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Human life within a narrow range: The lethal ups and downs of type I interferons 狭小范围内的人类生命I 型干扰素的致命起伏。
IF 17.6 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-07-05 DOI: 10.1126/sciimmunol.adm8185
Yanick J. Crow, Jean-Laurent Casanova
The past 20 years have seen the definition of human monogenic disorders and their autoimmune phenocopies underlying either defective or enhanced type I interferon (IFN) activity. These disorders delineate the impact of type I IFNs in natural conditions and demonstrate that only a narrow window of type I IFN activity is beneficial. Insufficient type I IFN predisposes humans to life-threatening viral diseases (albeit unexpectedly few) with a central role in immunity to respiratory and cerebral viral infection. Excessive type I IFN, perhaps counterintuitively, appears to underlie a greater number of autoinflammatory and/or autoimmune conditions known as type I interferonopathies, whose study has revealed multiple molecular programs involved in the induction of type I IFN signaling. These observations suggest that the manipulation of type I IFN activity to within a physiological range may be clinically relevant for the prevention and treatment of viral and inflammatory diseases.
在过去的 20 年中,人类单基因遗传疾病及其自身免疫表型被定义为 I 型干扰素(IFN)活性缺陷或增强的基础疾病。这些疾病描述了 I 型干扰素在自然条件下的影响,并证明只有 I 型干扰素活性的狭窄窗口才是有益的。I 型 IFN 不足易使人类患上危及生命的病毒性疾病(尽管数量出乎意料地少),而 I 型 IFN 在呼吸道和脑部病毒感染的免疫中起着核心作用。也许与直觉相反,I 型干扰素过多似乎是更多自身炎症和/或自身免疫疾病的基础,这些疾病被称为 I 型干扰素病,其研究揭示了 I 型干扰素信号诱导过程中涉及的多种分子程序。这些观察结果表明,将 I 型干扰素活性控制在生理范围内可能对预防和治疗病毒性和炎症性疾病有临床意义。
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引用次数: 0
A CHip off the old block 一个老顽童。
IF 17.6 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-07-05 DOI: 10.1126/sciimmunol.adr2965
Giusy Della Gatta, Asha Pillai
Lineage-specific effects of upstream promoters affect ST2 expression and effector function in TH1 cells.
上游启动子的系特异性效应会影响 ST2 在 TH1 细胞中的表达和效应功能。
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引用次数: 0
Early symptom-associated inflammatory responses shift to type 2 responses in controlled human schistosome infection 在控制人类血吸虫感染的过程中,早期症状相关炎症反应转变为 2 型反应。
IF 17.6 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-07-05 DOI: 10.1126/sciimmunol.adl1965
Emma L. Houlder, Koen A. Stam, Jan Pieter R. Koopman, Marion H. König, Marijke C. C. Langenberg, Marie-Astrid Hoogerwerf, Paula Niewold, Friederike Sonnet, Jacqueline J. Janse, Miriam Casacuberta Partal, Jeroen C. Sijtsma, Laura H. M. de Bes-Roeleveld, Yvonne C. M. Kruize, Maria Yazdanbakhsh, Meta Roestenberg
Schistosomiasis is an infection caused by contact with Schistosoma-contaminated water and affects more than 230 million people worldwide with varying morbidity. The roles of T helper 2 (TH2) cells and regulatory immune responses in chronic infection are well documented, but less is known about human immune responses during acute infection. Here, we comprehensively map immune responses during controlled human Schistosoma mansoni infection using male or female cercariae. Immune responses to male or female parasite single-sex infection were comparable. An early TH1-biased inflammatory response was observed at week 4 after infection, which was particularly apparent in individuals experiencing symptoms of acute schistosomiasis. By week 8 after infection, inflammatory responses were followed by an expansion of TH2 and regulatory cell subsets. This study demonstrates the shift from TH1 to both TH2 and regulatory responses, typical of chronic schistosomiasis, in the absence of egg production and provides immunological insight into the clinical manifestations of acute schistosomiasis.
血吸虫病是一种因接触被血吸虫污染的水而引起的感染,全球有超过 2.3 亿人受到影响,发病率各不相同。T 辅助细胞 2(TH2)和调节性免疫反应在慢性感染中的作用有据可查,但对急性感染期间的人体免疫反应却知之甚少。在这里,我们利用雄性或雌性carcariae全面描绘了人类曼氏血吸虫受控感染期间的免疫反应。雄性或雌性寄生虫单性感染时的免疫反应相当。在感染后第 4 周观察到早期 TH1 偏重的炎症反应,这在出现急性血吸虫病症状的个体中尤为明显。到感染后第 8 周,炎症反应后 TH2 和调节细胞亚群扩大。这项研究表明,在没有产卵的情况下,慢性血吸虫病的典型反应是从TH1转变为TH2和调节反应,并为急性血吸虫病的临床表现提供了免疫学见解。
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引用次数: 0
IL-12 drives the differentiation of human T follicular regulatory cells IL-12 驱动人类 T 滤泡调节细胞的分化。
IF 17.6 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-07-05 DOI: 10.1126/sciimmunol.adf2047
Diana Castaño, Sidney Wang, Segovia Atencio-Garcia, Emily J. Shields, Maria C. Rico, Hannah Sharpe, Jacinta Bustamante, Allan Feng, Carole Le Coz, Neil Romberg, John W. Tobias, Paul J. Utz, Sarah E. Henrickson, Jean-Laurent Casanova, Roberto Bonasio, Michela Locci
T follicular regulatory (Tfr) cells can counteract the B cell helper activity of T follicular helper (Tfh) cells and hinder the production of antibodies against self-antigens or allergens. A mechanistic understanding of the cytokines initiating the differentiation of human regulatory T (Treg) cells into Tfr cells is still missing. Herein, we report that low doses of the pro-Tfh cytokine interleukin-12 (IL-12) drive the induction of a Tfr cell program on activated human Treg cells while also preserving their regulatory function. Mechanistically, we found that IL-12 led to STAT4 (signal transducer and activator of transcription 4) phosphorylation and binding to IL-12–driven follicular signature genes. Patients with inborn errors of immunity in the IL12RB1 gene presented with a strong decrease in circulating Tfr cells and produced higher levels of anti-actin autoantibodies in vivo. Overall, this study unveils IL-12 as an inducer of Tfr cell differentiation in vivo and provides an approach for the in vitro generation of human Tfr-like cells.
