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Transcription factor Ikzf1 associates with Foxp3 to repress gene expression in Treg cells and limit autoimmunity and anti-tumor immunity 转录因子 Ikzf1 与 Foxp3 相关联,抑制 Treg 细胞的基因表达,限制自身免疫和抗肿瘤免疫
IF 32.4 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-08-06 DOI: 10.1016/j.immuni.2024.07.010

The master transcription factor of regulatory T (Treg) cells, forkhead box protein P3 (Foxp3), controls Treg cell function by targeting certain genes for activation or repression, but the specific mechanisms by which it mediates this activation or repression under different conditions remain unclear. We found that Ikzf1 associates with Foxp3 via its exon 5 (IkE5) and that IkE5-deficient Treg cells highly expressed genes that would otherwise be repressed by Foxp3 upon T cell receptor stimulation, including Ifng. Treg-specific IkE5-deletion caused interferon-γ (IFN-γ) overproduction, which destabilized Foxp3 expression and impaired Treg suppressive function, leading to systemic autoimmune disease and strong anti-tumor immunity. Pomalidomide, which degrades IKZF1 and IKZF3, induced IFN-γ overproduction in human Treg cells. Mechanistically, the Foxp3-Ikzf1-Ikzf3 complex competed with epigenetic co-activators, such as p300, for binding to target gene loci via chromatin remodeling. Therefore, the Ikzf1 association with Foxp3 is essential for the gene-repressive function of Foxp3 and could be exploited to treat autoimmune disease and cancer.

调节性 T(Treg)细胞的主转录因子叉头盒蛋白 P3(Foxp3)通过靶向激活或抑制某些基因来控制 Treg 细胞的功能,但它在不同条件下介导这种激活或抑制的具体机制仍不清楚。我们发现,Ikzf1通过其第5外显子(IkE5)与Foxp3结合,缺失IkE5的Treg细胞高度表达在T细胞受体刺激下会被Foxp3抑制的基因,包括Ifng。Treg特异性IkE5缺失会导致干扰素-γ(IFN-γ)过度产生,从而破坏Foxp3表达的稳定性并损害Treg的抑制功能,导致全身性自身免疫性疾病和强大的抗肿瘤免疫力。泊马度胺能降解IKZF1和IKZF3,诱导人Treg细胞IFN-γ过度产生。从机制上讲,Foxp3-Ikzf1-Ikzf3复合物通过染色质重塑与p300等表观遗传共激活因子竞争结合到靶基因位点。因此,Ikzf1与Foxp3的结合对于Foxp3的基因抑制功能至关重要,可用于治疗自身免疫性疾病和癌症。
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引用次数: 0
The amalgam of naive CD4+ T cell transcriptional states is reconfigured by helminth infection to dampen the amplitude of the immune response 螺旋体感染会重新配置天真的 CD4+ T 细胞转录状态,从而抑制免疫反应的幅度
IF 32.4 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-08-02 DOI: 10.1016/j.immuni.2024.07.006

Naive CD4+ T cells in specific pathogen-free (SPF) mice are characterized by transcriptional heterogeneity and subpopulations distinguished by the expression of quiescence, the extracellular matrix (ECM) and cytoskeleton, type I interferon (IFN-I) response, memory-like, and T cell receptor (TCR) activation genes. We demonstrate that this constitutive heterogeneity, including the presence of the IFN-I response cluster, is commensal independent insofar as being identical in germ-free and SPF mice. By contrast, Nippostrongylus brasiliensis infection altered this constitutive heterogeneity. Naive T cell-intrinsic transcriptional changes acquired during helminth infection correlated with and accounted for decreased immunization response to an unrelated antigen. These compositional and functional changes were dependent variables of helminth infection, as they disappeared at the established time point of its clearance in mice. Collectively, our results indicate that the naive T cell pool is subject to dynamic transcriptional changes in response to certain environmental cues, which in turn permutes the magnitude of the immune response.

无特异性病原体(SPF)小鼠的幼稚 CD4+ T 细胞具有转录异质性和亚群特征,这些亚群通过静止、细胞外基质(ECM)和细胞骨架、I 型干扰素(IFN-I)反应、记忆样和 T 细胞受体(TCR)激活基因的表达来区分。我们证明,这种构成性异质性,包括 IFN-I 反应群的存在,与无菌小鼠和 SPF 小鼠中的共生体无关。与此相反,巴西镍丝虫感染改变了这种组成异质性。在蠕虫感染期间获得的幼稚T细胞内在转录变化与对无关抗原的免疫反应下降相关,并说明了这一点。这些组成和功能变化是蠕虫感染的因变量,因为它们在小鼠体内清除蠕虫的既定时间点消失了。总之,我们的研究结果表明,天真 T 细胞池会因某些环境线索而发生动态转录变化,进而改变免疫反应的程度。
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引用次数: 0
Non-classical monocytes scavenge the growth factor CSF1 from endothelial cells in the peripheral vascular tree to ensure survival and homeostasis 非典型单核细胞从外周血管树上的内皮细胞中清除生长因子 CSF1,以确保生存和平衡
IF 32.4 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-07-31 DOI: 10.1016/j.immuni.2024.07.005

