Abstract

The inflammasome components NLRP3 and ASC are cytosolic proteins, which upon sensing endotoxins or danger cues, form multimeric complexes to process interleukin (IL)-1β for secretion. Here we found that antigen (Ag)-triggered degranulation of IgE-sensitized mast cells (MCs) was mediated by NLRP3 and ASC. IgE–Ag stimulated NEK7 and Pyk2 kinases in MCs to induce the deposition of NLRP3 and ASC on granules and form a distinct protein complex (granulosome) that chaperoned the granules to the cell surface. MCs deficient in NLRP3 or ASC did not form granulosomes, degranulated poorly in vitro and did not evoke systemic anaphylaxis in mice. IgE–Ag-triggered anaphylaxis was prevented by an NLRP3 inhibitor. In endotoxin-primed MCs, pro-IL-1β was rapidly packaged into granules after IgE–Ag stimulation and processed within granule remnants by proteases after degranulation, causing lethal anaphylaxis in mice. During IgE–Ag-mediated degranulation of endotoxin-primed MCs, granulosomes promoted degranulation, combined with exteriorization and processing of IL-1β, resulting in severe inflammation.

摘要

炎症小体组分NLRP3和ASC是胞质蛋白，在感知内毒素或危险信号时，将形成多聚体复合物来加工处理白细胞介素 IL-1β，并促进自身分泌。在这里，我们发现抗原（Ag）触发的IgE致敏肥大细胞（MC）脱颗粒是由NLRP3和ASC介导的。IgE-Ag刺激MC中的NEK7和Pyk2 激酶，诱导NLRP3和ASC在颗粒上沉积，并形成一个独特的蛋白复合体（颗粒体），该复合体可将颗粒引导至细胞表面。NLRP3或ASC缺陷的MC不形成颗粒体，体外脱颗粒效果较差，并且不会引起小鼠全身过敏反应。NLRP3抑制剂可预防IgE-Ag引发的过敏反应。在内毒素引发的MC中，IL-1β前体在IgE-Ag刺激后迅速包装成颗粒，并在脱颗粒后被蛋白酶在颗粒残余物中加工，引起小鼠致命的过敏反应。在IgE-Ag介导的内毒素引发的MC脱颗粒过程中，颗粒体促进了脱颗粒，并结合了IL-1β的外化和处理，导致严重的炎症。

2024年3月，第25卷第3期共发表33篇文章，其中1篇Editorial；5篇World View；3篇Research Highlights；7篇News & Views；3篇Research Briefings；1篇Review Articles；1篇Letters以及12篇Articles。

1.BCG immunization induces CX3CR1hi effector memory T cells to provide cross-protection via IFN-γ-mediated trained immunity

卡介苗接种通过IFN-γ介导的训练免疫诱导CX3CR1hi效应记忆T细胞对其他病原体提供交叉保护

加拿大麦吉尔大学等研究中心联合发表

Abstract

After a century of using the Bacillus Calmette–Guérin (BCG) vaccine, our understanding of its ability to provide protection against homologous (Mycobacterium tuberculosis) or heterologous (for example, influenza virus) infections remains limited. Here we show that systemic (intravenous) BCG vaccination provides significant protection against subsequent influenza A virus infection in mice. We further demonstrate that the BCG-mediated cross-protection against influenza A virus is largely due to the enrichment of conventional CD4+ effector CX3CR1hi memory αβ T cells in the circulation and lung parenchyma. Importantly, pulmonary CX3CR1hi T cells limit early viral infection in an antigen-independent manner via potent interferon-γ production, which subsequently enhances long-term antimicrobial activity of alveolar macrophages. These results offer insight into the unknown mechanism by which BCG has persistently displayed broad protection against non-tuberculosis infections via cross-talk between adaptive and innate memory responses.

