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Comparison of Omicron breakthrough infection versus monovalent SARS-CoV-2 intramuscular booster reveals differences in mucosal and systemic humoral immunity 欧米克隆突破性感染与单价 SARS-CoV-2 肌肉注射增强剂的比较揭示了粘膜和全身体液免疫的差异。
IF 8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-04-01 DOI: 10.1016/j.mucimm.2024.01.004
Sabryna Nantel , Salma Sheikh-Mohamed , Gary Y.C. Chao , Alexandra Kurtesi , Queenie Hu , Heidi Wood , Karen Colwill , Zhijie Li , Ying Liu , Laurie Seifried , Benoîte Bourdin , Allison McGeer , William R. Hardy , Olga L. Rojas , Tho-Alfakar Al-Aubodah , Zhiyang Liu , Mario A. Ostrowski , Mark A. Brockman , Ciriaco A. Piccirillo , Caroline Quach , Jennifer L. Gommerman

Our understanding of the quality of cellular and humoral immunity conferred by COVID-19 vaccination alone versus vaccination plus SARS-CoV-2 breakthrough (BT) infection remains incomplete. While the current (2023) SARS-CoV-2 immune landscape of Canadians is complex, in late 2021 most Canadians had either just received a third dose of COVID-19 vaccine, or had received their two-dose primary series and then experienced an Omicron BT. Herein we took advantage of this coincident timing to contrast cellular and humoral immunity conferred by three doses of vaccine versus two doses plus BT. Our results show thatBT infection induces cell-mediated immune responses to variants comparable to an intramuscular vaccine booster dose. In contrast, BT subjects had higher salivary immunoglobulin (Ig)G and IgA levels against the Omicron spike and enhanced reactivity to the ancestral spike for the IgA isotype, which also reacted with SARS-CoV-1. Serumneutralizing antibody levels against the ancestral strain and the variants were also higher after BT infection. Our results support the need for the development of intranasal vaccines that could emulate the enhanced mucosal and humoral immunity induced by Omicron BT without exposing individuals to the risks associated with SARS-CoV-2 infection.

我们对单独接种 2019 年冠状病毒病(COVID-19)疫苗与接种疫苗加严重急性呼吸系统综合症冠状病毒 2(SARS-CoV-2)突破性 (BT) 感染所产生的细胞和体液免疫质量的了解仍不全面。虽然加拿大人目前(2023 年)的 SARS-CoV-2 免疫状况很复杂,但在 2021 年末,大多数加拿大人要么刚刚接种了第三剂 COVID-19 疫苗,要么接种了两剂初级系列疫苗,然后经历了一次 Omicron BT。在此,我们利用这一巧合时机,对比了接种三剂疫苗与接种两剂疫苗加 BT 所产生的细胞免疫和体液免疫。我们的研究结果表明,轻度 BT 感染诱导的细胞介导免疫反应变异与肌肉注射疫苗加强剂量相当。与此相反,BT 受试者唾液中针对 Omicron 穗状病毒的 IgG 和 IgA 水平较高,对祖先穗状病毒的 IgA 同工型反应性增强,后者也与 SARS-CoV-1 发生反应。BT 感染后,血清中针对祖先株和变异株的中和抗体水平也较高。我们的研究结果支持了对疫苗的需求,这种疫苗既能增强 Omicron BT 诱导的粘膜免疫和体液免疫,又不会使人面临感染 SARS-CoV-2 的风险。一句话总结 Omicron BT 可在接种疫苗的成年人中引起交叉反应性全身和粘膜免疫反应。
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引用次数: 0
Human alveolar lining fluid from the elderly promotes Mycobacterium tuberculosis intracellular growth and translocation into the cytosol of alveolar epithelial cells 老年人的肺泡内衬液能促进结核分枝杆菌在细胞内生长并转运到肺泡上皮细胞的细胞质中。
IF 8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-04-01 DOI: 10.1016/j.mucimm.2024.01.001
Angélica M. Olmo-Fontánez , Julia M. Scordo , Alyssa Schami , Andreu Garcia-Vilanova , Paula A. Pino , Amberlee Hicks , Richa Mishra , Diego Jose Maselli , Jay I. Peters , Blanca I. Restrepo , Kievershen Nargan , Threnesan Naidoo , Daniel L. Clemens , Adrie J.C. Steyn , Vivek V. Thacker , Joanne Turner , Larry S. Schlesinger , Jordi B. Torrelles

