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Investigation of the Immunogenic Properties of Ovalbumin Modified by Urban Airborne Particulate Matter 城市空气颗粒物修饰卵清蛋白免疫原性的研究
IF 3.2 4区 医学 Q3 IMMUNOLOGY Pub Date : 2023-05-28 DOI: 10.1007/s00005-023-00679-8
Bernadeta Nowak, Anna Wądołek, Olga Mazuryk, Anna Poznańska, Katarzyna Majzner, Grzegorz Majka, Maria Oszajca, Małgorzata Barańska, Grażyna Stochel, Janusz Marcinkiewicz

Exposure to air particulate matter (PM) is linked to the blood oxidative stress and systemic inflammation. The aim of this study was to elucidate whether oxidative PM modification of ovalbumin (OVA), the major antioxidant serum protein, may alter its antigenicity and/or immunogenicity. Ovalbumin was exposed via dialysis to the standard urban PM (SRM 1648a) or to PM with removed organic content (encoded as LAP). Both structural changes and biological properties of PM-modified OVA were measured. T lymphocytes and dendritic cells (the major antigen-presenting cells) isolated from C57BL/6 and OT-II (323–339 epitope) OVA-specific T cell receptor (TCR)-transgenic mice were used to test the effect of PM on OVA immunogenicity. The immunogenicity of both SRM 1648a and LAP-modified OVA was significantly higher than that of control OVA, as measured by the epitope-specific T cell proliferation and interferon γ production by the stimulated cells. This effect was associated with mild oxidative changes in the carrier molecule outside the structure of the OVA epitope and with increased resistance to proteolysis of PM-modified OVA. Interestingly, dendritic cells showed enhanced capacity for the uptake of proteins when the cells were cultured with PM-modified OVA. Our results suggest that the enhanced immunogenicity of PM-modified OVA is not associated with altered antigenicity or antigen presentation. However, it may result from slower degradation and longer persistence of modified antigens in dendritic cells. Whether this phenomenon is associated with enhanced risk prevalence of autoimmune diseases observed in the areas with high urban PM pollution needs to be explained.

暴露于空气颗粒物(PM)与血液氧化应激和全身炎症有关。本研究的目的是阐明氧化PM对主要抗氧化血清蛋白卵清蛋白(OVA)的修饰是否会改变其抗原性和/或免疫原性。卵清蛋白通过透析暴露于标准城市PM (SRM 1648a)或去除有机含量的PM(编码为LAP)。测定了pm修饰OVA的结构变化和生物学特性。采用从C57BL/6和OT-II(323-339表位)OVA特异性T细胞受体(TCR)转基因小鼠中分离的T淋巴细胞和树突状细胞(主要抗原呈递细胞)检测PM对OVA免疫原性的影响。通过刺激细胞的表位特异性T细胞增殖和干扰素γ的产生,SRM 1648a和lap修饰的OVA的免疫原性均显著高于对照OVA。这种作用与OVA表位结构外的载体分子的轻度氧化变化以及pm修饰的OVA对蛋白水解的抵抗力增加有关。有趣的是,当树突状细胞用pm修饰的OVA培养时,树突状细胞显示出增强的蛋白质摄取能力。我们的研究结果表明,pm修饰的OVA的免疫原性增强与抗原性或抗原呈递的改变无关。然而,这可能是由于修饰抗原在树突状细胞中降解较慢和持续时间较长。这一现象是否与在城市PM高污染地区观察到的自身免疫性疾病风险患病率增加有关,需要解释。
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引用次数: 0
Omics are Getting Us Closer to Understanding IgA Nephropathy 组学让我们更接近了解IgA肾病
IF 3.2 4区 医学 Q3 IMMUNOLOGY Pub Date : 2023-04-15 DOI: 10.1007/s00005-023-00677-w
Krzysztof Mucha, Michał Pac, Leszek Pączek