摘要

使用卡介苗 (BCG) 疫苗一个世纪以来，我们对它抵御同源（结核分枝杆菌）或异源（例如流感病毒）感染的能力依然了解有限。在此，我们证明全身（静脉）BCG疫苗接种能够显著保护小鼠免受随后A型流感病毒感染。我们还进一步证实，BCG介导的对A型流感病毒的交叉保护主要是由于循环系统和肺实质中CD4+效应CX3CR1hi记忆αβ T细胞的富集。值得注意的是，肺部的CX3CR1hi T细胞通过产生强大的γ干扰素，以抗原非依赖的方式抵御早期病毒感染，这随后增强了肺泡巨噬细胞的长期抗菌活性。这些结果揭示了BCG通过适应性免疫和先天性免疫记忆反应之间的交叉作用，持续显示出针对非结核病感染的广泛保护作用。

2.The astrocyte-produced growth factor HB-EGF limits autoimmune CNS pathology

星形胶质细胞产生的生长因子HB-EGF限制自身免疫性中枢神经系统（CNS）病理改变的产生

德国埃尔兰根大学医院等研究中心联合发表

Abstract

Central nervous system (CNS)-resident cells such as microglia, oligodendrocytes and astrocytes are gaining increasing attention in respect to their contribution to CNS pathologies including multiple sclerosis (MS). Several studies have demonstrated the involvement of pro-inflammatory glial subsets in the pathogenesis and propagation of inflammatory events in MS and its animal models. However, it has only recently become clear that the underlying heterogeneity of astrocytes and microglia can not only drive inflammation, but also lead to its resolution through direct and indirect mechanisms. Failure of these tissue-protective mechanisms may potentiate disease and increase the risk of conversion to progressive stages of MS, for which currently available therapies are limited. Using proteomic analyses of cerebrospinal fluid specimens from patients with MS in combination with experimental studies, we here identify Heparin-binding EGF-like growth factor (HB-EGF) as a central mediator of tissue-protective and anti-inflammatory effects important for the recovery from acute inflammatory lesions in CNS autoimmunity. Hypoxic conditions drive the rapid upregulation of HB-EGF by astrocytes during early CNS inflammation, while pro-inflammatory conditions suppress trophic HB-EGF signaling through epigenetic modifications. Finally, we demonstrate both anti-inflammatory and tissue-protective effects of HB-EGF in a broad variety of cell types in vitro and use intranasal administration of HB-EGF in acute and post-acute stages of autoimmune neuroinflammation to attenuate disease in a preclinical mouse model of MS. Altogether, we identify astrocyte-derived HB-EGF and its epigenetic regulation as a modulator of autoimmune CNS inflammation and potential therapeutic target in MS.

摘要

中枢神经系统（CNS）内的常驻细胞，如小胶质细胞、少突胶质细胞和星形胶质细胞，在包括多发性硬化症（MS）在内的CNS病理学改变中的作用正日益受到关注。多项研究表明，促炎胶质细胞亚群在MS及其动物模型中炎症事件的发病和传播中起着重要作用。然而，最近才明确，星形胶质细胞和小胶质细胞的潜在异质性不仅可以驱动炎症，还可以通过直接和间接机制导致炎症的消退。这些组织保护机制的失败可能会加剧疾病，并增加MS向进展阶段转化的风险，而目前针对这一阶段的治疗手段有限。通过对多发性硬化症患者脑脊液样本的蛋白质组学分析并与实验研究相结合，我们在这里鉴定出肝素结合型EGF样生长因子（HB-EGF）是组织保护和抗炎作用的关键中介，对CNS自身免疫性急性炎症病变的恢复至关重要。在CNS炎症早期，缺氧条件会促使星形胶质细胞迅速上调HB-EGF的表达，而促炎条件则通过表观遗传修饰抑制营养性HB-EGF信号。最后，我们在体外多种细胞类型中展示了HB-EGF的抗炎和组织保护作用，并在MS临床前小鼠模型的急性和亚急性期通过鼻内给予HB-EGF来减轻疾病。总的来说，我们鉴定出星形胶质细胞来源的HB-EGF及其表观遗传调控是自身免疫性CNS炎症的调节剂，也是MS的潜在治疗靶点。

