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Dendritic cell-mediated responses to secreted Cryptosporidium effectors promote parasite-specific CD8+ T cell responses 树突状细胞介导的对隐孢子虫分泌效应因子的反应可促进寄生虫特异性 CD8+ T 细胞反应
IF 8 2区 医学 Q1 Medicine Pub Date : 2024-06-01 DOI: 10.1016/j.mucimm.2024.03.003
Breanne E. Haskins , Jodi A. Gullicksrud , Bethan A. Wallbank , Jennifer E. Dumaine , Amandine Guérin , Ian S. Cohn , Keenan M. O'Dea , Ryan D. Pardy , Maria I. Merolle , Lindsey A. Shallberg , Emma N. Hunter , Jessica H. Byerly , Eleanor J. Smith , Gracyn Y. Buenconsejo , Briana I. McLeod , David A. Christian , Boris Striepen , Christopher A. Hunter

Cryptosporidium causes debilitating diarrheal disease in patients with primary and acquired defects in T cell function. However, it has been a challenge to understand how this infection generates T cell responses and how they mediate parasite control. Here, Cryptosporidium was engineered to express a parasite effector protein (MEDLE-2) that contains the major histocompatibility complex-I restricted SIINFEKL epitope which is recognized by T cell receptor transgenic OT-I(OVA-TCR-I) clusters of differentiation (CD)8+ T cells. These modified parasites induced expansion of endogenous SIINFEKL-specific and OT-I CD8+ T cells that were a source of interferon-gamma (IFN-γ) that could restrict growth of Cryptosporidium. This T cell response was dependent on the translocation of the effector and similar results were observed with another secreted parasite effector (rhoptry protein 1). Although infection and these translocated effector proteins are restricted to intestinal epithelial cells, type 1 conventional dendritic cells were required to generate CD8+ T cell responses to these model antigens. These data sets highlight Cryptosporidium effectors as potential targets of the immune system and suggest that crosstalk between enterocytes and type 1 conventional dendritic cells is crucial for CD8+ T cell responses to Cryptosporidium.

然而,了解这种感染如何产生 T 细胞反应以及它们如何介导寄生虫控制一直是个挑战。在这里,我们设计表达了一种寄生虫效应蛋白(MEDLE-2),它含有 MHC-I 限制性 SIINFEKL 表位,可被 TCR 转基因 OT-I CD8 T 细胞识别。这些改造过的寄生虫诱导了内源性 SIINFEKL 特异性和 OT-I CD8 T 细胞的扩增,这些 T 细胞是 IFN-γ 的来源,可以限制 SIINFEKL 的生长。 这种 T 细胞反应依赖于效应物的易位,在另一种分泌型寄生虫效应物(ROP1)上也观察到了类似的结果。虽然感染和这些转位效应蛋白仅限于肠上皮细胞(IEC),但需要 I 型树突状细胞(cDC1)才能产生 CD8 T 细胞对这些模型抗原的反应。这些数据集强调了效应蛋白是免疫系统的潜在靶标,并表明肠细胞和 cDC1 之间的串联对于 CD8 T 细胞对......的应答至关重要。
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引用次数: 0
Interaction of microbiota, mucosal malignancies, and immunotherapy—Mechanistic insights 微生物群、粘膜恶性肿瘤和免疫疗法的相互作用--机理启示。
IF 8 2区 医学 Q1 Medicine Pub Date : 2024-06-01 DOI: 10.1016/j.mucimm.2024.03.007
Lukas F. Mager , Tim Krause , Kathy D. McCoy

The microbiome has emerged as a crucial modulator of host-immune interactions and clearly impacts tumor development and therapy efficacy. The microbiome is a double-edged sword in cancer development and therapy as both pro-tumorigenic and anti-tumorigenic bacterial taxa have been identified. The staggering number of association-based studies in various tumor types has led to an enormous amount of data that makes it difficult to identify bacteria that promote tumor development or modulate therapy efficacy from bystander bacteria. Here we aim to comprehensively summarize the current knowledge of microbiome-host immunity interactions and cancer therapy in various mucosal tissues to find commonalities and thus identify potential functionally relevant bacterial taxa. Moreover, we also review recent studies identifying specific bacteria and mechanisms through which the microbiome modulates cancer development and therapy efficacy.

