Pub Date : 2024-07-05DOI: 10.1126/sciimmunol.adr2967
Andre Monteleone, Gabriel K. Griffin
Histone demethylation by PHF8 initiates innate immune signaling in acute myeloid leukemia, elucidating a novel therapeutic strategy.
PHF8 的组蛋白去甲基化启动了急性髓性白血病的先天免疫信号转导，阐明了一种新的治疗策略。
{"title":"Histone demethylation tones down leukemia through innate immunity","authors":"Andre Monteleone, Gabriel K. Griffin","doi":"10.1126/sciimmunol.adr2967","DOIUrl":"10.1126/sciimmunol.adr2967","url":null,"abstract":"<div >Histone demethylation by PHF8 initiates innate immune signaling in acute myeloid leukemia, elucidating a novel therapeutic strategy.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":17.6,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141538515","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}
Pub Date : 2024-06-28DOI: 10.1126/sciimmunol.adj8356
Erin D. Lucas, Matthew A. Huggins, Changwei Peng, Christine O’Connor, Abigail R. Gress, Claire E. Thefaine, Emma M. Dehm, Yoshiaki Kubota, Stephen C. Jameson, Sara E. Hamilton
KLRG1+ CD8 T cells persist for months after clearance of acute infections and maintain high levels of effector molecules, contributing protective immunity against systemic pathogens. Upon secondary infection, these long-lived effector cells (LLECs) are incapable of forming other circulating KLRG1− memory subsets such as central and effector memory T cells. Thus, KLRG1+ memory T cells are frequently referred to as a terminally differentiated population that is relatively short lived. Here, we show that after viral infection of mice, effector cells derived from LLECs rapidly enter nonlymphoid tissues and reduce pathogen burden but are largely dependent on receiving antigen cues from vascular endothelial cells. Single-cell RNA sequencing reveals that secondary memory cells in nonlymphoid tissues arising from either KLRG1+ or KLRG1− memory precursors develop a similar resident memory transcriptional signature. Thus, although LLECs cannot differentiate into other circulating memory populations, they still retain the flexibility to enter tissues and establish residency.
KLRG1 + CD8 T 细胞在急性感染清除后可存活数月，并保持高水平的效应分子，对全身性病原体产生保护性免疫力。二次感染后，这些长效效应细胞（LLECs）无法形成其他循环的 KLRG1 - 记忆亚群，如中枢记忆 T 细胞和效应记忆 T 细胞。因此，KLRG1 + 记忆 T 细胞经常被称为寿命相对较短的终末分化群体。在这里，我们发现在小鼠受到病毒感染后，来自 LLECs 的效应细胞会迅速进入非淋巴组织并减轻病原体的负担，但在很大程度上依赖于从血管内皮细胞接收抗原线索。单细胞 RNA 测序显示，非淋巴组织中由 KLRG1 + 或 KLRG1 - 记忆前体产生的次级记忆细胞具有类似的常驻记忆转录特征。因此，虽然 LLECs 无法分化成其他循环记忆群体，但它们仍能灵活地进入组织并建立驻留。
{"title":"Circulating KLRG1+ long-lived effector memory T cells retain the flexibility to become tissue resident","authors":"Erin D. Lucas, Matthew A. Huggins, Changwei Peng, Christine O’Connor, Abigail R. Gress, Claire E. Thefaine, Emma M. Dehm, Yoshiaki Kubota, Stephen C. Jameson, Sara E. Hamilton","doi":"10.1126/sciimmunol.adj8356","DOIUrl":"10.1126/sciimmunol.adj8356","url":null,"abstract":"<div >KLRG1<sup>+</sup> CD8 T cells persist for months after clearance of acute infections and maintain high levels of effector molecules, contributing protective immunity against systemic pathogens. Upon secondary infection, these long-lived effector cells (LLECs) are incapable of forming other circulating KLRG1<sup>−</sup> memory subsets such as central and effector memory T cells. Thus, KLRG1<sup>+</sup> memory T cells are frequently referred to as a terminally differentiated population that is relatively short lived. Here, we show that after viral infection of mice, effector cells derived from LLECs rapidly enter nonlymphoid tissues and reduce pathogen burden but are largely dependent on receiving antigen cues from vascular endothelial cells. Single-cell RNA sequencing reveals that secondary memory cells in nonlymphoid tissues arising from either KLRG1<sup>+</sup> or KLRG1<sup>−</sup> memory precursors develop a similar resident memory transcriptional signature. Thus, although LLECs cannot differentiate into other circulating memory populations, they still retain the flexibility to enter tissues and establish residency.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":17.6,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141463027","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}