3.Distinct ontogenetic lineages dictate cDC2 heterogeneity

不同的本体发生系决定了 cDC2 的异质性

英国弗朗西斯·克里克研究所免疫生物学实验室等研究中心联合发表

Abstract

Conventional dendritic cells (cDCs) include functionally and phenotypically diverse populations, such as cDC1s and cDC2s. The latter population has been variously subdivided into Notch-dependent cDC2s, KLF4-dependent cDC2s, T-bet+ cDC2As and T-bet− cDC2Bs, but it is unclear how all these subtypes are interrelated and to what degree they represent cell states or cell subsets. All cDCs are derived from bone marrow progenitors called pre-cDCs, which circulate through the blood to colonize peripheral tissues. Here, we identified distinct mouse pre-cDC2 subsets biased to give rise to cDC2As or cDC2Bs. We showed that a Siglec-H+ pre-cDC2A population in the bone marrow preferentially gave rise to Siglec-H− CD8α+ pre-cDC2As in tissues, which differentiated into T-bet+ cDC2As. In contrast, a Siglec-H− fraction of pre-cDCs in the bone marrow and periphery mostly generated T-bet− cDC2Bs, a lineage marked by the expression of LysM. Our results showed that cDC2A versus cDC2B fate specification starts in the bone marrow and suggest that cDC2 subsets are ontogenetically determined lineages, rather than cell states imposed by the peripheral tissue environment.

摘要

树突状细胞（cDCs）包括功能和表型各异的群体，如cDC1s和cDC2s。后者被进一步细分为Notch依赖型cDC2s、KLF4依赖型cDC2s、T-bet+ cDC2As和T-bet− cDC2Bs，但目前还不清楚所有这些亚型之间的相互关系，也不清楚它们在多大程度上代表细胞状态或细胞亚群。所有的cDCs都来源于被称为前cDCs的骨髓祖细胞，它们通过血液循环定殖于外周组织。在这里，我们鉴定出小鼠中不同的前cDC2亚群，这些亚群倾向于产生cDC2As或cDC2Bs。我们研究结果表明骨髓中Siglec-H+的前cDC2A亚群更倾向于在组织中产生Siglec-H− CD8α+的前cDC2As，这些前cDC2As进一步分化为T-bet+ cDC2As。相比之下，骨髓和外周血中Siglec-H−的前cDC亚群主要产生T-bet− cDC2Bs，这是一种以LysM表达为标志的谱系。我们的结果表明，cDC2A与cDC2B的命运始于骨髓，并表明cDC2亚群是本体发育上确定的谱系，而不是由外周组织环境强加的细胞状态。

4.Bispecific antibodies promote natural killer cell-mediated elimination of HIV-1 reservoir cells

双特异性抗体在促进自然杀伤细胞介导的消除HIV-1潜伏感染的细胞方面起重要作用。

美国约翰·霍普金斯大学医学院医学系等研究中心联合发表

Abstract

The persistence of CD4+ T cells carrying latent human immunodeficiency virus-1 (HIV-1) proviruses is the main barrier to a cure. New therapeutics to enhance HIV-1-specific immune responses and clear infected cells will probably be necessary to achieve reduction of the latent reservoir. In the present study, we report two single-chain diabodies (scDbs) that target the HIV-1 envelope protein (Env) and the human type III Fcγ receptor (CD16). We show that the scDbs promoted robust and HIV-1-specific natural killer (NK) cell activation and NK cell-mediated lysis of infected cells. Cocultures of CD4+ T cells from people with HIV-1 on antiretroviral therapy (ART) with autologous NK cells and the scDbs resulted in marked elimination of reservoir cells that was dependent on latency reversal. Treatment of human interleukin-15 transgenic NSG mice with one of the scDbs after ART initiation enhanced NK cell activity and reduced reservoir size. Thus, HIV-1-specific scDbs merit further evaluation as potential therapeutics for clearance of the latent reservoir.

摘要

携带潜伏人类免疫缺陷病毒-1（HIV-1）的CD4+ T细胞的持久存在是治愈艾滋病的主要障碍。为了降低潜伏病毒的数量，可能需要开发新的疗法来增强针对HIV-1的特异性免疫反应并清除感染细胞。在本研究中，我们报告了两种单链双特异性抗体（scDbs），它们分别靶向HIV-1的包膜蛋白（Env）和人类III型Fcγ受体（CD16）。我们证明，这些scDbs促进了靶向HIV-1的自然杀伤（NK）细胞的激活，以及NK细胞介导的感染细胞的裂解。将接受抗逆转录病毒治疗 (ART) 的 HIV-1 患者的 CD4+ T 细胞与自体 NK 细胞和 scDb 共培养，可显著消除依赖于潜伏期逆转的储存细胞。ART开始后，用一种 scDb 治疗人白细胞介素-15 转基因 NSG 小鼠可增强 NK 细胞活性并减小潜伏病毒储库的数量。因此，HIV-1特异性scDb值得进一步评估，作为清除潜伏病毒库的潜在疗法。

