【Immunity】2024年1-2月刊论文导读
期刊介绍：
《Immunity》杂志由Cell出版社出版，发表了免疫学研究最重要的进展，感兴趣的领域包括但不限于癌症、传染病、神经免疫学、自身免疫性疾病、过敏、黏膜免疫、代谢疾病和体内平衡。影响因子32.4。
《Immunity》2024年1月刊共发表article 8篇。
1.Neutralizing antibodies evolve to exploit vulnerable sites in the HCV envelope glycoprotein E2 and mediate spontaneous clearance of infection
中和抗体进化为利用 HCV 包膜糖蛋白 E2 的易感位点并介导感染的自发清除
约翰霍普金斯大学医学院
Summary
Individuals who clear primary hepatitis C virus (HCV) infections clear subsequent reinfections more than 80% of the time, but the mechanisms are poorly defined. Here, we used HCV variants and plasma from individuals with repeated clearance to characterize longitudinal changes in envelope glycoprotein E2 sequences, function, and neutralizing antibody (NAb) resistance. Clearance of infection was associated with early selection of viruses with NAb resistance substitutions that also reduced E2 binding to CD81, the primary HCV receptor. Later, peri-clearance plasma samples regained neutralizing capacity against these variants. We identified a subset of broadly NAbs (bNAbs) for which these loss-of-fitness substitutions conferred resistance to unmutated bNAb ancestors but increased sensitivity to mature bNAbs. These data demonstrate a mechanism by which neutralizing antibodies contribute to repeated immune-mediated HCV clearance, identifying specific bNAbs that exploit fundamental vulnerabilities in E2. The induction of bNAbs with these specificities should be a goal of HCV vaccine development. 清除初次丙型肝炎病毒（HCV）感染的患者在80%以上的情况下都能清除随后的再感染，但其中的机制却不甚明了。本研究中，我们利用反复清除感染者的 HCV 变体和血浆来表征包膜糖蛋白 E2序列、功能和中和抗体（NAb）抗性的纵向变化。感染清除与早期选择具有 NAb 抗性替代的病毒有关，这些替代也减少了 E2 与主要 HCV 受体 CD81 的结合。随后，清除期血浆样本恢复了对这些变体的中和能力。我们发现了广谱 NAbs（bNAbs）的一个子集，这些适配性缺失替代赋予了这些子集对未变异 bNAb 原型的抗性，但却增加了对成熟 bNAbs 的敏感性。这些数据证明了中和抗体有助于重复免疫介导的 HCV 清除的机制，确定了识别利用 E2 基本易感位点的特异性 bNAbs。诱导产生具有这些特异性的 bNAbs 应成为HCV疫苗开发的目标。 2.trans-Endothelial neutrophil migration activates bactericidal function via Piezo1 mechanosensing 跨内皮中性粒细胞迁移通过 Piezo1 细胞力学感应激活杀菌功能
芝加哥伊利诺伊大学医学院药理学和再生医学系
Summary
The regulation of polymorphonuclear leukocyte (PMN) function by mechanical forces encountered during their migration across restrictive endothelial cell junctions is not well understood. Using genetic, imaging, microfluidic, and in vivo approaches, we demonstrated that the mechanosensor Piezo1 in PMN plasmalemma induced spike-like Ca2+ signals during trans-endothelial migration. Mechanosensing increased the bactericidal function of PMN entering tissue. Mice in which Piezo1 in PMNs was genetically deleted were defective in clearing bacteria, and their lungs were predisposed to severe infection. Adoptive transfer of Piezo1-activated PMNs into the lungs of Pseudomonas aeruginosa-infected mice or exposing PMNs to defined mechanical forces in microfluidic systems improved bacterial clearance phenotype of PMNs. Piezo1 transduced the mechanical signals activated during transmigration to upregulate nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4, crucial for the increased PMN bactericidal activity. Thus, Piezo1 mechanosensing of increased PMN tension, while traversing the narrow endothelial adherens junctions, is a central mechanism activating the host-defense function of transmigrating PMNs. 多形核白细胞（PMN）在跨限制性内皮细胞连接处迁移的过程中遇到的机械力对其功能的调节作用尚不清楚。我们利用遗传、成像、微流控和体内实验方法证明，PMN 质膜中的机械传感器 Piezo1 在跨内皮迁移过程中诱导尖峰样 Ca2+ 信号。机械感应增强了进入组织的 PMN 的杀菌功能。PMN 中Piezo1基因敲除的小鼠在清除细菌方面存在缺陷，其肺部易受严重感染。将Piezo1激活的PMN移入铜绿假单胞菌感染的小鼠肺部，或在微流体系统中将PMN置于特定的机械力下，可改善PMN的细菌清除表型。Piezo1通过转运过程中激活的机械信号上调还原型烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶4，这对提高PMN的杀菌活性至关重要。因此，在穿越狭窄的内皮紧密连接时，Piezo1 对 PMN 张力增加的机械传感是激活PMN 宿主防御功能的核心机制。 3. Tissue factor binds to and inhibits interferon-α receptor 1 signaling 组织因子与干扰素-α受体 1 结合并抑制其信号传导