The elderly population is highly susceptible to developing respiratory diseases, including tuberculosis, a devastating disease caused by the airborne pathogen Mycobacterium tuberculosis (M.tb) that kills one person every 18 seconds. Once M.tb reaches the alveolar space, it contacts alveolar lining fluid (ALF), which dictates host-cell interactions. We previously determined that age-associated dysfunction of soluble innate components in human ALF leads to accelerated M.tb growth within human alveolar macrophages. Here we determined the impact of human ALF on M.tb infection of alveolar epithelial type cells (ATs), another critical lung cellular determinant of infection. We observed that elderly ALF (E-ALF)-exposed M.tb had significantly increased intracellular growth with rapid replication in ATs compared to adult ALF (A-ALF)-exposed bacteria, as well as a dampened inflammatory response. A potential mechanism underlying this accelerated growth in ATs was our observation of increased bacterial translocation into the cytosol, a compartment that favors bacterial replication. These findings in the context of our previous studies highlight how the oxidative and dysfunctional status of the elderly lung mucosa determines susceptibility to M.tb infection, including dampening immune responses and favoring bacterial replication within alveolar resident cell populations, including ATs, the most abundant resident cell type within the alveoli.

老年人极易罹患呼吸道疾病,包括结核病(TB),这是一种由空气传播的病原体结核分枝杆菌(M.tb)引起的毁灭性疾病,每 18 秒钟就有一人死亡。一旦结核分枝杆菌到达肺泡空间,它就会接触肺泡内衬液(ALF),而肺泡内衬液决定着宿主细胞之间的相互作用。我们以前曾发现,人类 ALF 中与年龄相关的可溶性先天性成分功能障碍会导致 M.tb 在人类肺泡巨噬细胞内加速生长。在这里,我们确定了人 ALF 对肺泡上皮细胞(ATs)M.tb 感染的影响,肺泡上皮细胞是肺部细胞感染的另一个关键决定因素。我们观察到,与暴露于成人 ALF(A-ALF)的细菌相比,暴露于老年 ALF(E-ALF)的 M.tb 在肺泡上皮细胞中的胞内生长和快速复制显著增加,炎症反应也有所减弱。细菌在ATs中加速生长的一个潜在机制是我们观察到细菌向细胞质转位的增加,而细胞质是有利于细菌复制的一个区室。这些研究结果与我们之前的研究相结合,突显了老年肺粘膜的氧化和功能失调状态如何决定了对 M.tb 感染的易感性,包括抑制免疫反应和有利于细菌在肺泡常住细胞群中复制,其中包括肺泡中最丰富的常住细胞类型--ATs。
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引用次数: 0
Epithelial regulation of microbiota-immune cell dynamics 上皮细胞对微生物群-免疫细胞动态的调控。
IF 8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-04-01 DOI: 10.1016/j.mucimm.2024.02.008
Bailey J. Didriksen , Emily M. Eshleman , Theresa Alenghat

The mammalian gastrointestinal tract hosts a diverse community of trillions of microorganisms, collectively termed the microbiota, which play a fundamental role in regulating tissue physiology and immunity. Recent studies have sought to dissect the cellular and molecular mechanisms mediating communication between the microbiota and host immune system. Epithelial cells line the intestine and form an initial barrier separating the microbiota from underlying immune cells, and disruption of epithelial function has been associated with various conditions ranging from infection to inflammatory bowel diseases and cancer. From several studies, it is now clear that epithelial cells integrate signals from commensal microbes. Importantly, these non-hematopoietic cells also direct regulatory mechanisms that instruct the recruitment and function of microbiota-sensitive immune cells. In this review, we discuss the central role that has emerged for epithelial cells in orchestrating intestinal immunity and highlight epithelial pathways through which the microbiota can calibrate tissue-intrinsic immune responses.