5.Iron dysregulation and inflammatory stress erythropoiesis associates with long-term outcome of COVID-19

铁代谢异常和炎症应激性红细胞生成与COVID-19的长期预后有关。

澳大利亚维多利亚州帕克维尔沃尔特和伊丽莎霍尔医学研究所等研究中心联合发表

Abstract

Persistent symptoms following SARS-CoV-2 infection are increasingly reported, although the drivers of post-acute sequelae (PASC) of COVID-19 are unclear. Here we assessed 214 individuals infected with SARS-CoV-2, with varying disease severity, for one year from COVID-19 symptom onset to determine the early correlates of PASC. A multivariate signature detected beyond two weeks of disease, encompassing unresolving inflammation, anemia, low serum iron, altered iron-homeostasis gene expression and emerging stress erythropoiesis; differentiated those who reported PASC months later, irrespective of COVID-19 severity. A whole-blood heme-metabolism signature, enriched in hospitalized patients at month 1–3 post onset, coincided with pronounced iron-deficient reticulocytosis. Lymphopenia and low numbers of dendritic cells persisted in those with PASC, and single-cell analysis reported iron maldistribution, suggesting monocyte iron loading and increased iron demand in proliferating lymphocytes. Thus, defects in iron homeostasis, dysregulated erythropoiesis and immune dysfunction due to COVID-19 possibly contribute to inefficient oxygen transport, inflammatory disequilibrium and persisting symptomatology, and may be therapeutically tractable.

摘要

随着SARS-CoV-2感染的报道增加，感染后的后遗症也越来越多见，但导致COVID-19急性后综合征（PASC）的原因尚不清楚。本研究中，我们对214名感染SARS-CoV-2的个体进行了为期一年的评估以确定PASC的早期相关因素，这些个体均在COVID-19症状出现后表现出不同程度的其他疾病。在PASC发生两周后的个体中检测到的多个特征，包括持续的炎症、贫血、血清铁含量低、铁稳态基因表达改变以及新出现的应激性红细胞生成，这些特征能够将该类病人与数月后报告PASC的患者区分开来。全血血红素代谢特征则在PASC发病后 1-3 个月的住院患者中集中出现，常与缺铁网织红细胞增多症同时发生。在PASC患者中，持续出现淋巴细胞减少和树突状细胞数量减少的症状，单细胞分析报告显示其铁分布不均，提示单核细胞铁负荷和增殖淋巴细胞铁需求增加。因此，COVID-19导致的铁稳态缺陷、红细胞生成失调和免疫功能障碍可能导致氧运输效率低下、炎症不平衡等持续症状，并且可能在治疗上是可行的。

6.Carnosine regulation of intracellular pH homeostasis promotes lysosome-dependent tumor immunoevasion

肌肽通过维持胞内pH稳态及溶酶体活性促进肿瘤免疫逃逸的新机制

中国南方医科大学广东省人民医院医学研究所等研究中心联合发表

Abstract

Tumor cells and surrounding immune cells undergo metabolic reprogramming, leading to an acidic tumor microenvironment. However, it is unclear how tumor cells adapt to this acidic stress during tumor progression. Here we show that carnosine, a mobile buffering metabolite that accumulates under hypoxia in tumor cells, regulates intracellular pH homeostasis and drives lysosome-dependent tumor immune evasion. A previously unrecognized isoform of carnosine synthase, CARNS2, promotes carnosine synthesis under hypoxia. Carnosine maintains intracellular pH (pHi) homeostasis by functioning as a mobile proton carrier to accelerate cytosolic H+ mobility and release, which in turn controls lysosomal subcellular distribution, acidification and activity. Furthermore, by maintaining lysosomal activity, carnosine facilitates nuclear transcription factor X-box binding 1 (NFX1) degradation, triggering galectin-9 and T-cell-mediated immune escape and tumorigenesis. These findings indicate an unconventional mechanism for pHi regulation in cancer cells and demonstrate how lysosome contributes to immune evasion, thus providing a basis for development of combined therapeutic strategies against hepatocellular carcinoma that exploit disrupted pHi homeostasis with immune checkpoint blockade.