During the last decade, thanks to omics technologies, new light has been shed on the pathogenesis of many diseases. Genomics, epigenomics, transcriptomics, and proteomics have helped to provide a better understanding of the origin and heterogeneity of several diseases. However, the risk factors for most autoimmune diseases remain unknown. The successes and pitfalls of omics have also been observed in nephrology, including immunoglobulin A nephropathy (IgAN), the most common form of glomerulonephritis and a principal cause of end-stage renal disease worldwide. Unfortunately, the immense progress in basic research has not yet been followed by the satisfactory development of a targeted treatment. Although, most omics studies describe changes in the immune system, there is still insufficient data to apply their results in the constantly evolving multi-hit pathogenesis model and thus do to provide a complete picture of the disease. Here, we describe recent findings regarding the pathophysiology of IgAN and link omics studies with immune system dysregulation. This review provides insights into specific IgAN markers, which may lead to the identification of potential targets for personalised treatment in the future.

在过去的十年中,多亏了组学技术,许多疾病的发病机制有了新的认识。基因组学、表观基因组学、转录组学和蛋白质组学有助于更好地了解几种疾病的起源和异质性。然而,大多数自身免疫性疾病的危险因素仍然未知。组学的成功和缺陷也在肾脏病学中被观察到,包括免疫球蛋白A肾病(IgAN),这是肾小球肾炎最常见的形式,也是世界范围内终末期肾脏疾病的主要原因。不幸的是,在基础研究取得巨大进展之后,针对性治疗的发展还没有令人满意。尽管大多数组学研究描述了免疫系统的变化,但仍然没有足够的数据将其结果应用于不断发展的多打击发病模型,从而无法提供疾病的完整图景。在这里,我们描述了关于IgAN病理生理学的最新发现,并将组学研究与免疫系统失调联系起来。这篇综述提供了对特定IgAN标记物的见解,这可能会导致未来个性化治疗的潜在目标的确定。
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引用次数: 2
Mast Cells and Resistance to Immunotherapy in Cancer 肥大细胞与肿瘤免疫治疗的耐药性
IF 3.2 4区 医学 Q3 IMMUNOLOGY Pub Date : 2023-04-11 DOI: 10.1007/s00005-023-00676-x
Domenico Ribatti

Mast cells are involved in tumor growth and their mediators exert both pro- and anti-tumorigenic roles in different human cancers. The identification of defined immunosuppressive pathways that are present in the tumor microenvironment has pointed therapeutic strategies that may promote inflammation and/or innate immune activation in this context. Mast cells can contribute to the immune suppressive tumor microenvironment and may also enhance anti-tumor responses. This review article is focused on the analysis of the mechanisms of the role of mast cells in resistance to immunotherapy in cancer.

肥大细胞参与肿瘤生长,其介质在不同的人类癌症中发挥促肿瘤和抗肿瘤作用。肿瘤微环境中存在的免疫抑制途径的确定,为在这种情况下促进炎症和/或先天免疫激活提供了有针对性的治疗策略。肥大细胞可以促进免疫抑制肿瘤微环境,也可能增强抗肿瘤反应。本文就肥大细胞在肿瘤免疫治疗耐药中的作用机制作一综述。
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引用次数: 0
Effect of Hematopoietic Stem Cell Transplantation and Post-Transplantation Cyclophosphamide on the Microglia Phenotype in Rats with Experimental Allergic Encephalomyelitis 造血干细胞移植和移植后环磷酰胺对实验性变应性脑脊髓炎大鼠小胶质细胞表型的影响
IF 3.2 4区 医学 Q3 IMMUNOLOGY Pub Date : 2023-03-24 DOI: 10.1007/s00005-023-00675-y
Kaja Kasarełło, Martyna Seta, Dorota Sulejczak, Emilian Snarski, Agnieszka Cudnoch-Jędrzejewska