哺乳动物胃肠道内有数万亿微生物组成的多样化群落,统称为微生物群,它们在调节组织生理和免疫方面发挥着重要作用。最近的研究试图剖析介导微生物群与宿主免疫系统之间交流的细胞和分子机制。上皮细胞排列在肠道内,形成了将微生物群与底层免疫细胞隔开的最初屏障,上皮细胞功能的破坏与从感染到炎症性肠病和癌症等各种疾病有关。多项研究表明,上皮细胞能整合来自共生微生物的信号。重要的是,这些非造血细胞还能引导调节机制,指导对微生物群敏感的免疫细胞的招募和功能。在本综述中,我们将讨论上皮细胞在协调肠道免疫中的核心作用,并重点介绍微生物群校准组织内在免疫反应的上皮途径。
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引用次数: 0
B cell-mediated CD4 T-cell costimulation via CD86 exacerbates pro-inflammatory cytokine production during autoimmune intestinal inflammation 在自身免疫性肠道炎症过程中,B细胞介导的CD4 T细胞通过CD86的共刺激加剧了促炎细胞因子的产生。
IF 8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-02-01 DOI: 10.1016/j.mucimm.2023.10.005
Iana Gadjalova , Julia M. Heinze , Marie C. Goess , Julian Hofmann , Annalisa Buck , Marie-Christin Weber , Birgit Blissenbach , Maximilian Kampick , Oleg Krut , Katja Steiger , Klaus-Peter Janssen , Philipp-Alexander Neumann , Jürgen Ruland , Selina J. Keppler

Dysregulated B cell responses have been described in inflammatory bowel disease (IBD) patients; however, the role of B cells in IBD pathology remained incompletely understood. We here provide evidence for the detrimental role of activated B cells during the onset of autoimmune intestinal inflammation. Using Wiskott-Aldrich Syndrome interacting protein deficient (Wipf1−/−) mice as a mouse model of chronic colitis, we identified clusters of differentiation (CD)86 expression on activated B cells as a crucial factor exacerbating pro-inflammatory cytokine production of intestinal CD4 T cells. Depleting B cells through anti-CD20 antibody treatment or blocking costimulatory signals mediated by CD86 through cytotoxic T lymphocyte antigen-4-immunoglobulin (CTLA-4-Ig) diminished intestinal inflammation in our mouse model of chronic IBD at the onset of disease. This was due to a reduction in aberrant humoral immune responses and reduced CD4 T cell pro-inflammatory cytokine production, especially interferon-g (IFN-g) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Interestingly, in addition to B cells isolated from the inflamed colon of Wipf1−/− mice, we also found CD86 mRNA and protein expression upregulated on activated B cells isolated from inflamed tissue of human patients with IBD. B cell activation and CD86 expression were boosted by soluble CD40L in vitro, which we found in the serum of mice and human patients with IBD. In summary, our data provides detailed insight into the contribution of B cells to intestinal inflammation, with implications for the treatment of IBD.

炎症性肠病(IBD)患者的B细胞反应失调;然而,B细胞在IBD病理中的作用仍不完全清楚。我们在此为活化的B细胞在自身免疫性肠道炎症发作过程中的有害作用提供了证据。使用Wiskott-Aldrich综合征相互作用蛋白缺陷(Wipf1-/-)小鼠作为慢性结肠炎的小鼠模型,我们确定活化的B细胞上CD86的表达是加剧肠道CD4 T细胞促炎细胞因子产生的关键因素。在我们的慢性IBD小鼠模型中,通过抗CD20抗体治疗消耗B细胞或通过CTLA-4-Ig阻断CD86介导的共刺激信号可在疾病发作时减轻肠道炎症。这是由于异常体液免疫反应减少,CD4 T细胞促炎细胞因子产生减少,尤其是IFN-γ和GM-CSF。有趣的是,除了从Wipf1-/-小鼠炎症结肠中分离的B细胞外,我们还发现从人类IBD患者炎症组织中分离的活化B细胞上CD86mRNA和蛋白表达上调。我们在小鼠和人IBD患者的血清中发现,可溶性CD40L在体外促进了B细胞的活化和CD86的表达。总之,我们的数据为B细胞对肠道炎症的贡献提供了详细的见解,对IBD的治疗有启示。
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引用次数: 0
Role reversals: non-canonical roles for immune and non-immune cells in the gut 作用逆转:肠道中免疫细胞和非免疫细胞的非规范作用。
IF 8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-02-01 DOI: 10.1016/j.mucimm.2023.11.004
Jacqueline L.E. Tearle , Adelynn Tang , Ajithkumar Vasanthakumar , Kylie R. James

The intestine is home to an intertwined network of epithelial, immune, and neuronal cells as well as the microbiome, with implications for immunity, systemic metabolism, and behavior. While the complexity of this microenvironment has long since been acknowledged, recent technological advances have propelled our understanding to an unprecedented level. Notably, the microbiota and non-immune or structural cells have emerged as important conductors of intestinal immunity, and by contrast, cells of both the innate and adaptive immune systems have demonstrated non-canonical roles in tissue repair and metabolism. This review highlights recent works in the following two streams: non-immune cells of the intestine performing immunological functions; and traditional immune cells exhibiting non-immune functions in the gut.