摘要

肿瘤细胞和周围的免疫细胞经历代谢重编程，导致酸性肿瘤微环境。然而，目前尚不清楚肿瘤细胞在肿瘤进展过程中如何适应这种酸性应激。在这里，我们发现肌肽是一种可移动的缓冲代谢物，在肿瘤细胞缺氧下积聚，调节细胞内pH稳态并驱动溶酶体依赖性肿瘤免疫逃避。一种以前未被识别的肌肽合酶异构体CARNS2在缺氧条件下促进肌肽合成。肌肽通过充当移动性质子载体来加速胞质H+的移动和释放，进而控制溶酶体的细胞分布、酸化和活性，从而维持细胞内 pH (pHi) 稳态。此外，肌肽通过维持溶酶体活性，促进核转录因子 X-box 结合 1 (NFX1) 降解，触发半乳糖凝集素-9 和 T 细胞介导的免疫逃逸和肿瘤发生。这些发现表明了癌细胞中 pHi 调节的非常规机制，并证明了溶酶体如何促进免疫逃避，从而为开发基于破坏pHi 稳态的治疗策略奠定了基础。

7.Two regulatory T cell populations in the visceral adipose tissue shape systemic metabolism

内脏脂肪组织中的两种调节性T细胞群体参与调控全身代谢

澳大利亚墨尔本大学微生物学和免疫学系等研究中心联合发表

Abstract

Visceral adipose tissue (VAT) is an energy store and endocrine organ critical for metabolic homeostasis. Regulatory T (Treg) cells restrain inflammation to preserve VAT homeostasis and glucose tolerance. Here, we show that the VAT harbors two distinct Treg cell populations: prototypical serum stimulation 2-positive (ST2+) Treg cells that are enriched in males and a previously uncharacterized population of C–X–C motif chemokine receptor 3-positive (CXCR3+) Treg cells that are enriched in females. We show that the transcription factors GATA-binding protein 3 and peroxisome proliferator-activated receptor-γ, together with the cytokine interleukin-33, promote the differentiation of ST2+ VAT Treg cells but repress CXCR3+ Treg cells. Conversely, the differentiation of CXCR3+ Treg cells is mediated by the cytokine interferon-γ and the transcription factor T-bet, which also antagonize ST2+ Treg cells. Finally, we demonstrate that ST2+ Treg cells preserve glucose homeostasis, whereas CXCR3+ Treg cells restrain inflammation in lean VAT and prevent glucose intolerance under high-fat diet conditions. Overall, this study defines two molecularly and developmentally distinct VAT Treg cell types with unique context- and sex-specific functions.

摘要

内脏脂肪组织（VAT）是一个对代谢稳态至关重要的能量储存库和内分泌器官。调节性T（Treg）细胞通过抑制炎症来维持VAT稳态和葡萄糖耐受。在本文中，我们展示了VAT中存在两种不同的Treg细胞群体：典型的血清刺激2阳性（ST2+）Treg细胞，在男性中含量丰富，以及之前未被表征的C–X–C趋化因子受体3阳性（CXCR3+）Treg细胞，在女性中含量丰富。我们表明，转录因子GATA结合蛋白3和过氧化物酶体增殖物激活受体-γ，以及细胞因子白细胞介素-33，共同促进了ST2+ VAT Treg细胞的分化，但抑制了CXCR3+ Treg细胞的分化。相反，CXCR3+ Treg细胞的分化是由细胞因子干扰素-γ和转录因子T-bet介导的，但它们也对抗ST2+ Treg细胞的分化。最后，我们证明ST2+ Treg细胞能维持葡萄糖稳态，而CXCR3+ Treg细胞在瘦型VAT中能抑制炎症，并在高脂饮食条件下防止葡萄糖不耐受。总的来说，这项研究定义了两种在分子和发育上不同的VAT Treg细胞类型，它们各具有独特的功能。