Microglia are the resident immune cells of the central nervous system, playing a role in the inflammatory process development and resolution, presenting two main phenotypes, pro-inflammatory M1, and anti-inflammatory M2. Therapies affecting the microglia phenotype may be beneficial in treating inflammatory neurodegenerative diseases. In our experiments, we used the animal multiple sclerosis model, experimental allergic encephalomyelitis (EAE). Rats were treated during the pre- or symptomatic phase of the disease with cyclophosphamide, followed by hematopoietic stem cell transplantation, and with/without post-transplantation cyclophosphamide. Our study aimed to analyze the microglia phenotype in animals subjected to this treatment. The number of M1 cells in the spinal cord, and inducible nitric oxide synthase (iNOS) levels in the brain were similar in all experimental groups. The differences were observed in M2 cells number and arginase 1 (Arg1) levels, which were decreased in EAE animals, and increased after treatment in the symptomatic phase of EAE, and in the pre-symptomatic phase, but only with post-transplantation cyclophosphamide. Analysis of gene expression in the brain showed decreased iNOS expression in EAE animals treated in the symptomatic phase of EAE and no differences in Arg1 expression. Results indicate that treatment applied to experimental animals influences the microglia phenotype, promoting differentiation towards M2 cells.

小胶质细胞是中枢神经系统的常驻免疫细胞,在炎症过程的发生和消退中发挥作用,主要表现为促炎M1和抗炎M2两种表型。影响小胶质细胞表型的疗法可能对治疗炎症性神经退行性疾病有益。在我们的实验中,我们使用动物多发性硬化模型,实验性过敏性脑脊髓炎(EAE)。在疾病前期或症状期用环磷酰胺治疗大鼠,然后进行造血干细胞移植,移植后用/不用环磷酰胺治疗。我们的研究旨在分析受这种治疗的动物的小胶质细胞表型。各实验组脊髓M1细胞数量和脑内诱导型一氧化氮合酶(iNOS)水平相似。M2细胞数量和精氨酸酶1 (Arg1)水平在EAE动物中呈下降趋势,在EAE症状期和症状前治疗后升高,但仅在移植后使用环磷酰胺治疗后升高。脑内基因表达分析显示,在EAE症状期治疗的EAE动物iNOS表达降低,Arg1表达无差异。结果表明,实验动物的处理影响小胶质细胞表型,促进向M2细胞分化。
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引用次数: 0
Activating NKG2C Receptor: Functional Characteristics and Current Strategies in Clinical Applications 激活NKG2C受体:功能特征及当前临床应用策略
IF 3.2 4区 医学 Q3 IMMUNOLOGY Pub Date : 2023-03-10 DOI: 10.1007/s00005-023-00674-z
Jagoda Siemaszko, Aleksandra Marzec-Przyszlak, Katarzyna Bogunia-Kubik

The interest in NK cells and their cytotoxic activity against tumour, infected or transformed cells continuously increases as they become a new efficient and off-the-shelf agents in immunotherapies. Their actions are balanced by a wide set of activating and inhibitory receptors, recognizing their complementary ligands on target cells. One of the most studied receptors is the activating CD94/NKG2C molecule, which is a member of the C-type lectin-like family. This review is intended to summarise latest research findings on the clinical relevance of NKG2C receptor and to examine its contribution to current and potential therapeutic strategies. It outlines functional characteristics and molecular features of CD94/NKG2C, its interactions with HLA-E molecule and presented antigens, pointing out a key role of this receptor in immunosurveillance, especially in the human cytomegalovirus infection. Additionally, the authors attempt to shed some light on receptor’s unique interaction with its ligand which is shared with another receptor (CD94/NKG2A) with rather opposite properties.