肠道是上皮细胞、免疫细胞和神经细胞以及微生物群交织在一起的网络的家园,对免疫、全身代谢和行为都有影响。虽然这种微环境的复杂性早已得到承认,但最近的技术进步将我们的理解推向了前所未有的水平。值得注意的是,微生物群和非免疫细胞或结构细胞已成为肠道免疫的重要载体,相比之下,先天免疫系统和适应性免疫系统的细胞已在组织修复和代谢中表现出非规范的作用。本文综述了以下两方面的最新研究成果:肠道非免疫细胞的免疫功能;传统的免疫细胞在肠道中表现出非免疫功能。
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引用次数: 0
A pro-inflammatory gut mucosal cytokine response is associated with mild COVID-19 disease and superior induction of serum antibodies 促炎肠道黏膜细胞因子反应与轻度COVID-19疾病和血清抗体的良好诱导相关。
IF 8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-02-01 DOI: 10.1016/j.mucimm.2023.11.005
Dana Costigan , Joe Fenn , Sandi Yen , Nicholas Ilott , Samuel Bullers , Jessica Hale , William Greenhalf , Emily Conibear , Aleksandra Koycheva , Kieran Madon , Ishrat Jahan , Ming Huang , Anjna Badhan , Eleanor Parker , Carolina Rosadas , Kelsey Jones , Myra McClure , Richard Tedder , Graham Taylor , Kenneth J. Baillie , Emily E. Thornton

The relationship between gastrointestinal tract infection, the host immune response, and the clinical outcome of disease is not well understood in COVID-19. We sought to understand the effect of intestinal immune responses to SARS-CoV-2 on patient outcomes including the magnitude of systemic antibody induction. Combining two prospective cohort studies, International Severe Acute Respiratory and emerging Infections Consortium Comprehensive Clinical Characterisations Collaboration (ISARIC4C) and Integrated Network for Surveillance, Trials and Investigations into COVID-19 Transmission (INSTINCT), we acquired samples from 88 COVID-19 cases representing the full spectrum of disease severity and analysed viral RNA and host gut cytokine responses in the context of clinical and virological outcome measures. There was no correlation between the upper respiratory tract and faecal viral loads. Using hierarchical clustering, we identified a group of fecal cytokines including Interleukin-17A, Granulocyte macrophage colony-stimulating factor, Tumor necrosis factorα, Interleukin-23, and S100A8, that were transiently elevated in mild cases and also correlated with the magnitude of systemic anti-Spike-receptor-binding domain antibody induction. Receiver operating characteristic curve analysis showed that expression of these gut cytokines at study enrolment in hospitalised COVID-19 cases was associated negatively with overall clinical severity implicating a protective role in COVID-19. This suggests that a productive intestinal immune response may be beneficial in the response to a respiratory pathogen and a biomarker of a successful barrier response.

COVID-19患者胃肠道感染、宿主免疫反应与疾病临床结局之间的关系尚不清楚。我们试图了解肠道对SARS-CoV-2的免疫反应对患者结局的影响,包括全身抗体诱导的程度。结合ISARIC4C和INSTINCT两项前瞻性队列研究,我们从88例COVID-19病例中获取了代表疾病严重程度全谱的样本,并在临床和病毒学结果测量的背景下分析了病毒RNA和宿主肠道细胞因子反应。上呼吸道与粪便病毒载量无相关性。通过分层聚类,我们发现了一组粪便细胞因子,包括IL-17A、GM-CSF、TNFα、IL-23和S100A8,这些细胞因子在轻度病例中会短暂升高,并且与全身抗Spike-RBD抗体诱导的程度相关。ROC分析显示,在入院的COVID-19病例中,研究入组时这些肠道细胞因子的表达与总体临床严重程度呈负相关,暗示在COVID-19中具有保护作用。这表明,一个有效的肠道免疫反应可能在对呼吸道病原体的反应中是有益的,也是一个成功的屏障反应的生物标志物。
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引用次数: 0
Acrylamide, an air pollutant, enhances allergen-induced eosinophilic lung inflammation via group 2 innate lymphoid cells 丙烯酰胺是一种空气污染物,通过第2组固有淋巴细胞增强过敏原诱导的嗜酸性肺炎症。
IF 8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-02-01 DOI: 10.1016/j.mucimm.2023.09.007
Hsiang-Han Su , Chih-Mei Cheng , Yung-Ning Yang , Yu-Wei Chang , Chia-Yang Li , Shin-Ting Wu , Chia-Chi Lin , Hsin-En Wu , Jau-Ling Suen