微生物组已成为宿主免疫相互作用的关键调节因子,并对肿瘤的发展和治疗效果产生明显影响。微生物组在癌症的发展和治疗中是一把双刃剑,因为人们已经发现了促致癌细菌类群和抗致癌细菌类群。在各种肿瘤类型中进行的基于关联的研究数量惊人,导致数据量巨大,很难从旁观细菌中找出促进肿瘤发展或调节治疗效果的细菌。在此,我们旨在全面总结目前关于各种粘膜组织中微生物组-宿主免疫相互作用和癌症治疗的知识,以发现共性,从而确定潜在的功能相关细菌类群。此外,我们还回顾了最近的一些研究,这些研究确定了微生物组调节癌症发展和疗效的特定细菌和机制。
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引用次数: 0
Single-cell landscape reveals the epithelial cell-centric pro-inflammatory immune microenvironment in dry eye development 单细胞景观揭示了干眼发育中上皮细胞为中心的促炎免疫微环境。
IF 8 2区 医学 Q1 Medicine Pub Date : 2024-06-01 DOI: 10.1016/j.mucimm.2023.11.008
Zihao Liu , He Xie , Ling Li , Dan Jiang , Yuna Qian , Xinhao Zhu , Mali Dai , Yanxiao Li , Ruifen Wei , Zan Luo , Weihao Xu , Qinxiang Zheng , Jianliang Shen , Meng Zhou , Wenwen Zeng , Wei Chen

Dry eye disease (DED) is a prevalent chronic eye disease characterized by an aberrant inflammatory response in ocular surface mucosa. The immunological alterations underlying DED remain largely unknown. In this study, we employed single-cell transcriptome sequencing of conjunctival tissue from environment-induced DED mice to investigate multicellular ecosystem and functional changes at different DED stages. Our results revealed an epithelial subtype with fibroblastic characteristics and pro-inflammatory effects emerging in the acute phase of DED. We also found that T helper (Th)1, Th17, and regulatory T cells (Treg) were the dominant clusters of differentiation (CD)4+ T-cell types involved in regulating immune responses and identified three distinct macrophage subtypes, with the CD72+CD11c+ subtype enhancing chronic inflammation. Furthermore, bulk transcriptome analysis of video display terminal-induced DED consistently suggested the presence of the pro-inflammatory epithelial subtype in human conjunctiva. Our findings have uncovered a DED-associated pro-inflammatory microenvironment in the conjunctiva, centered around epithelial cells, involving interactions with macrophages and CD4+ T cells, which deepens our understanding of ocular surface mucosal immune responses during DED progression.

干眼病(DED)是一种常见的慢性眼病,其特征是眼表面黏膜的异常炎症反应。DED背后的免疫学改变在很大程度上仍然未知。在本研究中,我们利用环境诱导的DED小鼠结膜组织的单细胞转录组测序来研究DED不同阶段的多细胞生态系统和功能变化。我们的研究结果显示,在DED的急性期出现了一种具有成纤维细胞特征和促炎作用的上皮亚型。我们还发现Th1、Th17和Treg细胞是参与调节免疫应答的主要CD4+ t细胞类型,并确定了三种不同的巨噬细胞亚型,其中CD72+CD11c+亚型增强慢性炎症。此外,视频显示终端(VDT)诱导的DED的大量转录组分析一致表明,人结膜中存在促炎上皮亚型。我们的研究结果揭示了以上皮细胞为中心的结膜中与DED相关的促炎微环境,涉及巨噬细胞和CD4+ T细胞的相互作用,这加深了我们对DED进展过程中眼表粘膜免疫反应的理解。
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引用次数: 0
PD-1 regulates ILC3-driven intestinal immunity and homeostasis PD-1调节ILC3驱动的肠道免疫和稳态。
IF 8 2区 医学 Q1 Medicine Pub Date : 2024-06-01 DOI: 10.1016/j.mucimm.2024.03.002
Nicolas Jacquelot , Le Xiong , Wang H.J. Cao , Qiutong Huang , Huiyang Yu , Azin Sayad , Casey J.A. Anttila , Tracey M. Baldwin , Peter F. Hickey , Daniela Amann-Zalcenstein , Pamela S. Ohashi , Stephen L. Nutt , Gabrielle T. Belz , Cyril Seillet