随着NK细胞成为免疫治疗中一种新的、有效的现成药物,人们对NK细胞及其对肿瘤、感染或转化细胞的细胞毒性活性的兴趣不断增加。它们的作用通过广泛的激活和抑制受体来平衡,识别它们在靶细胞上的互补配体。研究最多的受体之一是活化CD94/NKG2C分子,它是c型凝集素样家族的成员。本文旨在总结NKG2C受体临床相关性的最新研究成果,并探讨其对当前和潜在治疗策略的贡献。概述了CD94/NKG2C的功能特征和分子特征,及其与HLA-E分子和呈递抗原的相互作用,指出了该受体在免疫监视中,特别是在人巨细胞病毒感染中的关键作用。此外,作者试图阐明受体与其配体的独特相互作用,该配体与另一个具有相反性质的受体(CD94/NKG2A)共享。
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引用次数: 0
The Effects of Statins on Respiratory Symptoms and Pulmonary Fibrosis in COVID-19 Patients with Diabetes Mellitus: A Longitudinal Multicenter Study 他汀类药物对COVID-19合并糖尿病患者呼吸系统症状和肺纤维化的影响:一项纵向多中心研究
IF 3.2 4区 医学 Q3 IMMUNOLOGY Pub Date : 2023-02-28 DOI: 10.1007/s00005-023-00672-1
Mohammadamin Sadeghdoust, Farnaz Aligolighasemabadi, Tania Dehesh, Nima Taefehshokr, Adel Sadeghdoust, Katarzyna Kotfis, Amirhossein Hashemiattar, Amir Ravandi, Neda Aligolighasemabadi, Omid Vakili, Beniamin Grabarek, Rafał Staszkiewicz, Marek J. Łos, Pooneh Mokarram, Saeid Ghavami

The aim of this prospective cohort study was to explore the effect of statins on long-term respiratory symptoms and pulmonary fibrosis in coronavirus disease 2019 (COVID-19) patients with diabetes mellitus (DM). Patients were recruited from three tertiary hospitals, categorized into Statin or Non-statin groups, and assessed on days 0, 28, and 90 after symptoms onset to record the duration of symptoms. Pulmonary fibrosis was scored at baseline and follow-up time points by high-resolution computed tomography scans. Each group comprised 176 patients after propensity score matching. Data analysis revealed that the odds of having cough and dyspnea were significantly higher in the Non-statin group compared to the Statin group during the follow-up period. Overall, there was no significant difference in the change in pulmonary fibrosis score between groups. However, Non-statin patients with > 5 years of DM were more likely to exhibit a significantly higher fibrosis score during the follow-up period as compared to their peers in the Statin group. Our results suggest that the use of statins is associated with a lower risk of developing chronic cough and dyspnea in diabetic patients with COVID-19, and may reduce pulmonary fibrosis associated with COVID-19 in patients with long-term (> 5 years) DM.

Graphical Abstract

本前瞻性队列研究的目的是探讨他汀类药物对2019冠状病毒病(COVID-19)合并糖尿病(DM)患者长期呼吸道症状和肺纤维化的影响。从三家三级医院招募患者,将其分为他汀类药物组和非他汀类药物组,并在症状出现后第0、28和90天进行评估,记录症状持续时间。通过高分辨率计算机断层扫描在基线和随访时间点对肺纤维化进行评分。倾向评分匹配后,每组176例。数据分析显示,在随访期间,非他汀类药物组咳嗽和呼吸困难的几率明显高于他汀类药物组。总体而言,两组间肺纤维化评分变化无显著差异。然而,与他汀类药物组相比,非他汀类药物5年糖尿病患者在随访期间更有可能表现出明显更高的纤维化评分。我们的研究结果表明,他汀类药物的使用与糖尿病合并COVID-19患者发生慢性咳嗽和呼吸困难的风险较低相关,并可能减少长期(5年)dm患者与COVID-19相关的肺纤维化
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引用次数: 0
Immunity in SARS-CoV-2 Infection: Clarity or Mystery? A Broader Perspective in the Third Year of a Worldwide Pandemic SARS-CoV-2感染的免疫力:清晰还是神秘?全球大流行第三年的更广阔视野
IF 3.2 4区 医学 Q3 IMMUNOLOGY Pub Date : 2023-02-21 DOI: 10.1007/s00005-023-00673-0
Katarzyna Kapten, Krzysztof Orczyk, Elzbieta Smolewska

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and its mechanisms have been thoroughly studied by researchers all over the world with the hope of finding answers that may aid the discovery of new treatment options or effective means of prevention. Still, over 2 years into the pandemic that is an immense burden on health care and economic systems, there seem to be more questions than answers. The character and multitude of immune responses elicited in coronavirus disease 2019 (COVID-19) vary from uncontrollable activation of the inflammatory system, causing extensive tissue damage and consequently leading to severe or even fatal disease, to mild or asymptomatic infections in the majority of patients, resulting in the unpredictability of the current pandemic. The aim of the study was to systematize the available data regarding the immune response to SARS-CoV-2, to provide some clarification among the abundance of the knowledge available. The review contains concise and current information on the most significant immune reactions to COVID-19, including components of both innate and adaptive immunity, with an additional focus on utilizing humoral and cellular responses as effective diagnostic tools. Moreover, the authors discussed the present state of knowledge on SARS-CoV-2 vaccines and their efficacy in cases of immunodeficiency.

