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Fasting reshapes tissue-specific niches to improve NK cell-mediated anti-tumor immunity. 禁食重塑组织特异性龛位,改善 NK 细胞介导的抗肿瘤免疫。
IF 25.5 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-08-13 Epub Date: 2024-06-14 DOI: 10.1016/j.immuni.2024.05.021
Rebecca B Delconte, Mark Owyong, Endi K Santosa, Katja Srpan, Sam Sheppard, Tomi J McGuire, Aamna Abbasi, Carlos Diaz-Salazar, Jerold Chun, Inez Rogatsky, Katharine C Hsu, Stefan Jordan, Miriam Merad, Joseph C Sun

Fasting is associated with improved outcomes in cancer. Here, we investigated the impact of fasting on natural killer (NK) cell anti-tumor immunity. Cyclic fasting improved immunity against solid and metastatic tumors in an NK cell-dependent manner. During fasting, NK cells underwent redistribution from peripheral tissues to the bone marrow (BM). In humans, fasting also reduced circulating NK cell numbers. NK cells in the spleen of fasted mice were metabolically rewired by elevated concentrations of fatty acids and glucocorticoids, augmenting fatty acid metabolism via increased expression of the enzyme CPT1A, and Cpt1a deletion impaired NK cell survival and function in this setting. In parallel, redistribution of NK cells to the BM during fasting required the trafficking mediators S1PR5 and CXCR4. These cells were primed by an increased pool of interleukin (IL)-12-expressing BM myeloid cells, which improved IFN-γ production. Our findings identify a link between dietary restriction and optimized innate immune responses, with the potential to enhance immunotherapy strategies.

禁食与改善癌症预后有关。在这里,我们研究了禁食对自然杀伤(NK)细胞抗肿瘤免疫力的影响。周期性禁食以一种依赖 NK 细胞的方式提高了对实体瘤和转移性肿瘤的免疫力。禁食期间,NK细胞从外周组织重新分布到骨髓(BM)。在人体中,禁食也会减少循环中的NK细胞数量。禁食小鼠脾脏中的 NK 细胞在脂肪酸和糖皮质激素浓度升高的作用下发生了新陈代谢,通过增加 CPT1A 酶的表达增强了脂肪酸代谢,而 Cpt1a 基因缺失会损害 NK 细胞在这种情况下的存活和功能。与此同时,在禁食期间,NK细胞重新分布到BM需要转运介质S1PR5和CXCR4。白细胞介素(IL)-12表达的基质骨髓细胞池的增加为这些细胞提供了能量,从而改善了IFN-γ的产生。我们的研究结果确定了饮食限制与优化的先天性免疫反应之间的联系,有望加强免疫疗法策略。
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引用次数: 0
A non-canonical function of OAS1 to combat viral and bacterial infections OAS1 对抗病毒和细菌感染的非经典功能
IF 32.4 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-08-13 DOI: 10.1016/j.immuni.2024.07.018

The interferon-stimulated gene OAS1 has well-defined antiviral properties. In two recent issues of Immunity, Harioudh et al. describe a non-canonical function of OAS1 that selectively protects the translation of proteins involved in defense against viral or bacterial infections.

干扰素刺激基因 OAS1 具有明确的抗病毒特性。在最近两期《免疫》杂志上,Harioudh 等人描述了 OAS1 的一种非经典功能,它能选择性地保护参与防御病毒或细菌感染的蛋白质的翻译。
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引用次数: 0
The biology and function of extracellular vesicles in immune response and immunity 细胞外囊泡在免疫反应和免疫中的生物学作用和功能
IF 32.4 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-08-13 DOI: 10.1016/j.immuni.2024.07.009

Extracellular vesicles (EVs), such as ectosomes and exosomes, contain DNA, RNA, proteins and are encased in a phospholipid bilayer. EVs provide intralumenal cargo for delivery into the cytoplasm of recipient cells with an impact on the function of immune cells, in part because their biogenesis can also intersect with antigen processing and presentation. Motile EVs from activated immune cells may increase the frequency of immune synapses on recipient cells in a proximity-independent manner for local and long-distance modulation of systemic immunity in inflammation, autoimmunity, organ fibrosis, cancer, and infections. Natural and engineered EVs exhibit the ability to impact innate and adaptive immunity and are entering clinical trials. EVs are likely a component of an optimally functioning immune system, with the potential to serve as immunotherapeutics. Considering the evolving evidence, it is possible that EVs could be the original primordial organic units that preceded the creation of the first cell.