Interleukin-(IL) 22 production by intestinal group 3 innate lymphoid cells (ILC3) is critical to maintain gut homeostasis. However, IL-22 needs to be tightly controlled; reduced IL-22 expression is associated with intestinal epithelial barrier defect while its overexpression promotes tumor development. Here, using a single-cell ribonucleic acid sequencing approach, we identified a core set of genes associated with increased IL-22 production by ILC3. Among these genes, programmed cell death 1 (PD-1), extensively studied in the context of cancer and chronic infection, was constitutively expressed on a subset of ILC3. These cells, found in the crypt of the small intestine and colon, displayed superior capacity to produce IL-22. PD-1 expression on ILC3 was dependent on the microbiota and was induced during inflammation in response to IL-23 but, conversely, was reduced in the presence of Notch ligand. PD-1+ ILC3 exhibited distinct metabolic activity with increased glycolytic, lipid, and polyamine synthesis associated with augmented proliferation compared with their PD-1 counterparts. Further, PD-1+ ILC3 showed increased expression of mitochondrial antioxidant proteins which enable the cells to maintain their levels of reactive oxygen species. Loss of PD-1 signaling in ILC3 led to reduced IL-22 production in a cell-intrinsic manner. During inflammation, PD-1 expression was increased on natural cytotoxicity receptor (NCR) ILC3 while deficiency in PD-1 expression resulted in increased susceptibility to experimental colitis and failure to maintain gut barrier integrity. Collectively, our findings uncover a new function of the PD-1 and highlight the role of PD-1 signaling in the maintenance of gut homeostasis mediated by ILC3 in mice.

肠道第 3 组先天性淋巴细胞(ILC3)产生的白细胞介素(IL)22 对维持肠道平衡至关重要。然而,IL-22 需要严格控制;IL-22 表达减少与肠上皮屏障缺陷有关,而其过度表达则会促进肿瘤发生。在这里,我们利用单细胞 RNAseq 方法,确定了一组与 ILC3 IL-22 生成增加相关的核心基因。在这些基因中,在癌症和慢性感染背景下被广泛研究的程序性细胞死亡 1(PD-1)在 ILC3 亚群中呈组成型表达。这些细胞存在于小肠和结肠的隐窝中,具有产生 IL-22 的超强能力。PD-1在ILC3上的表达依赖于微生物群,并在炎症期间被诱导对IL-23做出反应,但相反,在Notch配体存在的情况下则会减少。PD-1+的ILC3表现出独特的代谢活性,与PD-1-的ILC3相比,其糖酵解、脂质和多胺合成增加,增殖加快。此外,PD-1+ ILC3 的线粒体抗氧化蛋白表达量增加,使细胞能够维持活性氧(ROS)的水平。PD-1信号在ILC3中的缺失导致IL-22以细胞内在方式产生。在炎症期间,NCR- ILC3 上的 PD-1 表达增加,而 PD-1 表达缺乏会导致对实验性结肠炎的易感性增加,并且无法维持肠道屏障的完整性。总之,我们的研究结果揭示了 PD-1 的一种新功能,并强调了 PD-1 信号在小鼠 ILC3 介导的肠道稳态维持中的作用。
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引用次数: 0
Metabolic fitness of IgA+ plasma cells in the gut requires DOCK8 肠道中 IgA+ 浆细胞的代谢适应性需要 DOCK8。
IF 8 2区 医学 Q1 Medicine Pub Date : 2024-06-01 DOI: 10.1016/j.mucimm.2023.12.001
Biyan Zhang , Shuting Chen , Xiangyun Yin , Caleb D. McBride , Jake A. Gertie , Marina Yurieva , Agata A. Bielecka , Brian Hoffmann , J. Travis Hinson , Jessica Grassmann , Lan Xu , Emily R. Siniscalco , Arielle Soldatenko , Laura Hoyt , Julie Joseph , Elizabeth B. Norton , Gowthaman Uthaman , Noah W. Palm , Elise Liu , Stephanie C. Eisenbarth , Adam Williams

