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Aire in Autoimmunity. 自身免疫中的空气
IF 26.9 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-06-01 Epub Date: 2024-06-14 DOI: 10.1146/annurev-immunol-090222-101050
Corey N Miller, Michael R Waterfield, James M Gardner, Mark S Anderson

The role of the autoimmune regulator (Aire) in central immune tolerance and thymic self-representation was first described more than 20 years ago, but fascinating new insights into its biology continue to emerge, particularly in the era of advanced single-cell genomics. We briefly describe the role of human genetics in the discovery of Aire, as well as insights into its function gained from genotype-phenotype correlations and the spectrum of Aire-associated autoimmunity-including insights from patients with Aire mutations with broad and diverse implications for human health. We then highlight emerging trends in Aire biology, focusing on three topic areas. First, we discuss medullary thymic epithelial diversity and the role of Aire in thymic epithelial development. Second, we highlight recent developments regarding the molecular mechanisms of Aire and its binding partners. Finally, we describe the rapidly evolving biology of the identity and function of extrathymic Aire-expressing cells (eTACs), and a novel eTAC subset called Janus cells, as well as their potential roles in immune homeostasis.

自身免疫调节剂(Aire)在中枢免疫耐受和胸腺自我代表中的作用早在20多年前就被首次描述,但对其生物学特性的新见解仍在不断涌现,尤其是在先进的单细胞基因组学时代。我们简要介绍了人类遗传学在发现 Aire 过程中的作用,以及从基因型与表型的相关性和 Aire 相关自身免疫的范围中获得的对其功能的见解--包括从 Aire 基因突变患者身上获得的对人类健康具有广泛而多样影响的见解。然后,我们将重点介绍 Aire 生物学的新趋势,主要集中在三个主题领域。首先,我们讨论了髓质胸腺上皮的多样性和 Aire 在胸腺上皮发育中的作用。其次,我们强调了有关 Aire 及其结合伙伴的分子机制的最新进展。最后,我们描述了胸腺外Aire表达细胞(eTACs)和一种名为Janus细胞的新型eTAC亚群的身份和功能的快速发展的生物学特性,以及它们在免疫稳态中的潜在作用。免疫学年刊》(Annual Review of Immunology)第42卷的最终在线出版日期预计为2024年4月。修订后的预计日期请参见 http://www.annualreviews.org/page/journal/pubdates。
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引用次数: 0
Immune Responses in Controllers of HIV Infection. HIV感染控制者的免疫反应。
IF 26.9 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-06-01 Epub Date: 2024-06-14 DOI: 10.1146/annurev-immunol-083122-035233
Abena K Kwaa, Joel N Blankson

Elite controllers are a heterogeneous group of people living with HIV who control viral replication without antiretroviral therapy. There is substantial evidence that at least some elite controllers are infected with replication-competent virus, thus they may serve as a model of a functional cure of HIV. The mechanisms responsible for virologic control have been actively studied. The most objective data support CD8+ T cell-based mechanisms of control, but other immune responses, mediated by antibodies and natural killer cells, may also play a role in controlling viral replication. In this article, we review the evidence for different mechanisms of immune control in these remarkable individuals.

精英控制者是一组异质性的艾滋病毒感染者,他们在没有抗逆转录病毒治疗的情况下控制病毒复制。有大量证据表明,至少有一些精英控制者感染了具有复制能力的病毒,因此他们可能成为功能性治愈艾滋病毒的典范。负责病毒学控制的机制已得到积极研究。最客观的数据支持基于CD8+T细胞的控制机制,但由抗体和自然杀伤细胞介导的其他免疫反应也可能在控制病毒复制中发挥作用。在这篇文章中,我们回顾了这些杰出个体的不同免疫控制机制的证据。《免疫学年度评论》第42卷预计最终在线出版日期为2024年4月。请参阅http://www.annualreviews.org/page/journal/pubdates用于修订估算。
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引用次数: 0
Poxvirus Immune Evasion. 痘病毒的免疫逃避
IF 26.9 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-06-01 DOI: 10.1146/annurev-immunol-090222-110227
Bruno Hernaez, Antonio Alcamí

Poxviruses have evolved a wide array of mechanisms to evade the immune response, and we provide an overview of the different immunomodulatory strategies. Poxviruses prevent the recognition of viral DNA that triggers the immune responses and inhibit signaling pathways within the infected cell. A unique feature of poxviruses is the production of secreted proteins that mimic cytokines and cytokine receptors, acting as decoy receptors to neutralize the activity of cytokines and chemokines. The capacity of these proteins to evade cellular immune responses by inhibiting cytokine activation is complemented by poxviruses' strategies to block natural killer cells and cytotoxic T cells, often through interfering with antigen presentation pathways. Mechanisms that target complement activation are also encoded by poxviruses. Virus-encoded proteins that target immune molecules and pathways play a major role in immune modulation, and their contribution to viral pathogenesis, facilitating virus replication or preventing immunopathology, is discussed.