Pub Date : 2024-06-28DOI: 10.1126/sciimmunol.adj2898
Miguel de Jesus, Alexander H. Settle, Daan Vorselen, Thomas K. Gaetjens, Michael Galiano, Yevgeniy Romin, Esther Lee, Yung Yu Wong, Tian-Ming Fu, Endi Santosa, Benjamin Y. Winer, Fella Tamzalit, Mitchell S. Wang, Anthony Santella, Zhirong Bao, Joseph C. Sun, Pavak Shah, Julie A. Theriot, Steven M. Abel, Morgan Huse
Immune cells have intensely physical lifestyles characterized by structural plasticity and force exertion. To investigate whether specific immune functions require stereotyped mechanical outputs, we used super-resolution traction force microscopy to compare the immune synapses formed by cytotoxic T cells with contacts formed by other T cell subsets and by macrophages. T cell synapses were globally compressive, which was fundamentally different from the pulling and pinching associated with macrophage phagocytosis. Spectral decomposition of force exertion patterns from each cell type linked cytotoxicity to compressive strength, local protrusiveness, and the induction of complex, asymmetric topography. These features were validated as cytotoxic drivers by genetic disruption of cytoskeletal regulators, live imaging of synaptic secretion, and in silico analysis of interfacial distortion. Synapse architecture and force exertion were sensitive to target stiffness and size, suggesting that the mechanical potentiation of killing is biophysically adaptive. We conclude that cellular cytotoxicity and, by implication, other effector responses are supported by specialized patterns of efferent force.
{"title":"Single-cell topographical profiling of the immune synapse reveals a biomechanical signature of cytotoxicity","authors":"Miguel de Jesus, Alexander H. Settle, Daan Vorselen, Thomas K. Gaetjens, Michael Galiano, Yevgeniy Romin, Esther Lee, Yung Yu Wong, Tian-Ming Fu, Endi Santosa, Benjamin Y. Winer, Fella Tamzalit, Mitchell S. Wang, Anthony Santella, Zhirong Bao, Joseph C. Sun, Pavak Shah, Julie A. Theriot, Steven M. Abel, Morgan Huse","doi":"10.1126/sciimmunol.adj2898","DOIUrl":"10.1126/sciimmunol.adj2898","url":null,"abstract":"<div >Immune cells have intensely physical lifestyles characterized by structural plasticity and force exertion. To investigate whether specific immune functions require stereotyped mechanical outputs, we used super-resolution traction force microscopy to compare the immune synapses formed by cytotoxic T cells with contacts formed by other T cell subsets and by macrophages. T cell synapses were globally compressive, which was fundamentally different from the pulling and pinching associated with macrophage phagocytosis. Spectral decomposition of force exertion patterns from each cell type linked cytotoxicity to compressive strength, local protrusiveness, and the induction of complex, asymmetric topography. These features were validated as cytotoxic drivers by genetic disruption of cytoskeletal regulators, live imaging of synaptic secretion, and in silico analysis of interfacial distortion. Synapse architecture and force exertion were sensitive to target stiffness and size, suggesting that the mechanical potentiation of killing is biophysically adaptive. We conclude that cellular cytotoxicity and, by implication, other effector responses are supported by specialized patterns of efferent force.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":17.6,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141463010","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}