Dedicator of cytokinesis 8 (DOCK8) mutations lead to a primary immunodeficiency associated with recurrent gastrointestinal infections and poor antibody responses but, paradoxically, heightened IgE to food antigens, suggesting that DOCK8 is central to immune homeostasis in the gut. Using Dock8-deficient mice, we found that DOCK8 was necessary for mucosal IgA production to multiple T cell-dependent antigens, including peanut and cholera toxin. Yet DOCK8 was not necessary in T cells for this phenotype. Instead, B cell-intrinsic DOCK8 was required for maintenance of antigen-specific IgA-secreting plasma cells (PCs) in the gut lamina propria. Unexpectedly, DOCK8 was not required for early B cell activation, migration, or IgA class switching. An unbiased interactome screen revealed novel protein partners involved in metabolism and apoptosis. Dock8-deficient IgA+ B cells had impaired cellular respiration and failed to engage glycolysis appropriately. These results demonstrate that maintenance of the IgA+ PC compartment requires DOCK8 and suggest that gut IgA+ PCs have unique metabolic requirements for long-term survival in the lamina propria.

细胞分裂诱导因子 8(DOCK8)突变会导致一种原发性免疫缺陷,这种缺陷与反复胃肠道感染和抗体反应低下有关,但矛盾的是,对食物抗原的 IgE 会增加,这表明 DOCK8 是肠道免疫平衡的核心。利用 Dock8 缺陷小鼠,我们发现 DOCK8 对多种 T 细胞依赖性抗原(包括花生和霍乱毒素)的粘膜 IgA 生成是必需的。然而 DOCK8 并不是 T 细胞产生这种表型的必要条件。相反,肠道固有层中抗原特异性 IgA 分泌浆细胞(PCs)的维持需要 B 细胞固有的 DOCK8。意想不到的是,DOCK8 并非早期 B 细胞活化、迁移或 IgA 类别转换所必需。一项无偏见的相互作用组筛选发现了参与新陈代谢和细胞凋亡的新型蛋白质伙伴。Dock8缺陷的IgA+ B细胞细胞呼吸功能受损,不能适当地参与糖酵解。这些结果表明,维持 IgA+ PC 区需要 DOCK8,并表明肠道 IgA+ PC 在固有膜中长期存活有独特的代谢要求。
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引用次数: 0
HIV infection impairs the host response to Mycobacterium tuberculosis infection by altering surfactant protein D function in the human lung alveolar mucosa 艾滋病病毒感染通过改变人体肺泡黏膜表面活性蛋白 D 的功能,损害宿主对结核分枝杆菌感染的反应。
IF 8 2区 医学 Q1 Medicine Pub Date : 2024-06-01 DOI: 10.1016/j.mucimm.2023.12.003
Anwari Akhter , Juan I. Moliva , Abul K. Azad , Angélica Olmo-Fontánez , Andreu Garcia-Vilanova , Julia M. Scordo , Mikhail A. Gavrilin , Phillip T. Diaz , Janice J. Endsley , Susan T. Weintraub , Larry S. Schlesinger , Mark D. Wewers , Jordi B. Torrelles

