management necessitates a deep understanding of the complex interplay between tumor cells, their microenvironment and immune responses that we provide with this Review. This Review on the interplay between the immune system and metastasis is part of our wider Series of Reviews on Cancer Immunology and Immunotherapy.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":null,"pages":null},"PeriodicalIF":27.7,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142234453","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}
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