Pub Date : 2024-06-28DOI: 10.1126/sciimmunol.adk4893
Jennifer A. Foltz, Jennifer Tran, Pamela Wong, Changxu Fan, Evelyn Schmidt, Bryan Fisk, Michelle Becker-Hapak, David A. Russler-Germain, Jeanette Johnson, Nancy D. Marin, Celia C. Cubitt, Patrick Pence, Joseph Rueve, Sushanth Pureti, Kimberly Hwang, Feng Gao, Alice Y. Zhou, Mark Foster, Timothy Schappe, Lynne Marsala, Melissa M. Berrien-Elliott, Amanda F. Cashen, Jeffrey J. Bednarski, Elana Fertig, Obi L. Griffith, Malachi Griffith, Ting Wang, Allegra A. Petti, Todd A. Fehniger
Activation of natural killer (NK) cells with the cytokines interleukin-12 (IL-12), IL-15, and IL-18 induces their differentiation into memory-like (ML) NK cells; however, the underlying epigenetic and transcriptional mechanisms are unclear. By combining ATAC-seq, CITE-seq, and functional analyses, we discovered that IL-12/15/18 activation results in two main human NK fates: reprogramming into enriched memory-like (eML) NK cells or priming into effector conventional NK (effcNK) cells. eML NK cells had distinct transcriptional and epigenetic profiles and enhanced function, whereas effcNK cells resembled cytokine-primed cNK cells. Two transcriptionally discrete subsets of eML NK cells were also identified, eML-1 and eML-2, primarily arising from CD56bright or CD56dim mature NK cell subsets, respectively. Furthermore, these eML subsets were evident weeks after transfer of IL-12/15/18–activated NK cells into patients with cancer. Our findings demonstrate that NK cell activation with IL-12/15/18 results in previously unappreciated diverse cellular fates and identifies new strategies to enhance NK therapies.
用白细胞介素-12（IL-12）、IL-15 和 IL-18 等细胞因子激活自然杀伤（NK）细胞可诱导其分化为记忆样（ML）NK 细胞；然而，其潜在的表观遗传和转录机制尚不清楚。通过结合ATAC-seq、CITE-seq和功能分析，我们发现IL-12/15/18激活会导致两种主要的人类NK命运：重编程为富集记忆样（eML）NK细胞或激发为效应传统NK（effcNK）细胞。研究还发现了两个转录离散的 eML NK 细胞亚群：eML-1 和 eML-2，它们分别主要来自 CD56 明亮或 CD56 模糊的成熟 NK 细胞亚群。此外，这些eML亚群在将IL-12/15/18激活的NK细胞转移到癌症患者体内数周后显现出来。我们的研究结果表明，用IL-12/15/18激活NK细胞会产生以前未曾认识到的多种细胞命运，并确定了加强NK疗法的新策略。
{"title":"Cytokines drive the formation of memory-like NK cell subsets via epigenetic rewiring and transcriptional regulation","authors":"Jennifer A. Foltz, Jennifer Tran, Pamela Wong, Changxu Fan, Evelyn Schmidt, Bryan Fisk, Michelle Becker-Hapak, David A. Russler-Germain, Jeanette Johnson, Nancy D. Marin, Celia C. Cubitt, Patrick Pence, Joseph Rueve, Sushanth Pureti, Kimberly Hwang, Feng Gao, Alice Y. Zhou, Mark Foster, Timothy Schappe, Lynne Marsala, Melissa M. Berrien-Elliott, Amanda F. Cashen, Jeffrey J. Bednarski, Elana Fertig, Obi L. Griffith, Malachi Griffith, Ting Wang, Allegra A. Petti, Todd A. Fehniger","doi":"10.1126/sciimmunol.adk4893","DOIUrl":"10.1126/sciimmunol.adk4893","url":null,"abstract":"<div >Activation of natural killer (NK) cells with the cytokines interleukin-12 (IL-12), IL-15, and IL-18 induces their differentiation into memory-like (ML) NK cells; however, the underlying epigenetic and transcriptional mechanisms are unclear. By combining ATAC-seq, CITE-seq, and functional analyses, we discovered that IL-12/15/18 activation results in two main human NK fates: reprogramming into enriched memory-like (eML) NK cells or priming into effector conventional NK (effcNK) cells. eML NK cells had distinct transcriptional and epigenetic profiles and enhanced function, whereas effcNK cells resembled cytokine-primed cNK cells. Two transcriptionally discrete subsets of eML NK cells were also identified, eML-1 and eML-2, primarily arising from CD56<sup>bright</sup> or CD56<sup>dim</sup> mature NK cell subsets, respectively. Furthermore, these eML subsets were evident weeks after transfer of IL-12/15/18–activated NK cells into patients with cancer. Our findings demonstrate that NK cell activation with IL-12/15/18 results in previously unappreciated diverse cellular fates and identifies new strategies to enhance NK therapies.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":17.6,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141462903","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}