Tuberculosis is the leading cause of death for people living with HIV (PLWH). We hypothesized that altered functions of innate immune components in the human alveolar lining fluid of PLWH (HIV-ALF) drive susceptibility to Mycobacterium tuberculosis (M.tb) infection. Our results indicate a significant increase in oxidation of innate proteins and chemokine levels and significantly lower levels and function of complement components and Th1/Th2/Th17 cytokines in HIV-ALF versus control-ALF (non-HIV-infected people). We further found a deficiency of surfactant protein D (SP-D) and reduced binding of SP-D to M.tb that had been exposed to HIV-ALF. Primary human macrophages infected with M.tb exposed to HIV-ALF were significantly less capable of controlling the infection, which was reversed by SP-D replenishment in HIV-ALF. Thus, based on the limited number of participants in this study, our data suggest that PLWH without antiretroviral therapy (ART) have declining host innate defense function in their lung mucosa, thereby favoring M.tb and potentially other pulmonary infections.

结核病是艾滋病病毒感染者(PLWH)的主要死因。我们假设,艾滋病病毒感染者肺泡内衬液(HIV-ALF)中先天性免疫成分功能的改变会导致对结核分枝杆菌(M.tb)感染的易感性。我们的研究结果表明,与对照-ALF(非艾滋病毒感染者)相比,HIV-ALF 中的先天性蛋白氧化和趋化因子水平明显升高,补体成分和 Th1/Th2/Th17 细胞因子的水平和功能明显降低。我们还发现表面活性蛋白-D(SP-D)缺乏,SP-D与接触过HIV-ALF的M.tb的结合减少。原代人类巨噬细胞感染了暴露于 HIV-ALF 的 M.tb 后,控制感染的能力明显降低,而这种情况在补充了 HIV-ALF 中的 SP-D 后得到了逆转。因此,基于本研究中有限的参与人数,我们的数据表明,未接受抗逆转录病毒疗法的 PLWH 肺粘膜宿主先天防御功能下降,从而有利于 M.tb,并可能导致其他肺部感染。
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引用次数: 0
Stress systems exacerbate the inflammatory response after corneal abrasion in sleep-deprived mice via the IL-17 signaling pathway 应激系统通过 IL-17 信号通路加剧睡眠不足小鼠角膜擦伤后的炎症反应。
IF 8 2区 医学 Q1 Medicine Pub Date : 2024-06-01 DOI: 10.1016/j.mucimm.2024.02.009
Yunxia Xue , Pengyang Xu , Yu Hu , Sijing Liu , Ruyu Yan , Shutong Liu , Yan Li , Jun Liu , Ting Fu , Zhijie Li

Sleep deprivation (SD) has a wide range of adverse health effects. However, the mechanisms by which SD influences corneal pathophysiology and its post-wound healing remain unclear. This study aimed to examine the basic physiological characteristics of the cornea in mice subjected to SD and determine the pathophysiological response to injury after corneal abrasion. Using a multi-platform water environment method as an SD model, we found that SD leads to disturbances of corneal proliferative, sensory, and immune homeostasis as well as excessive inflammatory response and delayed repair after corneal abrasion by inducing hyperactivation of the sympathetic nervous system and hypothalamic-pituitary-adrenal axis. Pathophysiological changes in the cornea mainly occurred through the activation of the IL-17 signaling pathway. Blocking both adrenergic and glucocorticoid synthesis and locally neutralizing IL-17A significantly improved corneal homeostasis and the excessive inflammatory response and delay in wound repair following corneal injury in SD-treated mice. These results indicate that optimal sleep quality is essential for the physiological homeostasis of the cornea and its well-established repair process after injury. Additionally, these observations provide potential therapeutic targets to ameliorate SD-induced delays in corneal wound repair by inhibiting or blocking the activation of the stress system and its associated IL-17 signaling pathway.