痘病毒进化出了一系列逃避免疫反应的机制,我们将概述不同的免疫调节策略。痘病毒会阻止识别引发免疫反应的病毒 DNA,并抑制感染细胞内的信号通路。痘病毒的一个独特特征是产生模拟细胞因子和细胞因子受体的分泌蛋白,作为诱饵受体中和细胞因子和趋化因子的活性。痘病毒通常通过干扰抗原递呈途径来阻断自然杀伤细胞和细胞毒性 T 细胞,这与痘病毒通过抑制细胞因子活化来逃避细胞免疫反应的策略相辅相成。痘病毒还编码了针对补体激活的机制。针对免疫分子和免疫途径的病毒编码蛋白在免疫调节中发挥着重要作用,本文讨论了它们对病毒发病机制的贡献,即促进病毒复制或预防免疫病理。
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引用次数: 0
Kidney-Specific Interleukin-17 Responses During Infection and Injury. 感染和损伤过程中肾脏特异性白细胞介素17的反应。
IF 26.9 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-06-01 Epub Date: 2024-06-14 DOI: 10.1146/annurev-immunol-052523-015141
Doureradjou Peroumal, Partha S Biswas

The kidneys are life-sustaining organs that are vital to removing waste from our bodies. Because of their anatomic position and high blood flow, the kidneys are vulnerable to damage due to infections and autoinflammatory conditions. Even now, our knowledge of immune responses in the kidney is surprisingly rudimentary. Studying kidney-specific immune events is challenging because of the poor regenerative capacity of the nephrons, accumulation of uremic toxins, and hypoxia- and arterial blood pressure-mediated changes, all of which have unexpected positive or negative impacts on the immune response in the kidney. Kidney-specific defense confers protection against pathogens. On the other hand, unresolved inflammation leads to kidney damage and fibrosis. Interleukin-17 is a proinflammatory cytokine that has been linked to immunity against pathogens and pathogenesis of autoinflammatory diseases. In this review, we discuss current knowledge of IL-17 activities in the kidney in the context of infections, autoinflammatory diseases, and renal fibrosis.

肾脏是维持生命的器官,对清除体内废物至关重要。由于其解剖位置和高血流量,肾脏很容易因感染和自身炎症而受损。即使是现在,我们对肾脏免疫反应的了解也出奇地初级。研究肾脏特异性免疫事件具有挑战性,因为肾单位的再生能力差、尿毒症毒素的积累以及缺氧和动脉血压介导的变化,所有这些都会对肾脏的免疫反应产生意想不到的积极或消极影响。肾脏特异性防御可以抵御病原体。另一方面,未解决的炎症会导致肾脏损伤和纤维化。白细胞介素-17是一种促炎细胞因子,与对病原体的免疫和自身炎症性疾病的发病机制有关。在这篇综述中,我们讨论了在感染、自身炎症性疾病和肾纤维化的背景下,IL-17在肾脏中活性的最新知识。《免疫学年度评论》第42卷预计最终在线出版日期为2024年4月。请参阅http://www.annualreviews.org/page/journal/pubdates用于修订估算。
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引用次数: 0
Intraepithelial Lymphocytes of the Intestine. 肠上皮内淋巴细胞
IF 3.7 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-06-01 Epub Date: 2024-06-14 DOI: 10.1146/annurev-immunol-090222-100246
Ainsley Lockhart, Daniel Mucida, Angelina M Bilate

The intestinal epithelium, which segregates the highly stimulatory lumen from the underlying tissue, harbors one of the largest lymphocyte populations in the body, intestinal intraepithelial lymphocytes (IELs). IELs must balance tolerance, resistance, and tissue protection to maintain epithelial homeostasis and barrier integrity. This review discusses the ontogeny, environmental imprinting, T cell receptor (TCR) repertoire, and function of intestinal IELs. Despite distinct developmental pathways, IEL subsets share core traits including an epithelium-adapted profile, innate-like properties, cytotoxic potential, and limited TCR diversity. IELs also receive important developmental and functional cues through interactions with epithelial cells, microbiota, and dietary components. The restricted TCR diversity of IELs suggests that a limited set of intestinal antigens drives IEL responses, with potential functional consequences. Finally, IELs play a key role in promoting homeostatic immunity and epithelial barrier integrity but can become pathogenic upon dysregulation. Therefore, IELs represent intriguing but underexamined therapeutic targets for inflammatory diseases and cancer.