细胞外囊泡(EVs),如外泌体和外泌体,含有 DNA、RNA 和蛋白质,并包裹在磷脂双分子层中。EVs提供腔内货物,可输送到受体细胞的细胞质中,对免疫细胞的功能产生影响,部分原因是EVs的生物生成也可能与抗原处理和递呈产生交集。来自活化免疫细胞的运动性EVs可能会增加受体细胞上免疫突触的频率,从而在炎症、自身免疫、器官纤维化、癌症和感染中对全身免疫进行局部和远距离调节。天然和人工合成的 EVs 具有影响先天和适应性免疫的能力,目前正进入临床试验阶段。EVs 很可能是免疫系统最佳功能的组成部分,具有作为免疫疗法的潜力。考虑到不断发展的证据,EVs 有可能是第一个细胞诞生之前的原始有机单位。
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引用次数: 0
The effect of transient, constricted migration on neutrophil intracellular bacteria-killing capability 瞬时收缩迁移对中性粒细胞胞内细菌杀伤能力的影响
IF 32.4 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-08-13 DOI: 10.1016/j.immuni.2024.07.008
No Abstract
无摘要
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引用次数: 0
Macrophages dig into the obesity paradox in cancer 巨噬细胞挖掘癌症中的肥胖悖论
IF 32.4 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-08-13 DOI: 10.1016/j.immuni.2024.07.013

Response to immune checkpoint blockade is increased in obesity-related cancers, but the mechanisms remain unclear. In a recent issue of Nature, Bader et al. report that obesity in mice induces macrophage PD-1 upregulation to promote tumor growth while potentiating immunotherapy responses.

肥胖相关癌症患者对免疫检查点阻断剂的反应增加,但其机制仍不清楚。在最近一期《自然》杂志上,Bader 等人报告说,小鼠肥胖会诱导巨噬细胞 PD-1 上调,从而促进肿瘤生长,同时增强免疫疗法的反应。
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引用次数: 0
Neutrophils meet their fate in endothelial adherens junctions 中性粒细胞在内皮粘连接头处与命运相遇
IF 32.4 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-08-13 DOI: 10.1016/j.immuni.2024.07.015
No Abstract
无摘要
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引用次数: 0
Interleukin-2 immunotherapy reveals human regulatory T cell subsets with distinct functional and tissue-homing characteristics 白细胞介素-2 免疫疗法揭示了具有不同功能和组织归属特征的人类调节性 T 细胞亚群
IF 32.4 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-08-12 DOI: 10.1016/j.immuni.2024.07.016

Due to its stimulatory potential for immunomodulatory CD4+ regulatory T (Treg) cells, low-dose interleukin-2 (IL-2) immunotherapy has gained considerable attention for the treatment of autoimmune diseases. In this investigator-initiated single-arm non-placebo-controlled phase-2 clinical trial of low-dose IL-2 immunotherapy in systemic lupus erythematosus (SLE) patients, we generated a comprehensive atlas of in vivo human immune responses to low-dose IL-2. We performed an in-depth study of circulating and cutaneous immune cells by imaging mass cytometry, high-parameter flow cytometry, transcriptomics, and targeted serum proteomics. Low-dose IL-2 stimulated various circulating immune cells, including Treg cells with a skin-homing phenotype that appeared in the skin of SLE patients in close interaction with endothelial cells. Analysis of surface proteins and transcriptomes revealed different IL-2-driven Treg cell activation programs, including gut-homing CD38+, skin-homing HLA-DR+, and highly proliferative inflammation-homing CD38+ HLA-DR+ Treg cells. Collectively, these data define the distinct human Treg cell subsets that are responsive to IL-2 immunotherapy.

由于低剂量白介素-2(IL-2)免疫疗法具有刺激免疫调节CD4+调节性T(Treg)细胞的潜力,因此在治疗自身免疫性疾病方面受到了广泛关注。在这项由研究者发起的系统性红斑狼疮(SLE)患者低剂量IL-2免疫疗法单臂非安慰剂对照2期临床试验中,我们绘制了一幅低剂量IL-2体内人体免疫反应综合图谱。我们通过成像质谱、高参数流式细胞术、转录组学和靶向血清蛋白质组学对循环和皮肤免疫细胞进行了深入研究。低剂量IL-2刺激了各种循环免疫细胞,包括具有皮肤归巢表型的Treg细胞,这些细胞出现在系统性红斑狼疮患者的皮肤中,与内皮细胞密切相互作用。对表面蛋白和转录组的分析显示了不同的IL-2驱动的Treg细胞活化程序,包括肠道归巢CD38+、皮肤归巢HLA-DR+和高度增殖的炎症归巢CD38+ HLA-DR+ Treg细胞。这些数据共同定义了对IL-2免疫疗法有反应的不同人类Treg细胞亚群。
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引用次数: 0
Microglia in the hypothalamic paraventricular nucleus sense hemodynamic disturbance and promote sympathetic excitation in hypertension 下丘脑室旁核中的小胶质细胞感知血液动力学紊乱并促进高血压患者的交感神经兴奋
IF 32.4 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-08-07 DOI: 10.1016/j.immuni.2024.07.011