Unlike sessile macrophages that occupy specialized tissue niches, non-classical monocytes (NCMs)—circulating phagocytes that patrol and cleanse the luminal surface of the vascular tree—are characterized by constant movement. Here, we examined the nature of the NCM’s nurturing niche. Expression of the growth factor CSF1 on endothelial cells was required for survival of NCMs in the bloodstream. Lack of endothelial-derived CSF1 did not affect blood CSF1 concentration, suggesting that NCMs rely on scavenging CSF1 present on endothelial cells. Deletion of the transmembrane chemokine and adhesion factor CX3CL1 on endothelial cells impaired NCM survival. Mechanistically, endothelial-derived CX3CL1 and integrin subunit alpha L (ITGAL) facilitated the uptake of CSF1 by NCMs. CSF1 was produced by all tissular endothelial cells, and deletion of Csf1 in all endothelial cells except bone marrow sinusoids impaired NCM survival, arguing for a model where the full vascular tree acts as a niche for NCMs and where survival and patrolling function are connected.

与占据专门组织龛位的无柄巨噬细胞不同,非典型单核细胞(NCMs)--巡视和清洁血管树管腔表面的循环吞噬细胞--的特点是不断移动。在这里,我们研究了 NCM 培育龛的性质。内皮细胞上生长因子 CSF1 的表达是 NCM 在血液中存活的必要条件。缺乏内皮衍生的 CSF1 不会影响血液中 CSF1 的浓度,这表明 NCM 依赖于清除内皮细胞上的 CSF1。删除内皮细胞上的跨膜趋化因子和粘附因子 CX3CL1 会影响 NCM 的存活。从机制上讲,内皮衍生的 CX3CL1 和整合素亚基 alpha L(ITGAL)促进了 NCM 对 CSF1 的吸收。所有组织内皮细胞都能产生 CSF1,除骨髓窦外,所有内皮细胞中 Csf1 的缺失都会损害 NCM 的存活。
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引用次数: 0
Brain ischemia causes systemic Notch1 activity in endothelial cells to drive atherosclerosis 大脑缺血会导致内皮细胞中的 Notch1 系统性活动,从而引发动脉粥样硬化
IF 32.4 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-07-29 DOI: 10.1016/j.immuni.2024.07.002

Stroke leads to persistently high risk for recurrent vascular events caused by systemic atheroprogression that is driven by endothelial cell (EC) activation. However, whether and how stroke induces sustained pro-inflammatory and proatherogenic endothelial alterations in systemic vessels remain poorly understood. We showed that brain ischemia induces persistent activation, the upregulation of adhesion molecule VCAM1, and increased senescence in peripheral ECs until 4 weeks after stroke onset. This aberrant EC activity resulted from sustained Notch1 signaling, which was triggered by increased circulating Notch1 ligands DLL1 and Jagged1 after stroke in mice and humans. Consequently, this led to increased myeloid cell adhesion and atheroprogression by generating a senescent, pro-inflammatory endothelium. Notch1- or VCAM1-blocking antibodies and the genetic ablation of endothelial Notch1 reduced atheroprogression after stroke. Our findings revealed a systemic machinery that induces the persistent activation of peripheral ECs after stroke, which paves the way for therapeutic interventions or the prevention of recurrent vascular events following stroke.

内皮细胞(EC)的活化导致全身动脉粥样硬化,而脑卒中是导致复发性血管事件的持续高风险因素。然而,人们对中风是否以及如何诱导全身血管内皮细胞发生持续的促炎症和促动脉粥样硬化性改变仍然知之甚少。我们的研究表明,脑缺血会诱导外周EC持续活化、粘附分子VCAM1上调和衰老增加,直到中风发病后4周。小鼠和人类中风后,循环中增加的 Notch1 配体 DLL1 和 Jagged1 触发了持续的 Notch1 信号传导,从而导致心肌细胞活性异常。因此,这导致髓系细胞粘附性增加,并通过产生衰老、促炎的内皮层而导致动脉粥样硬化。Notch1或VCAM1阻断抗体和内皮Notch1基因消减可减少中风后的动脉粥样硬化。我们的研究结果揭示了诱导中风后外周EC持续活化的系统机制,这为治疗干预或预防中风后复发性血管事件的发生铺平了道路。
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引用次数: 0
Cancer stem cells release interleukin-33 within large oncosomes to promote immunosuppressive differentiation of macrophage precursors 癌症干细胞在大型瘤体内释放白细胞介素-33,促进巨噬细胞前体的免疫抑制分化
IF 32.4 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-07-29 DOI: 10.1016/j.immuni.2024.07.004