肠上皮细胞将高度刺激性的肠腔与下层组织隔离开来,它是人体内最大的淋巴细胞群之一,即肠上皮内淋巴细胞(IELs)。IELs 必须在耐受性、抵抗力和组织保护之间取得平衡,以维持上皮细胞的平衡和屏障的完整性。这篇综述讨论了肠道 IEL 的本体发育、环境印记、T 细胞受体(TCR)谱系和功能。尽管发育途径各不相同,但肠道 IEL 亚群具有共同的核心特征,包括上皮适应特征、先天类特性、细胞毒性潜力和有限的 TCR 多样性。IEL 还通过与上皮细胞、微生物群和饮食成分的相互作用获得重要的发育和功能线索。IELs 的 TCR 多样性受到限制,这表明只有有限的肠道抗原能驱动 IEL 反应,从而产生潜在的功能性后果。最后,IELs 在促进平衡免疫和上皮屏障完整性方面发挥着关键作用,但一旦失调就会成为致病因子。因此,IELs 是治疗炎症性疾病和癌症的令人感兴趣但尚未得到充分研究的靶点。免疫学年刊》第 42 卷的最终在线出版日期预计为 2024 年 4 月。修订后的预计日期请参见 http://www.annualreviews.org/page/journal/pubdates。
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引用次数: 0
Systemic Immune Modulation by Gastrointestinal Nematodes. 肠道线虫对全身免疫的调节作用
IF 26.9 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-06-01 Epub Date: 2024-06-14 DOI: 10.1146/annurev-immunol-090222-101331
Darshan N Kasal, Lindsey M Warner, Astra S Bryant, Elia Tait Wojno, Jakob von Moltke

Gastrointestinal nematode (GIN) infection has applied significant evolutionary pressure to the mammalian immune system and remains a global economic and human health burden. Upon infection, type 2 immune sentinels activate a common antihelminth response that mobilizes and remodels the intestinal tissue for effector function; however, there is growing appreciation of the impact GIN infection also has on the distal tissue immune state. Indeed, this effect is observed even in tissues through which GINs never transit. This review highlights how GIN infection modulates systemic immunity through (a) induction of host resistance and tolerance responses, (b) secretion of immunomodulatory products, and (c) interaction with the intestinal microbiome. It also discusses the direct consequences that changes to distal tissue immunity can have for concurrent and subsequent infection, chronic noncommunicable diseases, and vaccination efficacy.

胃肠道线虫(GIN)感染对哺乳动物免疫系统造成了巨大的进化压力,并一直是全球经济和人类健康的负担。感染后,2 型免疫哨兵会激活共同的抗蠕虫反应,调动和重塑肠道组织的效应功能;然而,人们越来越认识到 GIN 感染对远端组织免疫状态的影响。事实上,即使在 GIN 从未过境的组织中也能观察到这种影响。本综述强调了 GIN 感染如何通过(a)诱导宿主抵抗和耐受反应,(b)分泌免疫调节产物,以及(c)与肠道微生物组相互作用来调节全身免疫。报告还讨论了远端组织免疫力的变化可能对并发和继发感染、慢性非传染性疾病和疫苗接种效果产生的直接影响。免疫学年刊》第 42 卷的最终在线出版日期预计为 2024 年 4 月。修订后的预计日期请参见 http://www.annualreviews.org/page/journal/pubdates。
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引用次数: 0
Immune Activation in Alzheimer Disease. 阿尔茨海默病的免疫激活。
IF 26.9 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-06-01 Epub Date: 2024-06-14 DOI: 10.1146/annurev-immunol-101921-035222
Arnaud Mary, Renzo Mancuso, Michael T Heneka

Alzheimer disease (AD) is the most common neurodegenerative disease, and with no efficient curative treatment available, its medical, social, and economic burdens are expected to dramatically increase. AD is historically characterized by amyloid β (Aβ) plaques and tau neurofibrillary tangles, but over the last 25 years chronic immune activation has been identified as an important factor contributing to AD pathogenesis. In this article, we review recent and important advances in our understanding of the significance of immune activation in the development of AD. We describe how brain-resident macrophages, the microglia, are able to detect Aβ species and be activated, as well as the consequences of activated microglia in AD pathogenesis. We discuss transcriptional changes of microglia in AD, their unique heterogeneity in humans, and emerging strategies to study human microglia. Finally, we expose, beyond Aβ and microglia, the role of peripheral signals and different cell types in immune activation.