睡眠不足(SD)对健康有广泛的不利影响。然而,SD 影响角膜病理生理学及其创伤后愈合的机制仍不清楚。本研究旨在检测睡眠不足小鼠角膜的基本生理特征,并确定角膜擦伤后损伤的病理生理反应。我们采用多平台水环境法作为 SD 模型,发现 SD 通过诱导交感神经系统和下丘脑-垂体-肾上腺轴的过度激活,导致角膜增殖、感觉和免疫平衡紊乱以及过度炎症反应和角膜擦伤后的延迟修复。角膜的病理生理变化主要是通过激活 IL-17 信号通路发生的。阻断肾上腺素能和糖皮质激素的合成以及局部中和 IL-17A 能显著改善 SD 处理小鼠的角膜稳态、过度炎症反应以及角膜损伤后的伤口修复延迟。这些结果表明,最佳的睡眠质量对角膜的生理平衡及其损伤后的修复过程至关重要。此外,这些观察结果还提供了潜在的治疗靶点,可通过抑制或阻断应激系统及其相关 IL-17 信号通路的激活来改善 SD 引起的角膜伤口修复延迟。
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引用次数: 0
Pulmonary immune profiling reveals common inflammatory endotypes of childhood wheeze and suppurative lung disease 肺部免疫图谱揭示了儿童喘息和化脓性肺病的共同炎症内型。
IF 8 2区 医学 Q1 Medicine Pub Date : 2024-06-01 DOI: 10.1016/j.mucimm.2024.03.001
Melanie R. Neeland , Liam Gubbels , Anson Tsz Chun Wong , Hannah Walker , Sarath C. Ranganathan , Shivanthan Shanthikumar

Suppurative lung disease and wheezing are common respiratory diseases of childhood, however, due to poor understanding of underlying pathobiology, there are limited treatment options and disease recurrence is common. We aimed to profile the pulmonary and systemic immune response in children with wheeze and chronic suppurative lung disease for identification of endotypes that can inform improved clinical management. We used clinical microbiology data, highly multiplexed flow cytometry and immunoassays to compare pulmonary [bronchoalveolar lavage (BAL)] and systemic immunity in children with lung disease and controls. Unsupervised analytical approaches were applied to BAL immune data to explore biological endotypes. We identified two endotypes that were analogous in both frequency and immune signature across both respiratory diseases. The hyper-inflammatory endotype had a 12-fold increase in neutrophil infiltration and upregulation of 14 soluble signatures associated with type 2 inflammation and cell recruitment to tissue. The non-inflammatory endotype was not significantly different from controls. We showed these endotypes are measurable in a clinical setting and can be defined by measuring only three immune factors in BAL. We identified hyper-inflammatory and non-inflammatory endotypes common across pediatric wheeze and chronic suppurative lung disease that, if validated in future studies, have the potential to inform clinical management.

化脓性肺病和喘息是儿童时期常见的呼吸系统疾病,但由于对其潜在的病理生物学缺乏了解,治疗方案有限,疾病复发也很常见。我们的目的是分析喘息和 CSLD 儿童的肺部和全身免疫反应,以确定内型,为改善临床管理提供依据。我们利用临床微生物学数据、高度复用流式细胞术和免疫测定来比较肺病患儿和对照组的肺部(支气管肺泡灌洗液(BAL))和全身免疫。我们将无监督分析方法应用于 BAL 免疫数据,以探索生物内型。我们发现了两种内型,它们在两种呼吸系统疾病中的频率和免疫特征都类似。高炎症性内型的中性粒细胞浸润增加了 12 倍,与 2 型炎症和组织细胞募集相关的 14 个可溶性特征上调。非炎症内型与对照组无明显差异。我们的研究表明,这些内型在临床环境中是可以测量的,而且只需测量 BAL 中的三种免疫因子就能确定。我们确定了儿科喘息和 CSLD 中常见的高炎症性和非炎症性内型,如果在未来的研究中得到验证,将有可能为临床管理提供依据。
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引用次数: 0
MZB1-mediated IgA secretion suppresses the development and progression of colorectal cancer triggered by gut inflammation MZB1 介导的 IgA 分泌可抑制肠道炎症引发的结直肠癌的发展和恶化。
IF 8 2区 医学 Q1 Medicine Pub Date : 2024-06-01 DOI: 10.1016/j.mucimm.2023.12.002
Yue Tang , Xiaoqian Feng , Qing Lu , Chaoqun Cui , Meiping Yu , Zichao Wen , Yingying Luan , Lulu Dong , Ziying Hu , Runyun Zhang , Chunhui Lu , Jie Liu , Reiko Shinkura , Koji Hase , Ji-Yang Wang