In squamous cell carcinoma (SCC), macrophages responding to interleukin (IL)-33 create a TGF-β-rich stromal niche that maintains cancer stem cells (CSCs), which evade chemotherapy-induced apoptosis in part via activation of the NRF2 antioxidant program. Here, we examined how IL-33 derived from CSCs facilitates the development of an immunosuppressive microenvironment. CSCs with high NRF2 activity redistributed nuclear IL-33 to the cytoplasm and released IL-33 as cargo of large oncosomes (LOs). Mechanistically, NRF2 increased the expression of the lipid scramblase ATG9B, which exposed an “eat me” signal on the LO surface, leading to annexin A1 (ANXA1) loading. These LOs promoted the differentiation of AXNA1 receptor+ myeloid precursors into immunosuppressive macrophages. Blocking ATG9B’s scramblase activity or depleting ANXA1 decreased niche macrophages and hindered tumor progression. Thus, IL-33 is released from live CSCs via LOs to promote the differentiation of alternatively activated macrophage, with potential relevance to other settings of inflammation and tissue repair.

在鳞状细胞癌(SCC)中,响应白细胞介素(IL)-33的巨噬细胞创造了一个富含TGF-β的基质龛,它能维持癌症干细胞(CSCs),而癌症干细胞部分是通过激活NRF2抗氧化程序来逃避化疗诱导的细胞凋亡。在这里,我们研究了来自CSCs的IL-33如何促进免疫抑制微环境的发展。具有高NRF2活性的CSCs会将核IL-33重新分配到细胞质中,并将IL-33作为大型核小体(LOs)的载体释放出来。从机制上讲,NRF2增加了脂质扰乱酶ATG9B的表达,从而在LO表面暴露出 "吃我 "信号,导致附件素A1(ANXA1)的负载。这些LO促进了AXNA1受体+髓系前体向免疫抑制巨噬细胞的分化。阻断ATG9B的扰乱酶活性或消耗ANXA1可减少龛巨噬细胞,阻碍肿瘤进展。因此,IL-33可通过LOs从活的CSCs中释放出来,促进替代性活化巨噬细胞的分化,这可能与其他炎症和组织修复有关。
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引用次数: 0
Innate immune training restores pro-reparative myeloid functions to promote remyelination in the aged central nervous system 先天性免疫训练可恢复髓系恢复功能,促进老年中枢神经系统的髓鞘再形成
IF 32.4 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-07-24 DOI: 10.1016/j.immuni.2024.07.001

The reduced ability of the central nervous system to regenerate with increasing age limits functional recovery following demyelinating injury. Previous work has shown that myelin debris can overwhelm the metabolic capacity of microglia, thereby impeding tissue regeneration in aging, but the underlying mechanisms are unknown. In a model of demyelination, we found that a substantial number of genes that were not effectively activated in aged myeloid cells displayed epigenetic modifications associated with restricted chromatin accessibility. Ablation of two class I histone deacetylases in microglia was sufficient to restore the capacity of aged mice to remyelinate lesioned tissue. We used Bacillus Calmette-Guerin (BCG), a live-attenuated vaccine, to train the innate immune system and detected epigenetic reprogramming of brain-resident myeloid cells and functional restoration of myelin debris clearance and lesion recovery. Our results provide insight into aging-associated decline in myeloid function and how this decay can be prevented by innate immune reprogramming.

随着年龄的增长,中枢神经系统的再生能力下降,这限制了脱髓鞘损伤后的功能恢复。以前的研究表明,髓鞘碎片会压垮小胶质细胞的代谢能力,从而阻碍衰老过程中的组织再生,但其潜在机制尚不清楚。在脱髓鞘模型中,我们发现大量在衰老髓系细胞中不能有效激活的基因显示出与染色质可及性受限相关的表观遗传修饰。消减小胶质细胞中的两种I类组蛋白去乙酰化酶足以恢复老龄小鼠再髓鞘化病变组织的能力。我们使用卡介苗(Bacillus Calmette-Guerin,BCG)这种减毒活疫苗来训练先天性免疫系统,并检测到脑驻留髓系细胞的表观遗传学重编程以及髓鞘碎片清除和病变恢复的功能恢复。我们的研究结果让人们深入了解了与衰老相关的髓系功能衰退,以及如何通过先天性免疫重编程来防止这种衰退。
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引用次数: 0
Single-cell chromatin accessibility and transposable element landscapes reveal shared features of tissue-residing immune cells 单细胞染色质可及性和转座元件景观揭示了组织驻留免疫细胞的共同特征
IF 32.4 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-07-23 DOI: 10.1016/j.immuni.2024.06.015