阿尔茨海默病(AD)是最常见的神经退行性疾病,由于没有有效的治疗方法,预计其医疗、社会和经济负担将急剧增加。淀粉样β(Aβ)斑块和tau神经纤维缠结是阿尔茨海默病的历史特征,但在过去的25年中,慢性免疫激活已被确定为导致阿尔茨海默病发病的一个重要因素。在这篇文章中,我们回顾了最近在理解免疫激活在AD发病中的意义方面取得的重要进展。我们描述了大脑驻留的巨噬细胞--小胶质细胞如何能够检测到 Aβ 物种并被激活,以及激活的小胶质细胞在 AD 发病机制中的后果。我们讨论了 AD 中小胶质细胞的转录变化、它们在人类中的独特异质性以及研究人类小胶质细胞的新兴策略。最后,除了 Aβ 和小胶质细胞外,我们还揭示了外周信号和不同细胞类型在免疫激活中的作用。免疫学年刊》(Annual Review of Immunology)第42卷的最终在线出版日期预计为2024年4月。修订后的预计日期请参见 http://www.annualreviews.org/page/journal/pubdates。
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引用次数: 0
T Cell Exhaustion. T 细胞衰竭
IF 26.9 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-06-01 Epub Date: 2024-06-14 DOI: 10.1146/annurev-immunol-090222-110914
Andrew Baessler, Dario A A Vignali

T cell responses must be balanced to ensure adequate protection against malignant transformation and an array of pathogens while also limiting damage to healthy cells and preventing autoimmunity. T cell exhaustion serves as a regulatory mechanism to limit the activity and effector function of T cells undergoing chronic antigen stimulation. Exhausted T cells exhibit poor proliferative potential; high inhibitory receptor expression; altered transcriptome, epigenome, and metabolism; and, most importantly, reduced effector function. While exhaustion helps to restrain damage caused by aberrant T cells in settings of autoimmune disease, it also limits the ability of cells to respond against persistent infection and cancer, leading to disease progression. Here we review the process of T cell exhaustion, detailing the key characteristics and drivers as well as highlighting our current understanding of the underlying transcriptional and epigenetic programming. We also discuss how exhaustion can be targeted to enhance T cell functionality in cancer.

T 细胞反应必须保持平衡,以确保对恶性转化和一系列病原体提供充分保护,同时限制对健康细胞的损害并防止自身免疫。T 细胞衰竭是一种调节机制,可限制长期受抗原刺激的 T 细胞的活性和效应功能。衰竭的 T 细胞增殖潜力差;抑制性受体表达高;转录组、表观基因组和新陈代谢改变;最重要的是,效应功能降低。虽然衰竭有助于抑制自身免疫性疾病中异常 T 细胞造成的损害,但它也限制了细胞应对持续感染和癌症的能力,从而导致疾病进展。在此,我们回顾了 T 细胞衰竭的过程,详细介绍了其关键特征和驱动因素,并强调了我们目前对其背后的转录和表观遗传编程的理解。我们还将讨论如何以衰竭为靶点,增强癌症中 T 细胞的功能。免疫学年刊》(Annual Review of Immunology)第42卷的最终在线出版日期预计为2024年4月。修订后的预计日期请参见 http://www.annualreviews.org/page/journal/pubdates。
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引用次数: 0
Innate Immunity in Protection and Pathogenesis During Coronavirus Infections and COVID-19. 先天免疫在冠状病毒感染和 COVID-19 期间的保护和致病机制中的作用
IF 26.9 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-06-01 DOI: 10.1146/annurev-immunol-083122-043545
R K Subbarao Malireddi, Bhesh Raj Sharma, Thirumala-Devi Kanneganti