Pub Date : 2024-06-21DOI: 10.1126/sciimmunol.adj8526
Sophie L. Gray-Gaillard, Sabrina M. Solis, Han M. Chen, Clarice Monteiro, Grace Ciabattoni, Marie I. Samanovic, Amber R. Cornelius, Tijaana Williams, Emilie Geesey, Miguel Rodriguez, Mila Brum Ortigoza, Ellie N. Ivanova, Sergei B. Koralov, Mark J. Mulligan, Ramin Sedaghat Herati
Memory CD4 T cells are critical to human immunity, yet it is unclear whether viral inflammation during memory formation has long-term consequences. Here, we compared transcriptional and epigenetic landscapes of Spike (S)–specific memory CD4 T cells in 24 individuals whose first exposure to S was via SARS-CoV-2 infection or mRNA vaccination. Nearly 2 years after memory formation, S-specific CD4 T cells established by infection remained enriched for transcripts related to cytotoxicity and for interferon-stimulated genes, likely because of a chromatin accessibility landscape altered by inflammation. Moreover, S-specific CD4 T cells primed by infection had reduced proliferative capacity in vitro relative to vaccine-primed cells. Furthermore, the transcriptional state of S-specific memory CD4 T cells was minimally altered by booster immunization and/or breakthrough infection. Thus, infection-associated inflammation durably imprints CD4 T cell memory, which affects the function of these cells and may have consequences for long-term immunity.
记忆性 CD4 T 细胞对人体免疫至关重要，但目前还不清楚记忆形成过程中的病毒炎症是否会产生长期影响。在这里，我们比较了 24 个首次接触 SARS-CoV-2 感染或接种 mRNA 疫苗的人体内 Spike（S）特异性记忆 CD4 T 细胞的转录和表观遗传景观。记忆形成近两年后，通过感染建立的 S 特异性 CD4 T 细胞仍然富集与细胞毒性相关的转录本和干扰素刺激基因，这可能是因为染色质可及性景观因炎症而发生了改变。此外，与疫苗诱导的细胞相比，感染诱导的 S 特异性 CD4 T 细胞在体外的增殖能力降低。此外，S特异性记忆CD4 T细胞的转录状态受加强免疫和/或突破性感染的影响很小。因此，与感染相关的炎症会持久地印记 CD4 T 细胞记忆，从而影响这些细胞的功能，并可能对长期免疫产生影响。
{"title":"SARS-CoV-2 inflammation durably imprints memory CD4 T cells","authors":"Sophie L. Gray-Gaillard, Sabrina M. Solis, Han M. Chen, Clarice Monteiro, Grace Ciabattoni, Marie I. Samanovic, Amber R. Cornelius, Tijaana Williams, Emilie Geesey, Miguel Rodriguez, Mila Brum Ortigoza, Ellie N. Ivanova, Sergei B. Koralov, Mark J. Mulligan, Ramin Sedaghat Herati","doi":"10.1126/sciimmunol.adj8526","DOIUrl":"10.1126/sciimmunol.adj8526","url":null,"abstract":"<div >Memory CD4 T cells are critical to human immunity, yet it is unclear whether viral inflammation during memory formation has long-term consequences. Here, we compared transcriptional and epigenetic landscapes of Spike (S)–specific memory CD4 T cells in 24 individuals whose first exposure to S was via SARS-CoV-2 infection or mRNA vaccination. Nearly 2 years after memory formation, S-specific CD4 T cells established by infection remained enriched for transcripts related to cytotoxicity and for interferon-stimulated genes, likely because of a chromatin accessibility landscape altered by inflammation. Moreover, S-specific CD4 T cells primed by infection had reduced proliferative capacity in vitro relative to vaccine-primed cells. Furthermore, the transcriptional state of S-specific memory CD4 T cells was minimally altered by booster immunization and/or breakthrough infection. Thus, infection-associated inflammation durably imprints CD4 T cell memory, which affects the function of these cells and may have consequences for long-term immunity.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":17.6,"publicationDate":"2024-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adj8526","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141437483","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}