世界各地的研究人员对严重急性呼吸系统综合征冠状病毒-2 (SARS-CoV-2)及其机制进行了深入研究,希望找到有助于发现新的治疗方案或有效预防手段的答案。尽管如此,大流行对卫生保健和经济系统造成了巨大负担,但在过去两年多的时间里,问题似乎多于答案。2019冠状病毒病(COVID-19)引发的免疫反应的性质和数量各不相同,从炎症系统的不可控激活,引起广泛的组织损伤,从而导致严重甚至致命的疾病,到大多数患者的轻度或无症状感染,导致当前大流行的不可预测性。该研究的目的是将有关SARS-CoV-2免疫反应的现有数据系统化,以便在现有的丰富知识中提供一些澄清。该综述包含了针对COVID-19的最重要免疫反应的简明和最新信息,包括先天免疫和适应性免疫的组成部分,并额外侧重于利用体液和细胞反应作为有效的诊断工具。此外,作者还讨论了SARS-CoV-2疫苗的知识现状及其对免疫缺陷病例的疗效。
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引用次数: 2
A Comprehensive Study on the Anti-cancer Effects of Quercetin and Its Epigenetic Modifications in Arresting Progression of Colon Cancer Cell Proliferation 槲皮素及其表观遗传修饰在抑制结肠癌细胞增殖中的抗癌作用的综合研究
IF 3.2 4区 医学 Q3 IMMUNOLOGY Pub Date : 2023-02-20 DOI: 10.1007/s00005-023-00669-w
Meenu Bhatiya, Surajit Pathak, Ganesan Jothimani, Asim K. Duttaroy, Antara Banerjee

Colon cancer etiology involves a wide spectrum of genetic and epigenetic alterations, finding it challenging to find effective therapeutic strategies. Quercetin exhibits potent anti-proliferative/apoptotic properties. In the present study, we aimed to elucidate the anti-cancer and anti-aging effect of quercetin in colon cancer cell lines. The anti-proliferative effect of quercetin was assessed in vitro by CCK-8 in normal and colon cancer cell lines. To check the anti-aging potential of quercetin, collagenase, elastase, and hyaluronidase inhibitory activity assays were performed. The epigenetic and DNA damage assays were performed using the human NAD-dependent deacetylase Sirtuin-6, proteasome 20S, Klotho, Cytochrome-C, and telomerase ELISA kits. Furthermore, the aging-associated miRNA expression profiling was performed on colon cancer cells. The treatment with quercetin inhibited cell proliferation of colon cancer cells in a dose-dependent manner. Quercetin arrested colon cancer cell growth by modulating expression of aging proteins including Sirtuin-6 and Klotho and also by inhibiting telomerase activity to restrict the telomere length which is evident from qPCR analysis. Quercetin also exhibited DNA damage protection by reducing proteasome 20S levels. The miRNA expression profiling results displayed differential expression of miRNA in colon cancer cell, and in addition, the highly upregulated miRNA was involved in the regulation of cell cycle, proliferation, and transcription. Our data suggest that quercetin treatment inhibited cell proliferation in colon cancer cells through regulating the anti-aging protein expression and provides better understanding for quercetin’s potential use in colon cancer treatment.