Air pollution significantly impacts the aggravation of asthma. Exposure to acrylamide, a volatile organic compound in tobacco smoke, is associated with elevated risks of allergy-related outcomes among active smokers. As group 2 innate lymphoid cells (ILC2s) can act as an environmental sensor and significantly contribute to protease allergen-induced lung inflammation, we aimed to elucidate the causal relationship and how inhaled acrylamide worsens allergic lung inflammation via ILC2s. Intranasal acrylamide exposure at nanomolar levels significantly enhanced allergen-induced or recombinant mouse interleukin-33-induced lung inflammation in C57BL/6 mice or Rag1−/− mice, respectively. The cardinal features of lung inflammation included accumulated infiltration of ILC2s and eosinophils. Transcriptomic analysis revealed a gene expression pattern associated with proliferation-related pathways in acrylamide-treated ILC2s. Western blotting revealed significantly higher expression of Ras and phospho-Erk in acrylamide-treated ILC2s than the control, suggesting Ras-Erk signaling pathway involvement. Ex vivo and in vitro analysis showed that acrylamide treatment mainly increased Ki-67+ ILC2s and the cell number of ILC2s whereas PD98059, a highly selective Erk inhibitor, effectively counteracted the acrylamide effect. Intratracheal administration of acrylamide-treated ILC2s significantly enhanced eosinophil infiltration in Rag1−/− mice. This study suggests that airborne acrylamide may enhance the severity of allergen-induced airway eosinophilic inflammation, partly via altering ILC2 proliferative activity.

空气污染严重影响哮喘的恶化。暴露于丙烯酰胺(烟草烟雾中的一种挥发性有机化合物)与活跃吸烟者过敏相关后果的风险增加有关。由于第2组先天性淋巴细胞(ILC2s)可以作为环境传感器,并对蛋白酶过敏原诱导的肺部炎症有显著贡献,我们旨在阐明其因果关系,以及吸入丙烯酰胺如何通过ILC2s恶化过敏性肺部炎症。纳摩尔水平的鼻腔内丙烯酰胺暴露分别显著增强C57BL/6小鼠或Rag1-/-小鼠中过敏原诱导或rmIL-33诱导的肺部炎症。肺部炎症的主要特征包括ILC2和嗜酸性粒细胞的累积浸润。转录组学分析揭示了丙烯酰胺处理的ILC2中与增殖相关途径相关的基因表达模式。蛋白质印迹显示,丙烯酰胺处理的ILC2中Ras和p-Erk的表达显著高于对照,表明Ras-Erk信号通路参与。离体和体外分析表明,丙烯酰胺处理主要增加Ki-67+ILC2s和ILC2s的细胞数量,而高选择性Erk抑制剂PD98059有效地抵消了丙烯酰胺的作用。气管内给予丙烯酰胺处理的ILC2显著增强Rag1-/-小鼠的嗜酸性粒细胞浸润。这项研究表明,空气中的丙烯酰胺可能通过改变ILC2的增殖活性,增强过敏原诱导的气道嗜酸性炎症的严重程度。
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引用次数: 0
Intestinal immunological events of acute and resolved SARS-CoV-2 infection in non-human primates 非人灵长类动物急性和已解决的严重急性呼吸系统综合征冠状病毒2型感染的肠道免疫事件。
IF 8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-02-01 DOI: 10.1016/j.mucimm.2023.10.001
Stéphane Hua , Krishna Latha , Romain Marlin, Keltouma Benmeziane, Laetitia Bossevot, Sébastien Langlois, Francis Relouzat, Nathalie Dereuddre-Bosquet, Roger Le Grand, Mariangela Cavarelli