Pub Date : 2024-06-21DOI: 10.1126/sciimmunol.adi8954
Yara El Morr, Mariela Fürstenheim, Martin Mestdagh, Katarzyna Franciszkiewicz, Marion Salou, Claire Morvan, Thierry Dupré, Alexey Vorobev, Bakhos Jneid, Virginie Premel, Aurélie Darbois, Laetitia Perrin, Stanislas Mondot, Ludovic Colombeau, Hélène Bugaut, Anastasia du Halgouet, Sophie Richon, Emanuele Procopio, Mathieu Maurin, Catherine Philippe, Raphael Rodriguez, Olivier Lantz, François Legoux
Intestinal inflammation shifts microbiota composition and metabolism. How the host monitors and responds to such changes remains unclear. Here, we describe a protective mechanism by which mucosal-associated invariant T (MAIT) cells detect microbiota metabolites produced upon intestinal inflammation and promote tissue repair. At steady state, MAIT ligands derived from the riboflavin biosynthesis pathway were produced by aerotolerant bacteria residing in the colonic mucosa. Experimental colitis triggered luminal expansion of riboflavin-producing bacteria, leading to increased production of MAIT ligands. Modulation of intestinal oxygen levels suggested a role for oxygen in inducing MAIT ligand production. MAIT ligands produced in the colon rapidly crossed the intestinal barrier and activated MAIT cells, which expressed tissue-repair genes and produced barrier-promoting mediators during colitis. Mice lacking MAIT cells were more susceptible to colitis and colitis-driven colorectal cancer. Thus, MAIT cells are sensitive to a bacterial metabolic pathway indicative of intestinal inflammation.
{"title":"MAIT cells monitor intestinal dysbiosis and contribute to host protection during colitis","authors":"Yara El Morr, Mariela Fürstenheim, Martin Mestdagh, Katarzyna Franciszkiewicz, Marion Salou, Claire Morvan, Thierry Dupré, Alexey Vorobev, Bakhos Jneid, Virginie Premel, Aurélie Darbois, Laetitia Perrin, Stanislas Mondot, Ludovic Colombeau, Hélène Bugaut, Anastasia du Halgouet, Sophie Richon, Emanuele Procopio, Mathieu Maurin, Catherine Philippe, Raphael Rodriguez, Olivier Lantz, François Legoux","doi":"10.1126/sciimmunol.adi8954","DOIUrl":"10.1126/sciimmunol.adi8954","url":null,"abstract":"<div >Intestinal inflammation shifts microbiota composition and metabolism. How the host monitors and responds to such changes remains unclear. Here, we describe a protective mechanism by which mucosal-associated invariant T (MAIT) cells detect microbiota metabolites produced upon intestinal inflammation and promote tissue repair. At steady state, MAIT ligands derived from the riboflavin biosynthesis pathway were produced by aerotolerant bacteria residing in the colonic mucosa. Experimental colitis triggered luminal expansion of riboflavin-producing bacteria, leading to increased production of MAIT ligands. Modulation of intestinal oxygen levels suggested a role for oxygen in inducing MAIT ligand production. MAIT ligands produced in the colon rapidly crossed the intestinal barrier and activated MAIT cells, which expressed tissue-repair genes and produced barrier-promoting mediators during colitis. Mice lacking MAIT cells were more susceptible to colitis and colitis-driven colorectal cancer. Thus, MAIT cells are sensitive to a bacterial metabolic pathway indicative of intestinal inflammation.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":17.6,"publicationDate":"2024-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141437482","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}
Pub Date : 2024-06-14DOI: 10.1126/sciimmunol.adp4474
Stephanie A. Ragland, Jonathan C. Kagan
Single-stranded DNA containing CGT/A motifs binds to the helicase domain of Schlafen 11 (SLFN11) to initiate cell death and cytokine production via SLFN11 ribonuclease activity (see related Research Article by Zhang et al.).