结肠癌的病因涉及广泛的遗传和表观遗传改变,寻找有效的治疗策略具有挑战性。槲皮素显示出有效的抗增殖/凋亡特性。在本研究中,我们旨在阐明槲皮素对结肠癌细胞系的抗癌和抗衰老作用。通过体外CCK-8检测槲皮素对正常和结肠癌细胞株的抗增殖作用。为了检测槲皮素的抗衰老潜力,我们进行了胶原酶、弹性酶和透明质酸酶抑制活性的测定。表观遗传学和DNA损伤检测采用人nad依赖性脱乙酰酶Sirtuin-6、蛋白酶体20S、Klotho、Cytochrome-C和端粒酶ELISA试剂盒。此外,在结肠癌细胞上进行衰老相关的miRNA表达谱分析。槲皮素对结肠癌细胞增殖的抑制作用呈剂量依赖性。槲皮素通过调节衰老蛋白Sirtuin-6和Klotho的表达以及抑制端粒酶活性来限制端粒长度,从而抑制结肠癌细胞的生长,这从qPCR分析中可以看出。槲皮素还通过降低蛋白酶体20S水平来保护DNA损伤。miRNA表达谱分析结果显示,miRNA在结肠癌细胞中存在差异表达,并且高度上调的miRNA参与了细胞周期、增殖和转录的调控。我们的数据表明槲皮素通过调节抗衰老蛋白的表达抑制结肠癌细胞的增殖,为槲皮素在结肠癌治疗中的潜在应用提供了更好的理解。
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引用次数: 10
Heterogeneity of Extracellular Vesicles and Particles: Molecular Voxels in the Blood Borne “Hologram” of Organ Function, Dysfunction and Cancer 细胞外囊泡和颗粒的异质性:器官功能、功能障碍和癌症的血源性“全息图”中的分子体素
IF 3.2 4区 医学 Q3 IMMUNOLOGY Pub Date : 2023-02-02 DOI: 10.1007/s00005-023-00671-2
Janusz Rak, Leon Strzadala

Extracellular vesicles (EVs) and particles (EPs) serve as unique carriers of complex molecular information with increasingly recognized roles in health and disease. Individual EVs/EPs collectively contribute to the molecular fingerprint of their producing cell, reflecting its identity, state, function and phenotype. This property is of particular interest in cancer where enormous heterogeneity of cancer cells is compounded by the presence of altered stromal, vascular and immune cell populations, which is further complicated by systemic responses elicited by the disease in individual patients. These diverse and interacting cellular compartments are dynamically represented by myriads of EVs/EPs released into the circulating biofluids (blood) during cancer progression and treatment. Current approaches of liquid biopsy seek to follow specific elements of the EV/EP cargo that may have diagnostic utility (as biomarkers), such as cancer cell-derived mutant oncoproteins or nucleic acids. However, with emerging technologies enabling high-throughput EV/EP analysis at a single particle level, a more holistic approach may be on the horizon. Indeed, each EV/EP carries multidimensional information (molecular “voxel”) that could be integrated across thousands of particles into a larger and unbiased landscape (EV/EP “hologram”) reflecting the true cellular complexity of the disease, along with cellular interactions, systemic responses and effects of treatment. Thus, the longitudinal molecular mapping of EV/EP populations may add a new dimension to crucial aspects of cancer biology, personalized diagnostics, and therapy.

细胞外囊泡(EVs)和细胞外颗粒(EPs)作为复杂分子信息的独特载体,在健康和疾病中发挥着越来越多的作用。单个ev /EPs共同贡献了其产生细胞的分子指纹,反映了其身份,状态,功能和表型。这种特性在癌症中特别有趣,因为癌细胞的巨大异质性由于基质细胞、血管细胞和免疫细胞群的改变而变得复杂,而个体患者的疾病引起的全身反应使这种异质性进一步复杂化。在癌症进展和治疗过程中,无数ev /EPs释放到循环生物流体(血液)中,动态地代表了这些多样化和相互作用的细胞区室。目前的液体活检方法寻求追踪可能具有诊断效用(作为生物标志物)的EV/EP货物的特定元素,如癌细胞衍生的突变癌蛋白或核酸。然而,随着新兴技术能够在单个颗粒水平上进行高通量EV/EP分析,一种更全面的方法可能即将出现。事实上,每个EV/EP都携带着多维信息(分子“体素”),这些信息可以跨越数千个粒子整合成一个更大、更公正的景观(EV/EP“全息图”),反映出疾病的真实细胞复杂性,以及细胞相互作用、系统反应和治疗效果。因此,EV/EP群体的纵向分子定位可能为癌症生物学、个性化诊断和治疗的关键方面增加一个新的维度。
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引用次数: 2
Ly-6A-Induced Growth Inhibition and Cell Death in a Transformed CD4+ T Cell Line: Role of Tumor Necrosis Factor-α 肿瘤坏死因子-α在转化CD4+ T细胞系中诱导的生长抑制和细胞死亡的作用
IF 3.2 4区 医学 Q3 IMMUNOLOGY Pub Date : 2023-02-01 DOI: 10.1007/s00005-023-00670-3
Akshay G. Patel, Sarah Moxham, Anil K. Bamezai