SARS-CoV-2 infection has been associated with intestinal mucosal barrier damage, leading to microbial and endotoxin translocation, heightened inflammatory responses, and aggravated disease outcomes. This study aimed to investigate the immunological mechanisms associated with impaired intestinal barrier function. We conducted a comprehensive analysis of gut damage and inflammation markers and phenotypic characterization of myeloid and lymphoid populations in the ileum and colon of SARS-CoV-2-exposed macaques during both the acute and resolved infection phases. Our findings revealed a significant accumulation of terminally differentiated and activated CD4+ and CD8+ T cells, along with memory B cells, within the gastrointestinal tract up to 43 days after exposure to SARS-CoV-2. This robust infection-induced immune response was accompanied by a notable depletion of plasmacytoid dendritic cells, myeloid dendritic cells, and macrophages, particularly affecting the colon during the resolved infection phase. Additionally, we identified a population of CX3CR1Low inflammatory macrophages associated with intestinal damage during active viral replication. Elevated levels of immune activation and gut damage markers, and perturbation of macrophage homeostasis, persisted even after the resolution of the infection, suggesting potential long-term clinical sequelae. These findings enhance our understanding of gastrointestinal immune pathology following SARS-CoV-2 infection and provide valuable information for developing and testing medical countermeasures.

严重急性呼吸系统综合征冠状病毒2型感染与肠黏膜屏障损伤有关,导致微生物和内毒素移位、炎症反应加剧和疾病后果加重。本研究旨在探讨与肠屏障功能受损相关的免疫机制。我们对严重急性呼吸系统综合征冠状病毒2型暴露猕猴在急性和消退感染阶段的肠道损伤和炎症标志物,以及回肠和结肠中骨髓和淋巴群的表型特征进行了全面分析。我们的研究结果显示,暴露于严重急性呼吸系统综合征冠状病毒2型后43天,胃肠道内终末分化和活化的CD4+和CD8+T细胞以及记忆B细胞显著积聚。这种强大的感染诱导的免疫反应伴随着浆细胞样树突状细胞、髓系树突状细胞和巨噬细胞的显著耗竭,尤其是在感染消退阶段影响结肠。此外,我们还鉴定了一组CX3CR1低炎症巨噬细胞,这些巨噬细胞与病毒主动复制过程中的肠道损伤有关。即使在感染消退后,免疫激活和肠道损伤标志物水平的升高以及巨噬细胞稳态的紊乱仍持续存在,这表明潜在的长期临床后遗症。这些发现增强了我们对严重急性呼吸系统综合征冠状病毒2型感染后胃肠免疫病理的理解,并为制定和测试医疗对策提供了有价值的信息。
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引用次数: 0
The menstrual cycle regulates migratory CD4 T-cell surveillance in the female reproductive tract via CCR5 signaling 月经周期通过CCR5信号调节女性生殖道中CD4 T细胞迁移监测。
IF 8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-02-01 DOI: 10.1016/j.mucimm.2023.10.002
M. Elliott Williams , Felica P. Hardnett , Anandi N. Sheth , Alexander N. Wein , Zheng-Rong Tiger Li , Jessica Radzio-Basu , Chuong Dinh , Lisa B. Haddad , Elizabeth M.B. Collins , Igho Ofotokun , Rustom Antia , Christopher D. Scharer , J. Gerardo Garcia-Lerma , Jacob E. Kohlmeier , Alison Swaims-Kohlmeier

Despite their importance for immunity against sexually transmitted infections, the composition of female reproductive tract (FRT) memory T-cell populations in response to changes within the local tissue environment under the regulation of the menstrual cycle remains poorly defined. Here, we show that in humans and pig-tailed macaques, the cycle determines distinct clusters of differentiation 4 T-cell surveillance behaviors by subsets corresponding to migratory memory (TMM) and resident memory T cells. TMM displays tissue-itinerant trafficking characteristics, restricted distribution within the FRT microenvironment, and distinct effector responses to infection. Gene pathway analysis by RNA sequencing identified TMM-specific enrichment of genes involved in hormonal regulation and inflammatory responses. FRT T-cell subset fluctuations were discovered that synchronized to cycle-driven CCR5 signaling. Notably, oral administration of a CCR5 antagonist drug blocked TMM trafficking. Taken together, this study provides novel insights into the dynamic nature of FRT memory CD4 T cells and identifies the menstrual cycle as a key regulator of immune surveillance at the site of STI pathogen exposure.