T滤泡调节(Tfr)细胞可以抵消T滤泡辅助(Tfh)细胞的B细胞辅助活性,阻碍产生针对自身抗原或过敏原的抗体。目前还缺乏对启动人类调节性 T(Treg)细胞向 Tfr 细胞分化的细胞因子的机理认识。在这里,我们报告了低剂量的促Tfh细胞因子白细胞介素-12(IL-12)能在活化的人类Treg细胞上诱导Tfr细胞程序,同时还能保留它们的调节功能。从机理上讲,我们发现IL-12会导致STAT4(信号转导和转录激活因子4)磷酸化并与IL-12驱动的滤泡特征基因结合。IL12RB1基因存在先天性免疫错误的患者体内循环Tfr细胞显著减少,并产生更高水平的抗肌动蛋白自身抗体。总之,这项研究揭示了IL-12是体内Tfr细胞分化的诱导剂,并为体外生成人类Tfr样细胞提供了一种方法。
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引用次数: 0
Histone demethylation tones down leukemia through innate immunity 组蛋白去甲基化通过先天性免疫降低白血病发病率
IF 17.6 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-07-05 DOI: 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。
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引用次数: 0
Circulating KLRG1+ long-lived effector memory T cells retain the flexibility to become tissue resident 循环中的 KLRG1 + 长效效应记忆 T 细胞具有成为组织常驻细胞的灵活性
IF 17.6 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-06-28 DOI: 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。
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引用次数: 0
Single-cell topographical profiling of the immune synapse reveals a biomechanical signature of cytotoxicity 免疫突触的单细胞地形剖析揭示了细胞毒性的生物力学特征
IF 17.6 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-06-28 DOI: 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.
免疫细胞具有强烈的物理生活方式,其特点是结构可塑性和用力。为了研究特定的免疫功能是否需要定型的机械输出,我们使用超分辨率牵引力显微镜比较了细胞毒性T细胞形成的免疫突触与其他T细胞亚群和巨噬细胞形成的接触。T 细胞的突触是全局性的压迫,这与巨噬细胞吞噬时的拉扯和捏合有着本质区别。对每种细胞施力模式的频谱分解将细胞毒性与压迫强度、局部突起以及复杂的不对称地形诱导联系起来。通过对细胞骨架调节因子的基因干扰、突触分泌的实时成像以及界面变形的硅学分析,这些特征被验证为细胞毒性驱动因素。突触结构和作用力对目标的硬度和大小很敏感,这表明杀伤的机械增效具有生物物理适应性。我们的结论是,细胞毒性以及其他效应器反应是由专门的传出力模式支持的。
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引用次数: 0
Cytokines drive the formation of memory-like NK cell subsets via epigenetic rewiring and transcriptional regulation 细胞因子通过表观遗传改组和转录调控驱动记忆样 NK 细胞亚群的形成
IF 17.6 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-06-28 DOI: 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。
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引用次数: 0
SARS-CoV-2 inflammation durably imprints memory CD4 T cells SARS-CoV-2炎症会持久印记记忆CD4 T细胞。
IF 17.6 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-06-21 DOI: 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。
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引用次数: 0
MAIT cells monitor intestinal dysbiosis and contribute to host protection during colitis MAIT 细胞能监测肠道菌群失调,并在结肠炎期间为宿主提供保护。
IF 17.6 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-06-21 DOI: 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.
肠道炎症会改变微生物群的组成和新陈代谢。宿主如何监测和应对这种变化仍不清楚。在这里,我们描述了一种保护机制,通过这种机制,粘膜相关不变T(MAIT)细胞能检测到肠道炎症时产生的微生物群代谢产物,并促进组织修复。在稳定状态下,结肠粘膜中的耐气细菌会产生核黄素生物合成途径衍生的 MAIT 配体。实验性结肠炎会引发产生核黄素的细菌在管腔内扩张,从而导致 MAIT 配体的产生增加。对肠道氧气水平的调节表明,氧气在诱导 MAIT 配体的产生方面发挥了作用。结肠中产生的 MAIT 配体迅速穿过肠道屏障并激活 MAIT 细胞,这些细胞表达组织修复基因,并在结肠炎期间产生促进屏障的介质。缺乏 MAIT 细胞的小鼠更容易患结肠炎和结肠炎导致的结直肠癌。因此,MAIT细胞对表明肠道炎症的细菌代谢途径很敏感。
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引用次数: 0
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