Colorectal cancer (CRC) ranks among the top causes of mortality globally. Gut inflammation is one crucial risk factor that augments CRC development since patients suffering from inflammatory bowel disease have an increased incidence of CRC. The role of immunoglobulin (Ig)A in maintaining gut homeostasis and preventing inflammation has been well established. Our earlier work demonstrated that the marginal zone and B1 cell-specific protein (MZB1) promotes gut IgA secretion and its absence results in pronounced dextran sulfate sodium salt (DSS)-induced colitis. In the present study, we explored the role of MZB1 in CRC development using the azoxymethane (AOM)/DSS-induced CRC model. We observed an increase in both the number and size of the tumor nodules in Mzb1−/− mice compared with Mzb1+/+ mice. The increase in CRC development and progression in Mzb1−/− mice was associated with reduced intestinal IgA levels, altered gut flora, and more severe gut and systemic inflammation. Oral administration of the monoclonal IgA, W27, alleviated both the gut inflammation and AOM/DSS-induced CRC. Notably, cohousing Mzb1+/+ and Mzb1−/− mice from the 10th day after birth led to similar CRC development. Our findings underscore the pivotal role of MZB1-mediated IgA secretion in suppressing the onset and progression of CRC triggered by gut inflammation. Moreover, our study highlights the profound impact of microbiota composition, modulated by gut IgA levels, on gut inflammation. Nonetheless, establishing a direct correlation between the severity of colitis and subsequent CRC development and the presence or absence of a particular microbiota is challenging.

结肠直肠癌(CRC)在全球死亡原因中名列前茅。肠道炎症是诱发 CRC 的一个重要风险因素,因为患有炎症性肠病的患者会增加 CRC 的发病率。IgA 在维持肠道平衡和预防炎症方面的作用已得到公认。我们早前的研究表明,边缘区和 B1 细胞特异性蛋白(MZB1)能促进肠道 IgA 分泌,缺失该蛋白会导致明显的右旋糖酐硫酸钠盐(DSS)诱导的结肠炎。在本研究中,我们利用偶氮甲烷(AOM)/DSS诱导的结直肠癌模型探讨了MZB1在结直肠癌发展中的作用。与 Mzb1+/+ 小鼠相比,我们观察到 Mzb1-/- 小鼠肿瘤结节的数量和大小均有所增加。Mzb1-/-小鼠CRC发病和进展的增加与肠道IgA水平降低、肠道菌群改变以及更严重的肠道和全身炎症有关。口服单克隆 IgA W27 可减轻肠道炎症和 AOM/DSS 诱导的 CRC。值得注意的是,Mzb1+/+和Mzb1-/-小鼠从出生后第10天开始同群饲养会导致相似的CRC发展。我们的发现强调了 MZB1 介导的 IgA 分泌在抑制肠道炎症引发的 CRC 的发生和发展中的关键作用。此外,我们的研究还凸显了微生物群组成对肠道炎症的深远影响,而肠道 IgA 水平则可调节微生物群组成。尽管如此,要在结肠炎的严重程度和随后的 CRC 发展与特定微生物群的存在与否之间建立直接的相关性仍具有挑战性。
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引用次数: 0
PD-1 signaling in neonates restrains CD8+ T cell function and protects against respiratory viral immunopathology 新生儿体内的 PD-1 信号抑制 CD8+ T 细胞功能并保护其免受呼吸道病毒免疫病理的影响。
IF 8 2区 医学 Q1 Medicine Pub Date : 2024-06-01 DOI: 10.1016/j.mucimm.2023.12.004
Taylor Eddens , Olivia B. Parks , Yu Zhang , Michelle L. Manni , Jean-Laurent Casanova , Masato Ogishi , John V. Williams