{"title":"Waking the sleeping giant: Single-stranded DNA binds Schlafen 11 to initiate innate immune responses","authors":"Stephanie A. Ragland, Jonathan C. Kagan","doi":"10.1126/sciimmunol.adp4474","DOIUrl":"10.1126/sciimmunol.adp4474","url":null,"abstract":"<div >Single-stranded DNA containing CGT/A motifs binds to the helicase domain of Schlafen 11 (SLFN11) to initiate cell death and cytokine production via SLFN11 ribonuclease activity (see related Research Article by Zhang <i>et al.</i>).</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":24.8,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141321588","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}
Pub Date : 2024-06-14DOI: 10.1126/sciimmunol.add6774
Leon U. B. Enk, Malte Hellmig, Kristoffer Riecken, Christoph Kilian, Paul Datlinger, Saskia L. Jauch-Speer, Tobias Neben, Zeba Sultana, Varshi Sivayoganathan, Alina Borchers, Hans-Joachim Paust, Yu Zhao, Nariaki Asada, Shuya Liu, Theodora Agalioti, Penelope Pelczar, Thorsten Wiech, Christoph Bock, Tobias B. Huber, Samuel Huber, Stefan Bonn, Nicola Gagliani, Boris Fehse, Ulf Panzer, Christian F. Krebs
Pro-inflammatory CD4+ T cells are major drivers of autoimmune diseases, yet therapies modulating T cell phenotypes to promote an anti-inflammatory state are lacking. Here, we identify T helper 17 (TH17) cell plasticity in the kidneys of patients with antineutrophil cytoplasmic antibody–associated glomerulonephritis on the basis of single-cell (sc) T cell receptor analysis and scRNA velocity. To uncover molecules driving T cell polarization and plasticity, we established an in vivo pooled scCRISPR droplet sequencing (iCROP-seq) screen and applied it to mouse models of glomerulonephritis and colitis. CRISPR-based gene targeting in TH17 cells could be ranked according to the resulting transcriptional perturbations, and polarization biases into T helper 1 (TH1) and regulatory T cells could be quantified. Furthermore, we show that iCROP-seq can facilitate the identification of therapeutic targets by efficient functional stratification of genes and pathways in a disease- and tissue-specific manner. These findings uncover TH17 to TH1 cell plasticity in the human kidney in the context of renal autoimmunity.