8.IL-23 stabilizes an effector Treg cell program in the tumor microenvironment

IL-23可稳定肿瘤微环境中的效应调节性T细胞（Treg）程序

瑞士苏黎世大学实验免疫学研究所炎症研究部等研究中心联合发表

Abstract

Interleukin-23 (IL-23) is a proinflammatory cytokine mainly produced by myeloid cells that promotes tumor growth in various preclinical cancer models and correlates with adverse outcomes. However, as to how IL-23 fuels tumor growth is unclear. Here, we found tumor-associated macrophages to be the main source of IL-23 in mouse and human tumor microenvironments. Among IL-23-sensing cells, we identified a subset of tumor-infiltrating regulatory T (Treg) cells that display a highly suppressive phenotype across mouse and human tumors. The use of three preclinical models of solid cancer in combination with genetic ablation of Il23r in Treg cells revealed that they are responsible for the tumor-promoting effect of IL-23. Mechanistically, we found that IL-23 sensing represents a crucial signal driving the maintenance and stabilization of effector Treg cells involving the transcription factor Foxp3. Our data support that targeting the IL-23/IL-23R axis in cancer may represent a means of eliciting antitumor immunity.

摘要

白细胞介素-23（IL-23）是一种主要由髓系细胞产生的促炎细胞因子，在各种临床前癌症模型中促进肿瘤生长，并与不良预后相关。然而，IL-23如何促进肿瘤生长的机制尚不清楚。在这里，我们发现肿瘤相关巨噬细胞是小鼠和人类肿瘤微环境中IL-23的主要来源。在IL-23应答细胞中，我们识别出一类肿瘤浸润性调节性T（Treg）细胞亚群，这些细胞在小鼠和人类肿瘤中均显示出高度抑制性的表型。通过使用三种实体癌的临床前模型，并结合在Treg细胞中敲除Il23r的实验，我们发现这些细胞与 IL-23 的肿瘤促进作用有关。从机制上讲，我们发现IL-23感应是一个关键信号，它推动了涉及转录因子Foxp3的效应Treg细胞的维持和稳定。我们的数据支持在癌症中靶向IL-23/IL-23R轴可能是一种潜在的激发抗肿瘤免疫的方法。

9.Targeting JMJD1C to selectively disrupt tumor Treg cell fitness enhances antitumor immunity

靶向JMJD1C可选择性破坏肿瘤调节性T细胞，增强抗肿瘤免疫

中国南京医科大学等研究中心联合发表

Abstract

Regulatory T (Treg) cells are critical for immune tolerance but also form a barrier to antitumor immunity. As therapeutic strategies involving Treg cell depletion are limited by concurrent autoimmune disorders, identification of intratumoral Treg cell-specific regulatory mechanisms is needed for selective targeting. Epigenetic modulators can be targeted with small compounds, but intratumoral Treg cell-specific epigenetic regulators have been unexplored. Here, we show that JMJD1C, a histone demethylase upregulated by cytokines in the tumor microenvironment, is essential for tumor Treg cell fitness but dispensable for systemic immune homeostasis. JMJD1C deletion enhanced AKT signals in a manner dependent on histone H3 lysine 9 dimethylation (H3K9me2) demethylase and STAT3 signals independently of H3K9me2 demethylase, leading to robust interferon-γ production and tumor Treg cell fragility. We have also developed an oral JMJD1C inhibitor that suppresses tumor growth by targeting intratumoral Treg cells. Overall, this study identifies JMJD1C as an epigenetic hub that can integrate signals to establish tumor Treg cell fitness, and we present a specific JMJD1C inhibitor that can target tumor Treg cells without affecting systemic immune homeostasis.