Tissue adaptation is required for regulatory T (Treg) cell function within organs. Whether this program shares aspects with other tissue-localized immune populations is unclear. Here, we analyzed single-cell chromatin accessibility data, including the transposable element (TE) landscape of CD45+ immune cells from colon, skin, adipose tissue, and spleen. We identified features of organ-specific tissue adaptation across different immune cells. Focusing on tissue Treg cells, we found conservation of the Treg tissue adaptation program in other tissue-localized immune cells, such as amphiregulin-producing T helper (Th)17 cells. Accessible TEs can act as regulatory elements, but their contribution to tissue adaptation is not understood. TE landscape analysis revealed an enrichment of specific transcription factor binding motifs in TE regions within accessible chromatin peaks. TEs, specifically from the LTR family, were located in enhancer regions and associated with tissue adaptation. These findings broaden our understanding of immune tissue residency and provide an important step toward organ-specific immune interventions.

器官内的调节性 T(Treg)细胞功能需要组织适应。这一程序是否与其他组织定位的免疫群体有相同之处尚不清楚。在这里,我们分析了单细胞染色质可及性数据,包括来自结肠、皮肤、脂肪组织和脾脏的 CD45+ 免疫细胞的转座元件(TE)图谱。我们发现了不同免疫细胞的器官特异性组织适应特征。以组织Treg细胞为重点,我们发现Treg组织适应程序在其他组织定位的免疫细胞中也有保留,如产生两性胰岛素的T辅助细胞(Th)17。可获取的TE可作为调控元件,但它们对组织适应的贡献尚不清楚。TE景观分析表明,在可访问染色质峰内的TE区域富集了特定的转录因子结合基序。TE,特别是LTR家族的TE,位于增强子区域,与组织适应有关。这些发现拓宽了我们对免疫组织驻留的理解,为实现器官特异性免疫干预迈出了重要一步。
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引用次数: 0
Dynamic landscapes and protective immunity coordinated by influenza-specific lung-resident memory CD8+ T cells revealed by intravital imaging 通过眼内成像揭示流感特异性肺驻留记忆 CD8+ T 细胞的动态景观和协调保护性免疫力
IF 32.4 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-07-22 DOI: 10.1016/j.immuni.2024.06.016

Lung-tissue-resident memory (TRM) CD8+ T cells are critical for heterosubtypic immunity against influenza virus (IAV) reinfection. How TRM cells surveil the lung, respond to infection, and interact with other cells remains unresolved. Here, we used IAV infection of mice in combination with intravital and static imaging to define the spatiotemporal dynamics of lung TRM cells before and after recall infection. CD69+CD103+ TRM cells preferentially localized to lung sites of prior IAV infection, where they exhibited patrolling behavior. After rechallenge, lung TRM cells formed tight clusters in an antigen-dependent manner. Transcriptomic analysis of IAV-specific TRM cells revealed the expression of several factors that regulate myeloid cell biology. In vivo rechallenge experiments demonstrated that protection elicited by TRM cells is orchestrated in part by interferon (IFN)-γ-mediated recruitment of inflammatory monocytes into the lungs. Overall, these data illustrate the dynamic landscapes of CD103+ lung TRM cells that mediate early protective immunity against IAV infection.

肺组织驻留记忆(TRM)CD8+ T细胞对于对抗流感病毒(IAV)再感染的异种亚型免疫至关重要。TRM细胞如何监测肺部、对感染做出反应以及与其他细胞相互作用仍未解决。在这里,我们利用小鼠感染 IAV 的情况,结合眼内成像和静态成像来确定肺部 TRM 细胞在再次感染前后的时空动态。CD69+CD103+ TRM细胞优先定位在之前IAV感染的肺部位置,它们在那里表现出巡逻行为。再次感染后,肺部TRM细胞以抗原依赖的方式形成紧密的集群。对IAV特异性TRM细胞的转录组分析表明,它们表达了多种调节髓系细胞生物学的因子。体内再挑战实验表明,TRM细胞引起的保护作用部分是由干扰素(IFN)-γ介导的炎性单核细胞招募进入肺部所协调的。总之,这些数据说明了CD103+肺TRM细胞的动态景观,它们介导了对IAV感染的早期保护性免疫。
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引用次数: 0
Distinct epigenomic landscapes underlie tissue-specific memory T cell differentiation 不同的表观基因组景观是组织特异性记忆 T 细胞分化的基础
IF 32.4 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-07-22 DOI: 10.1016/j.immuni.2024.06.014