Ly-6A, a member of the Ly-6/uPAR supergene family of proteins, is a cell adhesion and cell signaling protein. Signaling through Ly-6A activates the cell-intrinsic apoptotic cell death pathway in CD4+ T cell lines, as indicated by the release of cytochrome C, and activation of caspases 9 and 3. In addition, Ly-6A induces cytokine production and growth inhibition. The mechanism underlying the distinct cellular responses that are triggered by engaging Ly-6A protein has remained unknown. To examine the relatedness of these distinct responses, we have quantified the production of pro-apoptotic, growth inhibitory and tumor suppressive cytokines, such as TNF-α, TGF-β and a related protein GDF-10, in response to Ly-6A signaling. Anti-Ly-6A monoclonal antibody-induced activation of YH16.33 CD4+ T cell line generated low levels of TGF-β and GDF-10 but elevated levels of TNF-α. Blocking the biological activity of TNF-α resulted in reduced Ly-6A-induced apoptosis in T cells. The Ly-6A-induced response in the T cell line was distinct, as signaling through the antigen receptor complex did not cause growth inhibition and apoptosis despite high levels of TGF-β and GDF-10 that were detected in these cultures. Additionally, in response to antigen receptor complex signaling, lower amount of TNF-α was detected. These results indicate the contribution of TNF-α in the observed Ly-6A-induced growth inhibition and apoptosis and provide a mechanistic explanation for the biologically distinct responses observed in CD4+ T cells after engaging Ly-6A protein. Additionally, the findings reported here will aid in the understanding of inhibitory signaling initiated by Ly-6A protein, especially in the context of its potential immune checkpoint inhibitory role in T cells.

Ly-6A是一种细胞粘附和细胞信号蛋白,是Ly-6/uPAR超基因蛋白家族的成员。通过Ly-6A信号通路激活CD4+ T细胞系细胞内凋亡细胞死亡通路,如细胞色素C的释放和caspases 9和caspases 3的激活。此外,Ly-6A诱导细胞因子的产生和生长抑制。参与Ly-6A蛋白引发的不同细胞反应的机制仍然未知。为了检验这些不同反应的相关性,我们量化了促凋亡、生长抑制和肿瘤抑制细胞因子的产生,如TNF-α、TGF-β和相关蛋白GDF-10,以响应Ly-6A信号。抗ly - 6a单克隆抗体诱导的YH16.33 CD4+ T细胞株的激活产生低水平的TGF-β和GDF-10,但TNF-α水平升高。阻断TNF-α的生物活性可减少ly - 6a诱导的T细胞凋亡。在T细胞系中,ly - 6a诱导的反应是不同的,尽管在这些培养物中检测到高水平的TGF-β和GDF-10,但通过抗原受体复合物的信号传导不会引起生长抑制和凋亡。此外,在对抗原受体复合物信号的反应中,检测到较低量的TNF-α。这些结果表明TNF-α在观察到的Ly-6A诱导的生长抑制和凋亡中的作用,并为参与Ly-6A蛋白后在CD4+ T细胞中观察到的生物学上不同的反应提供了机制解释。此外,本文报道的研究结果将有助于理解由Ly-6A蛋白启动的抑制信号,特别是在其潜在的免疫检查点抑制T细胞作用的背景下。
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Archivum Immunologiae et Therapiae Experimentalis
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