尽管它们对性传播感染(STIs)的免疫力很重要,但女性生殖道(FRT)记忆T细胞群的组成在月经周期调节下对局部组织环境变化的反应仍不明确。在这里,我们发现,在人类和猪尾猕猴中,该周期通过与迁移记忆(TMM)和驻留记忆(TRM)细胞相对应的亚群来决定不同的CD4 T细胞监测行为。TMM表现出组织巡回运输特征,在FRT微环境中的分布受限,以及对感染的不同效应反应。通过RNA测序的基因通路分析确定了TMM特异性富集的参与激素调节和炎症反应的基因。发现FRT细胞亚群波动与周期驱动的CCR5信号同步。值得注意的是,口服CCR5拮抗剂药物阻断了TMM的贩运。总之,这项研究为FRT记忆CD4 T细胞的动态性质提供了新的见解,并确定月经周期是STI病原体暴露部位免疫监测的关键调节因子。
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引用次数: 0
Disrupting endogenous retroelements with a reverse transcriptase inhibitor alleviates DSS-induced colitis in mice 用逆转录酶抑制剂干扰内源性逆转录素,可减轻 DSS 诱导的小鼠结肠炎
IF 8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-02-01 DOI: 10.1016/j.mucimm.2023.10.004
Yifan Niu , Yu Liu , Xiang Ma , Lu Liu , Sihong Li , Rui Li , Tao Wang , Houhui Song , Dong Niu

Endogenous retroelements play vital roles in sustaining immune homeostasis. Activation of endogenous retroelements can trigger cGAS/STING pathway and downstream pro-inflammatory cytokine production. Activated macrophages (M1), which can be induced by pro-inflammatory cytokines, are involved in the development of colitis. Here we aimed to determine whether a retrovirus reverse transcriptase inhibitor azidothymidine (AZT) could influence M1 macrophage polarization and rescue colitis by inhibiting the reverse transcription of murine endogenous retroelements. A dextran sodium sulfate salt (DSS)-induced colitis mouse model (male C57BL/6N) and a lipopolysaccharides-treated RAW264.7 cell line were used to evaluate the protective role of AZT in colitis alleviation. An upregulated expression of endogenous retroelements was first detected in both the colons of the mice with colitis and the lipopolysaccharides-stimulated M1 cells, and treatment with AZT significantly decreased the expression. Meanwhile, a downregulation of cGAS/STING/NF-κB pathway and pro-inflammatory cytokines that induce M1 macrophage polarization was also observed in AZT-treated colitis or M1 groups. Moreover, the symptoms of DSS-induced colitis could be significantly alleviated by AZT. In summary, the endogenous retroelement inhibitor AZT could rescue the DSS-induced colitis possibly via blocking M1 macrophage polarization through cGAS/STING/NF-κB pro-inflammatory pathway. Thus, a pharmacological blockade of endogenous retroelements would be a new strategy for clinical therapy of colitis.

内源性逆源因子在维持免疫平衡方面发挥着重要作用。激活内源性逆转录酶可触发 cGAS/STING 通路和下游促炎细胞因子的产生。激活的巨噬细胞(M1)可由促炎细胞因子诱导,参与结肠炎的发展。在此,我们旨在确定逆转录病毒逆转录酶抑制剂氮卓胸苷(AZT)是否能通过抑制小鼠内源性逆转录病毒的逆转录来影响 M1 巨噬细胞的极化并挽救结肠炎。研究人员使用葡聚糖硫酸钠盐(DSS)诱导的结肠炎小鼠模型(雄性 C57BL/6N)和脂多糖处理的 RAW264.7 细胞系来评估 AZT 在缓解结肠炎方面的保护作用。首先在结肠炎小鼠的结肠和脂多糖刺激的 M1 细胞中都检测到了内源性逆转录酶的上调表达,而用 AZT 治疗可显著降低其表达。同时,在 AZT 治疗的结肠炎组或 M1 组中,还观察到 cGAS/STING/NF-κB 通路和诱导 M1 巨噬细胞极化的促炎细胞因子的下调。此外,AZT 还能显著缓解 DSS 诱导的结肠炎症状。综上所述,内源性逆转录酶抑制剂 AZT 可通过 cGAS/STING/NF-κB 促炎途径阻断 M1 巨噬细胞极化,从而缓解 DSS 诱导的结肠炎。因此,药物阻断内源性逆转录酶将成为临床治疗结肠炎的新策略。
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引用次数: 0
期刊
Mucosal Immunology
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