The memory CD8+ T cell pool contains phenotypically and transcriptionally heterogeneous subsets with specialized functions and recirculation patterns. Here, we examined the epigenetic landscape of CD8+ T cells isolated from seven non-lymphoid organs across four distinct infection models, alongside their circulating T cell counterparts. Using single-cell transposase-accessible chromatin sequencing (scATAC-seq), we found that tissue-resident memory T (TRM) cells and circulating memory T (TCIRC) cells develop along distinct epigenetic trajectories. We identified organ-specific transcriptional regulators of TRM cell development, including FOSB, FOS, FOSL1, and BACH2, and defined an epigenetic signature common to TRM cells across organs. Finally, we found that although terminal TEX cells share accessible regulatory elements with TRM cells, they are defined by TEX-specific epigenetic features absent from TRM cells. Together, this comprehensive data resource shows that TRM cell development is accompanied by dynamic transcriptome alterations and chromatin accessibility changes that direct tissue-adapted and functionally distinct T cell states.

记忆性 CD8+ T 细胞池包含表型和转录异质性亚群,具有专门的功能和再循环模式。在这里,我们研究了在四种不同的感染模型中从七个非淋巴器官中分离出来的 CD8+ T 细胞的表观遗传学景观,以及它们的循环 T 细胞对应物。利用单细胞转座酶可获取染色质测序(scATAC-seq),我们发现组织驻留记忆T细胞(TRM)和循环记忆T细胞(TCIRC)沿着不同的表观遗传学轨迹发展。我们确定了TRM细胞发育的器官特异性转录调控因子,包括FOSB、FOS、FOSL1和BACH2,并定义了各器官TRM细胞共有的表观遗传学特征。最后,我们发现尽管末端TEX细胞与TRM细胞共享可访问的调控元件,但它们是由TRM细胞所没有的TEX特异性表观遗传特征所定义的。总之,这一全面的数据资源表明,TRM 细胞的发育伴随着动态转录组的改变和染色质可及性的改变,这些改变引导着组织适应性和功能上不同的 T 细胞状态。
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引用次数: 0
Deep mutational scanning reveals functional constraints and antibody-escape potential of Lassa virus glycoprotein complex 深度突变扫描揭示拉沙病毒糖蛋白复合物的功能限制和抗体逃逸潜力
IF 32.4 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-07-15 DOI: 10.1016/j.immuni.2024.06.013

Lassa virus is estimated to cause thousands of human deaths per year, primarily due to spillovers from its natural host, Mastomys rodents. Efforts to create vaccines and antibody therapeutics must account for the evolutionary variability of the Lassa virus’s glycoprotein complex (GPC), which mediates viral entry into cells and is the target of neutralizing antibodies. To map the evolutionary space accessible to GPC, we used pseudovirus deep mutational scanning to measure how nearly all GPC amino-acid mutations affected cell entry and antibody neutralization. Our experiments defined functional constraints throughout GPC. We quantified how GPC mutations affected neutralization with a panel of monoclonal antibodies. All antibodies tested were escaped by mutations that existed among natural Lassa virus lineages. Overall, our work describes a biosafety-level-2 method to elucidate the mutational space accessible to GPC and shows how prospective characterization of antigenic variation could aid the design of therapeutics and vaccines.

据估计,拉沙病毒每年造成数千人死亡,主要是由于其自然宿主马斯托米斯啮齿动物的传播。研制疫苗和抗体疗法必须考虑到拉沙病毒糖蛋白复合物(GPC)的进化变异性,该复合物介导病毒进入细胞,是中和抗体的靶标。为了绘制 GPC 的进化空间图,我们使用伪病毒深度突变扫描来测量几乎所有 GPC 氨基酸突变对细胞进入和抗体中和的影响。我们的实验确定了整个 GPC 的功能限制。我们用一组单克隆抗体量化了 GPC 突变对中和的影响。所有测试的抗体都因存在于天然拉沙病毒系中的突变而逸散。总之,我们的工作描述了一种生物安全二级方法来阐明 GPC 可访问的突变空间,并展示了抗原变异的前瞻性特征描述如何有助于治疗药物和疫苗的设计。
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引用次数: 0
期刊
Immunity
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