促炎性 CD4+ T 细胞是自身免疫性疾病的主要驱动因素，但目前还缺乏调节 T 细胞表型以促进抗炎状态的疗法。在这里，我们根据单细胞（sc）T细胞受体分析和scRNA速度，确定了抗中性粒细胞胞浆抗体相关性肾小球肾炎患者肾脏中T辅助细胞17（TH17）的可塑性。为了发现驱动 T 细胞极化和可塑性的分子，我们建立了体内集合 scCRISPR 液滴测序（iCROP-seq）筛选，并将其应用于肾小球肾炎和结肠炎小鼠模型。基于CRISPR的TH17细胞基因打靶可根据所产生的转录扰动进行排序，并可量化T辅助细胞1（TH1）和调节性T细胞的极化偏向。此外，我们还发现，iCROP-seq 能以疾病和组织特异性的方式对基因和通路进行有效的功能分层，从而促进治疗靶点的确定。这些发现揭示了肾脏自身免疫背景下人类肾脏中 TH17 到 TH1 细胞的可塑性。
{"title":"Targeting T cell plasticity in kidney and gut inflammation by pooled single-cell CRISPR screening","authors":"Leon U. B. Enk, Malte Hellmig, Kristoffer Riecken, Christoph Kilian, Paul Datlinger, Saskia L. Jauch-Speer, Tobias Neben, Zeba Sultana, Varshi Sivayoganathan, Alina Borchers, Hans-Joachim Paust, Yu Zhao, Nariaki Asada, Shuya Liu, Theodora Agalioti, Penelope Pelczar, Thorsten Wiech, Christoph Bock, Tobias B. Huber, Samuel Huber, Stefan Bonn, Nicola Gagliani, Boris Fehse, Ulf Panzer, Christian F. Krebs","doi":"10.1126/sciimmunol.add6774","DOIUrl":"10.1126/sciimmunol.add6774","url":null,"abstract":"<div >Pro-inflammatory CD4<sup>+</sup> T cells are major drivers of autoimmune diseases, yet therapies modulating T cell phenotypes to promote an anti-inflammatory state are lacking. Here, we identify T helper 17 (T<sub>H</sub>17) cell plasticity in the kidneys of patients with antineutrophil cytoplasmic antibody–associated glomerulonephritis on the basis of single-cell (sc) T cell receptor analysis and scRNA velocity. To uncover molecules driving T cell polarization and plasticity, we established an in vivo pooled scCRISPR droplet sequencing (iCROP-seq) screen and applied it to mouse models of glomerulonephritis and colitis. CRISPR-based gene targeting in T<sub>H</sub>17 cells could be ranked according to the resulting transcriptional perturbations, and polarization biases into T helper 1 (T<sub>H</sub>1) and regulatory T cells could be quantified. Furthermore, we show that iCROP-seq can facilitate the identification of therapeutic targets by efficient functional stratification of genes and pathways in a disease- and tissue-specific manner. These findings uncover T<sub>H</sub>17 to T<sub>H</sub>1 cell plasticity in the human kidney in the context of renal autoimmunity.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":24.8,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141321587","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}
Pub Date : 2024-06-14DOI: 10.1126/sciimmunol.adh5462
Elena Martinez-Terroba, Leah M. Plasek-Hegde, Ioannis Chiotakakos, Vincent Li, Fernando J. de Miguel, Camila Robles-Oteiza, Antariksh Tyagi, Katerina Politi, Jesse R. Zamudio, Nadya Dimitrova
Expression of the long noncoding RNA (lncRNA) metastasis–associated lung adenocarcinoma transcript 1 (MALAT1) correlates with tumor progression and metastasis in many tumor types. However, the impact and mechanism of action by which MALAT1 promotes metastatic disease remain elusive. Here, we used CRISPR activation (CRISPRa) to overexpress MALAT1/Malat1 in patient-derived lung adenocarcinoma (LUAD) cell lines and in the autochthonous K-ras/p53 LUAD mouse model. Malat1 overexpression was sufficient to promote the progression of LUAD to metastatic disease in mice. Overexpression of MALAT1/Malat1 enhanced cell mobility and promoted the recruitment of protumorigenic macrophages to the tumor microenvironment through paracrine secretion of CCL2/Ccl2. Ccl2 up-regulation was the result of increased global chromatin accessibility upon Malat1 overexpression. Macrophage depletion and Ccl2 blockade counteracted the effects of Malat1 overexpression. These data demonstrate that a single lncRNA can drive LUAD metastasis through reprogramming of the tumor microenvironment.