Respiratory viral infections, including human metapneumovirus (HMPV), remain a leading cause of morbidity and mortality in neonates and infants. However, the mechanisms behind the increased sensitivity to those respiratory viral infections in neonates are poorly understood. Neonates, unlike adults, have several anti-inflammatory mechanisms in the lung, including elevated baseline expression of programmed death ligand 1 (PD-L1), a ligand for the inhibitory receptor programmed cell death protein 1 (PD-1). We thus hypothesized that neonates would rely on PD-1:PD-L1 signaling to restrain antiviral CD8 responses. To test this, we developed a neonatal primary HMPV infection model using wild-type C57BL/6 (B6) and Pdcd1-/- (lacking PD-1) mice. HMPV-infected neonatal mice had increased PD-L1/PD-L2 co-expression on innate immune cells but a similar number of antigen-specific CD8+ T cells and upregulation of PD-1 to that of adult B6 mice. Neonatal CD8+ T cells had reduced interferon‐gamma (IFN-γ), granzyme B, and interleukin-2 production compared with B6 adults. Pdcd1-/- neonatal CD8+ T cells had markedly increased production of IFN-γ and granzyme B compared with B6 neonates. Pdcd1-/- neonates had increased acute pathology with HMPV or influenza. Pdcd1-/- neonates infected with HMPV had long-term changes in pulmonary physiology with evidence of immunopathology and a persistent CD8+ T-cell response with increased granzyme B production. Using single-cell ribonucleic acid sequencing from a child lacking PD-1 signaling, a similar activated CD8+ T-cell signature with increased granzyme B expression was observed. These data indicate that PD-1 signaling critically limits CD8+ T-cell effector functions and prevents immunopathology in response to neonatal respiratory viral infections.

包括人类偏肺病毒(HMPV)在内的呼吸道病毒感染仍然是新生儿和婴儿发病和死亡的主要原因。然而,人们对新生儿对这些呼吸道病毒感染的敏感性增加背后的机制却知之甚少。与成人不同,新生儿的肺部具有多种抗炎机制,包括抑制受体 PD-1 的配体 PD-L1 的基线表达升高。因此,我们假设新生儿会依赖 PD-1:PD-L1 信号来抑制抗病毒 CD8 反应。为了验证这一假设,我们使用 WT C57BL/6 (B6) 和 Pdcd1-/-(缺乏 PD-1)小鼠建立了新生儿原发性 HMPV 感染模型。与成年 B6 小鼠相比,HMPV 感染的新生小鼠先天性免疫细胞上的 PD-L1/PD-L2 共表达增加,但抗原特异性 CD8+ T 细胞的数量和 PD-1 的上调情况相似。与成年 B6 小鼠相比,新生儿 CD8+ T 细胞产生的 IFN-γ、粒酶 B 和 IL-2 减少了。与 B6 新生儿相比,Pdcd1-/-新生 CD8+ T 细胞产生的 IFN-γ 和颗粒酶 B 明显增加。Pdcd1-/-新生儿在感染HMPV或流感后急性病理变化增加。感染了HMPV的Pdcd1-/-新生儿的肺部生理机能会发生长期变化,并伴有免疫病理和CD8+T细胞持续反应的证据,同时颗粒酶B的生成也会增加。通过对缺乏 PD-1 信号的患儿进行单细胞 RNA 测序,观察到了类似的活化 CD8+ T 细胞特征,颗粒酶 B 表达增加。这些数据表明,PD-1 信号传导严重限制了 CD8+ T 细胞效应功能,并防止了新生儿呼吸道病毒感染引起的免疫病理反应。
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引用次数: 0
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Mucosal Immunology
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