The COVID-19 pandemic was caused by the recently emerged β-coronavirus SARS-CoV-2. SARS-CoV-2 has had a catastrophic impact, resulting in nearly 7 million fatalities worldwide to date. The innate immune system is the first line of defense against infections, including the detection and response to SARS-CoV-2. Here, we discuss the innate immune mechanisms that sense coronaviruses, with a focus on SARS-CoV-2 infection and how these protective responses can become detrimental in severe cases of COVID-19, contributing to cytokine storm, inflammation, long-COVID, and other complications. We also highlight the complex cross talk among cytokines and the cellular components of the innate immune system, which can aid in viral clearance but also contribute to inflammatory cell death, cytokine storm, and organ damage in severe COVID-19 pathogenesis. Furthermore, we discuss how SARS-CoV-2 evades key protective innate immune mechanisms to enhance its virulence and pathogenicity, as well as how innate immunity can be therapeutically targeted as part of the vaccination and treatment strategy. Overall, we highlight how a comprehensive understanding of innate immune mechanisms has been crucial in the fight against SARS-CoV-2 infections and the development of novel host-directed immunotherapeutic strategies for various diseases.

COVID-19 大流行是由最近出现的 β-冠状病毒 SARS-CoV-2 引起的。SARS-CoV-2 造成了灾难性的影响,迄今已导致全球近 700 万人死亡。先天性免疫系统是抵御感染的第一道防线,包括检测和应对 SARS-CoV-2。在此,我们讨论了感知冠状病毒的先天免疫机制,重点是 SARS-CoV-2 感染,以及这些保护性反应如何在 COVID-19 严重病例中变得有害,导致细胞因子风暴、炎症、长 COVID 和其他并发症。我们还强调了细胞因子与先天性免疫系统的细胞成分之间复杂的交叉反应,它们可以帮助清除病毒,但也会导致炎性细胞死亡、细胞因子风暴和严重 COVID-19 发病过程中的器官损伤。此外,我们还讨论了 SARS-CoV-2 如何逃避关键的先天性免疫保护机制以增强其毒力和致病性,以及如何将先天性免疫作为疫苗接种和治疗策略的治疗目标。总之,我们强调了对先天免疫机制的全面了解在抗击 SARS-CoV-2 感染和开发针对各种疾病的新型宿主导向免疫治疗策略中的关键作用。
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引用次数: 0
The CD4 Versus CD8 T Cell Fate Decision: A Multiomics-Informed Perspective. CD4 与 CD8 T 细胞命运的决定:从多组学的角度看问题。
IF 26.9 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-06-01 Epub Date: 2024-06-14 DOI: 10.1146/annurev-immunol-083122-040929
Zoë Steier, Esther Jeong Yoon Kim, Dominik A Aylard, Ellen A Robey

The choice of developing thymocytes to become CD8+ cytotoxic or CD4+ helper T cells has been intensely studied, but many of the underlying mechanisms remain to be elucidated. Recent multiomics approaches have provided much higher resolution analysis of gene expression in developing thymocytes than was previously achievable, thereby offering a fresh perspective on this question. Focusing on our recent studies using CITE-seq (cellular indexing of transcriptomes and epitopes) analyses of mouse thymocytes, we present a detailed timeline of RNA and protein expression changes during CD8 versus CD4 T cell differentiation. We also revisit our current understanding of the links between T cell receptor signaling and expression of the lineage-defining transcription factors ThPOK and RUNX3. Finally, we propose a sequential selection model to explain the tight linkage between MHC-I versus MHC-II recognition and T cell lineage choice. This model incorporates key aspects of previously proposed kinetic signaling, instructive, and stochastic/selection models.

人们对发育中的胸腺细胞选择成为 CD8+ 细胞毒性或 CD4+ 辅助性 T 细胞进行了深入研究,但许多内在机制仍有待阐明。最近的多组学方法提供了比以前更高分辨率的发育中胸腺细胞基因表达分析,从而为这一问题提供了新的视角。我们最近利用 CITE-seq(转录组和表位的细胞索引)分析小鼠胸腺细胞的研究为重点,详细介绍了 CD8 与 CD4 T 细胞分化过程中 RNA 和蛋白质表达变化的时间表。我们还重新审视了我们目前对 T 细胞受体信号转导与品系界定转录因子 ThPOK 和 RUNX3 表达之间联系的理解。最后,我们提出了一个顺序选择模型来解释 MHC-I 与 MHC-II 识别和 T 细胞系选择之间的紧密联系。该模型融合了之前提出的动力学信号转导模型、指导模型和随机/选择模型的主要方面。免疫学年刊》(Annual Review of Immunology)第 42 卷的最终在线出版日期预计为 2024 年 4 月。修订后的预计日期请参见 http://www.annualreviews.org/page/journal/pubdates。
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引用次数: 0
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Annual review of immunology
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