摘要

调节性T（Treg）细胞对于免疫耐受至关重要，但也构成了抗肿瘤免疫的一道障碍。系统性靶向Treg细胞会导致严重的自身免疫病副作用，从而限制了这一策略应用于肿瘤免疫治疗，只有鉴定肿瘤Treg特有的调控新机制，选择性靶向肿瘤Treg，才能在改善微环境提高效应T细胞的杀伤功能的同时，不影响系统性免疫稳态。尽管可以使用小分子化合物靶向表观遗传调节剂，但肿瘤内Treg细胞特异性表观遗传调控因子尚未被探索。在这里，我们表明JMJD1C——一种在肿瘤微环境中由细胞因子上调的组蛋白去甲基化酶——对于肿瘤Treg细胞的适应性至关重要，但对于系统性免疫稳态却是可有可无的。JMJD1C缺失以依赖于组蛋白H3赖氨酸9二甲基化(H3K9me2)去甲基化酶和独立于H3K9me2去甲基化酶的STAT3信号的方式增强AKT信号，导致干扰素-γ的生成增多和肿瘤Treg细胞的脆弱性增加。研究人员还开发了一种口服JMJD1C抑制剂，通过靶向肿瘤内Treg细胞来抑制肿瘤生长。这项研究确定了JMJD1C是一个表观遗传枢纽，可以整合信号以建立肿瘤Treg细胞适应性，并且研究人员提出了一种特异性的JMJD1C抑制剂，可以靶向肿瘤Treg细胞而不影响全身系统性免疫稳态。

10.Mucosal vaccine-induced cross-reactive CD8+ T cells protect against SARS-CoV-2 XBB.1.5 respiratory tract infection

黏膜疫苗诱导的交叉反应性CD8+ T细胞可预防 SARS-CoV-2 XBB.1.5 呼吸道感染

美国华盛顿大学医学院医学系等研究中心联合发表

Abstract

A nasally delivered chimpanzee adenoviral-vectored severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine (ChAd-SARS-CoV-2-S) is currently used in India (iNCOVACC). Here, we update this vaccine by creating ChAd-SARS-CoV-2-BA.5-S, which encodes a prefusion-stabilized BA.5 spike protein. Whereas serum neutralizing antibody responses induced by monovalent or bivalent adenoviral vaccines were poor against the antigenically distant XBB.1.5 strain and insufficient to protect in passive transfer experiments, mucosal antibody and cross-reactive memory T cell responses were robust, and protection was evident against WA1/2020 D614G and Omicron variants BQ.1.1 and XBB.1.5 in mice and hamsters. However, depletion of memory CD8+ T cells before XBB.1.5 challenge resulted in loss of protection against upper and lower respiratory tract infection. Thus, nasally delivered vaccines stimulate mucosal immunity against emerging SARS-CoV-2 strains, and cross-reactive memory CD8+ T cells mediate protection against lung infection by antigenically distant strains in the setting of low serum levels of cross-reactive neutralizing antibodies.

摘要

印度目前使用经鼻给药的黑猩猩腺病毒载体严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 疫苗 (ChAd-SARS-CoV-2-S) (iNCOVACC)。在这里，我们通过创建ChAd-SARS-CoV-2-BA.5-S来更新这种疫苗，该疫苗编码一种预融合稳定的BA.5刺突蛋白。虽然单价或双价腺病毒疫苗诱导的血清中和抗体反应对抗原性较远的XBB.1.5毒株较差，并且在被动转移实验中不足以提供保护，但黏膜抗体和交叉反应性记忆T细胞反应很强烈，在小鼠和仓鼠中对抗WA1/2020 D614G和奥密克戎变异株BQ.1.1以及XBB.1.5的保护是显而易见的。然而，在XBB.1.5感染之前耗尽记忆CD8+ T细胞会导致对上下呼吸道感染的保护丧失。因此，鼻用疫苗刺激了对新兴SARS-CoV-2毒株的黏膜免疫，并且在血清中交叉反应性中和抗体水平较低的情况下，交叉反应性记忆CD8+ T细胞介导了对抗原性较远毒株引起的肺部感染的保护。

11.Lithium carbonate revitalizes tumor-reactive CD8+ T cells by shunting lactic acid into mitochondria

碳酸锂通过将乳酸输送到线粒体中来激活肿瘤反应性CD8+ T细胞

中国华中科技大学同济医学院生物化学与分子生物学系等研究中心联合发表

Abstract

The steady flow of lactic acid (LA) from tumor cells to the extracellular space via the monocarboxylate transporter symport system suppresses antitumor T cell immunity. However, LA is a natural energy metabolite that can be oxidized in the mitochondria and could potentially stimulate T cells. Here we show that the lactate-lowering mood stabilizer lithium carbonate (LC) can inhibit LA-mediated CD8+ T cell immunosuppression. Cytoplasmic LA increased the pumping of protons into lysosomes. LC interfered with vacuolar ATPase to block lysosomal acidification and rescue lysosomal diacylglycerol–PKCθ signaling to facilitate monocarboxylate transporter 1 localization to mitochondrial membranes, thus transporting LA into the mitochondria as an energy source for CD8+ T cells. These findings indicate that targeting LA metabolism using LC could support cancer immunotherapy.