Hypertension is usually accompanied by elevated sympathetic tonicity, but how sympathetic hyperactivity is triggered is not clear. Recent advances revealed that microglia-centered neuroinflammation contributes to sympathetic excitation in hypertension. In this study, we performed a temporospatial analysis of microglia at both morphological and transcriptomic levels and found that microglia in the hypothalamic paraventricular nucleus (PVN), a sympathetic center, were early responders to hypertensive challenges. Vasculature analyses revealed that the PVN was characterized by high capillary density, thin vessel diameter, and complex vascular topology relative to other brain regions. As such, the PVN was susceptible to the penetration of ATP released from the vasculature in response to hemodynamic disturbance after blood pressure increase. Mechanistically, ATP ligation to microglial P2Y12 receptor was responsible for microglial inflammatory activation and the eventual sympathetic overflow. Together, these findings identified a distinct vasculature pattern rendering vulnerability of PVN pre-sympathetic neurons to hypertension-associated microglia-mediated inflammatory insults.

高血压通常伴有交感神经强直性增高,但交感神经亢进是如何引发的尚不清楚。最近的研究发现,以小胶质细胞为中心的神经炎症导致了高血压的交感神经兴奋。在这项研究中,我们从形态学和转录组水平对小胶质细胞进行了时空分析,发现交感中枢下丘脑室旁核(PVN)中的小胶质细胞是高血压挑战的早期响应者。血管分析表明,与其他脑区相比,下丘脑室旁核具有毛细血管密度高、血管直径细和血管拓扑结构复杂的特点。因此,当血压升高后血流动力学紊乱时,血管中释放的 ATP 很容易渗透到 PVN 中。从机理上讲,ATP 与小胶质细胞 P2Y12 受体的连接是导致小胶质细胞炎症激活和最终交感神经溢出的原因。总之,这些发现确定了一种独特的血管模式,它使 PVN 前交感神经元容易受到高血压相关的小胶质细胞介导的炎症损伤。
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引用次数: 0
The cytokine Meteorin-like inhibits anti-tumor CD8+ T cell responses by disrupting mitochondrial function 细胞因子 Meteorin-like 通过破坏线粒体功能抑制抗肿瘤 CD8+ T 细胞反应
IF 32.4 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-08-06 DOI: 10.1016/j.immuni.2024.07.003

Tumor-infiltrating lymphocyte (TIL) hypofunction contributes to the progression of advanced cancers and is a frequent target of immunotherapy. Emerging evidence indicates that metabolic insufficiency drives T cell hypofunction during tonic stimulation, but the signals that initiate metabolic reprogramming in this context are largely unknown. Here, we found that Meteorin-like (METRNL), a metabolically active cytokine secreted by immune cells in the tumor microenvironment (TME), induced bioenergetic failure of CD8+ T cells. METRNL was secreted by CD8+ T cells during repeated stimulation and acted via both autocrine and paracrine signaling. Mechanistically, METRNL increased E2F-peroxisome proliferator-activated receptor delta (PPARδ) activity, causing mitochondrial depolarization and decreased oxidative phosphorylation, which triggered a compensatory bioenergetic shift to glycolysis. Metrnl ablation or downregulation improved the metabolic fitness of CD8+ T cells and enhanced tumor control in several tumor models, demonstrating the translational potential of targeting the METRNL-E2F-PPARδ pathway to support bioenergetic fitness of CD8+ TILs.

肿瘤浸润淋巴细胞(TIL)功能低下是晚期癌症进展的一个因素,也是免疫疗法的一个常见靶点。新的证据表明,在强刺激过程中,新陈代谢不足会导致T细胞功能低下,但在这种情况下启动新陈代谢重编程的信号在很大程度上是未知的。在这里,我们发现肿瘤微环境(TME)中的免疫细胞分泌的代谢活性细胞因子 Meteorin-like (METRNL) 会诱导 CD8+ T 细胞的生物能衰竭。METRNL 由 CD8+ T 细胞在反复刺激过程中分泌,通过自分泌和旁分泌信号发挥作用。从机制上讲,METRNL增加了E2F-过氧化物酶体增殖激活受体δ(PPARδ)的活性,导致线粒体去极化和氧化磷酸化降低,从而引发生物能代偿性地转向糖酵解。METRNL的消减或下调改善了CD8+ T细胞的代谢能力,增强了几种肿瘤模型的肿瘤控制能力,证明了靶向METRNL-E2F-PPARδ途径支持CD8+ TILs生物能的转化潜力。
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引用次数: 0
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
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Immunity
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