{"title":"Overexpression of Malat1 drives metastasis through inflammatory reprogramming of the tumor microenvironment","authors":"Elena Martinez-Terroba, Leah M. Plasek-Hegde, Ioannis Chiotakakos, Vincent Li, Fernando J. de Miguel, Camila Robles-Oteiza, Antariksh Tyagi, Katerina Politi, Jesse R. Zamudio, Nadya Dimitrova","doi":"10.1126/sciimmunol.adh5462","DOIUrl":"10.1126/sciimmunol.adh5462","url":null,"abstract":"<div >Expression of the long noncoding RNA (lncRNA) metastasis–associated lung adenocarcinoma transcript 1 (<i>MALAT1</i>) correlates with tumor progression and metastasis in many tumor types. However, the impact and mechanism of action by which <i>MALAT1</i> promotes metastatic disease remain elusive. Here, we used CRISPR activation (CRISPRa) to overexpress <i>MALAT1/Malat1</i> in patient-derived lung adenocarcinoma (LUAD) cell lines and in the autochthonous K-ras/p53 LUAD mouse model. <i>Malat1</i> overexpression was sufficient to promote the progression of LUAD to metastatic disease in mice. Overexpression of <i>MALAT1/Malat1</i> enhanced cell mobility and promoted the recruitment of protumorigenic macrophages to the tumor microenvironment through paracrine secretion of CCL2/Ccl2. <i>Ccl2</i> up-regulation was the result of increased global chromatin accessibility upon <i>Malat1</i> overexpression. Macrophage depletion and Ccl2 blockade counteracted the effects of <i>Malat1</i> overexpression. These data demonstrate that a single lncRNA can drive LUAD metastasis through reprogramming of the tumor microenvironment.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":24.8,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141321585","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}
Nucleic acids are major structures detected by the innate immune system. Although intracellular single-stranded DNA (ssDNA) accumulates during pathogen infection or disease, it remains unclear whether and how intracellular ssDNA stimulates the innate immune system. Here, we report that intracellular ssDNA triggers cytokine expression and cell death in a CGT motif–dependent manner. We identified Schlafen 11 (SLFN11) as an ssDNA-activated RNase, which is essential for the innate immune responses induced by intracellular ssDNA and adeno-associated virus infection. We found that SLFN11 directly binds ssDNA containing CGT motifs through its carboxyl-terminal domain, translocates to the cytoplasm upon ssDNA recognition, and triggers innate immune responses through its amino-terminal ribonuclease activity that cleaves transfer RNA (tRNA). Mice deficient in Slfn9, a mouse homolog of SLFN11, exhibited resistance to CGT ssDNA–induced inflammation, acute hepatitis, and septic shock. This study identifies CGT ssDNA and SLFN11/9 as a class of immunostimulatory nucleic acids and pattern recognition receptors, respectively, and conceptually couples DNA immune sensing to controlled RNase activation and tRNA cleavage.
{"title":"Schlafen 11 triggers innate immune responses through its ribonuclease activity upon detection of single-stranded DNA","authors":"Peng Zhang, Xiaoqing Hu, Zekun Li, Qian Liu, Lele Liu, Yingying Jin, Sizhe Liu, Xiang Zhao, Jianqiao Wang, Delong Hao, Houzao Chen, Depei Liu","doi":"10.1126/sciimmunol.adj5465","DOIUrl":"10.1126/sciimmunol.adj5465","url":null,"abstract":"<div >Nucleic acids are major structures detected by the innate immune system. Although intracellular single-stranded DNA (ssDNA) accumulates during pathogen infection or disease, it remains unclear whether and how intracellular ssDNA stimulates the innate immune system. Here, we report that intracellular ssDNA triggers cytokine expression and cell death in a CGT motif–dependent manner. We identified Schlafen 11 (SLFN11) as an ssDNA-activated RNase, which is essential for the innate immune responses induced by intracellular ssDNA and adeno-associated virus infection. We found that SLFN11 directly binds ssDNA containing CGT motifs through its carboxyl-terminal domain, translocates to the cytoplasm upon ssDNA recognition, and triggers innate immune responses through its amino-terminal ribonuclease activity that cleaves transfer RNA (tRNA). Mice deficient in Slfn9, a mouse homolog of SLFN11, exhibited resistance to CGT ssDNA–induced inflammation, acute hepatitis, and septic shock. This study identifies CGT ssDNA and SLFN11/9 as a class of immunostimulatory nucleic acids and pattern recognition receptors, respectively, and conceptually couples DNA immune sensing to controlled RNase activation and tRNA cleavage.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":24.8,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141321586","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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