肿瘤细胞通过单羧酸转运体共转运系统将乳酸（LA）稳定地输送到细胞外空间，从而抑制了抗肿瘤T细胞的免疫。然而，乳酸也是一种可以在线粒体中氧化的天然能量代谢物，具有潜在的刺激T细胞的能力。在本文中，研究结果显示，情绪稳定剂碳酸锂（LC）可以降低乳酸水平，进而抑制乳酸介导的CD8+ T细胞免疫抑制。胞质中的乳酸促进了质子泵入溶酶体。LC干扰了空泡型ATP酶(作为质子泵维持溶酶体pH)以阻止溶酶体酸化，并恢复了溶酶体二酰甘油-PKCθ信号传导，从而促进单羧酸转运体1定位于线粒体膜，从而将乳酸作为CD8+ T细胞的能量来源输送到线粒体中作为CD8+T细胞的能量来源。这些发现表明，使用LC靶向乳酸代谢可能有助于癌症免疫治疗。

12.Memory B cell subsets have divergent developmental origins that are coupled to distinct imprinted epigenetic states

记忆B细胞亚群具有不同的发育起源，这些起源与独特的表观遗传状态相关联。

美国匹兹堡大学医学院免疫学系等研究中心联合发表

Abstract

Memory B cells (MBCs) are phenotypically and functionally diverse, but their developmental origins remain undefined. Murine MBCs can be divided into subsets by expression of CD80 and PD-L2. Upon re-immunization, CD80/PD-L2 double-negative (DN) MBCs spawn germinal center B cells (GCBCs), whereas CD80/PD-L2 double-positive (DP) MBCs generate plasmablasts but not GCBCs. Using multiple approaches, including generation of an inducible GCBC-lineage reporter mouse, we demonstrate in a T cell-dependent response that DN cells formed independently of the germinal center (GC), whereas DP cells exhibited either extrafollicular (DPEX) or GCBC (DPGC) origins. Chromatin and transcriptional profiling revealed similarity of DN cells with an early memory precursor. Reciprocally, GCBC-derived DP cells shared distinct genomic features with GCBCs, while DPEX cells had hybrid features. Upon restimulation, DPEX cells were more prone to divide, while DPGC cells differentiated toward IgG1+ plasmablasts. Thus, MBC functional diversity is generated through distinct developmental histories, which imprint characteristic epigenetic patterns onto their progeny, thereby programming them for divergent functional responses.

摘要

记忆B细胞（MBCs）在表型和功能上都是多样的，但它们的发育起源仍然不明确。小鼠MBCs可根据CD80和PD-L2的表达分为不同亚群。再次免疫时，CD80/PD-L2 双阴性 (DN) MBC 产生生发中心B细胞 (GCBC)，而CD80/PD-L2双阳性 (DP) MBC产生浆母细胞，但不产生 GCBC。通过使用多种方法，我们在T细胞依赖的反应实验中证明，DN细胞独立于生发中心（GC）形成，而DP细胞则表现出滤泡外（DPEX）或GCBC（DPGC）的起源。染色质和转录组分析揭示了DN细胞与早期记忆前体细胞的相似性。而GCBC衍生的DP细胞与GCBCs共享独特的基因组特征，而DPEX细胞具有更为复杂的混合特征。在重新刺激后，DPEX细胞更倾向于分裂，而DPGC细胞则分化为IgG1+浆母细胞。因此，MBC的功能多样性是通过不同的发育历史产生的，这些历史在其后代中留下了特征的表观遗传模式，从而为它们编程了不同的功能反应。

汇报人： 冯兰

导师：任建君、赵宇

审核：任建君、庞文都