德国莱比锡大学医院检验医学、临床化学和分子诊断研究所
Summary
Tissue factor (TF), which is a member of the cytokine receptor family, promotes coagulation and coagulation-dependent inflammation. TF also exerts protective effects through unknown mechanisms. Here, we showed that TF bound to interferon-α receptor 1 (IFNAR1) and antagonized its signaling, preventing spontaneous sterile inflammation and maintaining immune homeostasis. Structural modeling and direct binding studies revealed binding of the TF C-terminal fibronectin III domain to IFNAR1, which restricted the expression of interferon-stimulated genes (ISGs). Podocyte-specific loss of TF in mice (PodΔF3) resulted in sterile renal inflammation, characterized by JAK/STAT signaling, proinflammatory cytokine expression, disrupted immune homeostasis, and glomerulopathy. Inhibiting IFNAR1 signaling or loss of Ifnar1 expression in podocytes attenuated these effects in PodΔF3 mice. As a heteromer, TF and IFNAR1 were both inactive, while dissociation of the TF-IFNAR1 heteromer promoted TF activity and IFNAR1 signaling. These data suggest that the TF-IFNAR1 heteromer is a molecular switch that controls thrombo-inflammation. 组织因子（TF）是细胞因子受体家族的成员，可促进凝血和凝血依赖性炎症。TF 还通过未知机制发挥保护作用。在这里，我们发现 TF 与干扰素-α受体 1（IFNAR1）结合并阻断其信号传导，从而防止自发性无菌炎症并维持免疫稳态。结构建模和直接结合研究显示，TF C端纤维蛋白III结构域与IFNAR1结合，限制了干扰素刺激基因（ISGs）的表达。小鼠荚膜特异性缺失 TF（PodΔF3）可导致无菌性肾炎，表现为 JAK/STAT 信号传导、促炎细胞因子表达、免疫稳态紊乱和肾小球病变。抑制 IFNAR1 信号传导或荚膜细胞中 Ifnar1 的表达可减轻 PodΔF3 小鼠的上述病变。作为异源二聚体，TF 和 IFNAR1 都没有单体活性，而二聚体分离后，TF 活性和 IFNAR1 信号传递得到恢复。这些数据表明，TF-IFNAR1异构体是控制血栓-炎症的分子开关 4. Trem2 expression in microglia is required to maintain normal neuronal bioenergetics during development 小胶质细胞中 Trem2 表达是发育过程中维持正常神经元生物能的必要条件
意大利神经科学研究所国家研究委员会
Summary
Triggering receptor expressed on myeloid cells 2 (Trem2) is a myeloid cell-specific gene expressed in brain microglia, with variants that are associated with neurodegenerative diseases, including Alzheimer’s disease. Trem2 is essential for microglia-mediated synaptic refinement, but whether Trem2 contributes to shaping neuronal development remains unclear. Here, we demonstrate that Trem2 plays a key role in controlling the bioenergetic profile of pyramidal neurons during development. In the absence of Trem2, developing neurons in the hippocampal cornus ammonis (CA)1 but not in CA3 subfield displayed compromised energetic metabolism, accompanied by reduced mitochondrial mass and abnormal organelle ultrastructure. This was paralleled by the transcriptional rearrangement of hippocampal pyramidal neurons at birth, with a pervasive alteration of metabolic, oxidative phosphorylation, and mitochondrial gene signatures, accompanied by a delay in the maturation of CA1 neurons. Our results unveil a role of Trem2 in controlling neuronal development by regulating the metabolic fitness of neurons in a region-specific manner. 髓系细胞上表达的触发受体 2（Trem2）是一种在脑小胶质细胞中表达的髓系细胞特异基因，其变体与神经退行性疾病（包括阿尔茨海默病）有关。Trem2对小胶质细胞介导的突触细化至关重要，但Trem2是否有助于塑造神经元发育仍不清楚。在这里，我们证明了 Trem2 在控制锥体神经元发育过程中的生物能轮廓质谱图方面起着关键作用。在Trem2缺失的情况下，海马胼胝体（CA）1而非CA3亚区的发育中神经元表现出能量代谢受损，同时线粒体质量降低和细胞器超微结构异常。这与出生时海马锥体神经元的转录重排相平行，伴随代谢、氧化磷酸化和线粒体基因特征发生了普遍改变，同时 CA1 神经元的成熟也出现了延迟。我们的研究结果揭示了 Trem2 在控制神经元发育中的作用，它以区域特异性的方式调节神经元的代谢适应性。 5. Renal macrophages monitor and remove particles from urine to prevent tubule obstruction 肾脏巨噬细胞监控并清除尿液中的微粒，防止肾小管阻塞
浙江大学医学院附属第二医院
Summary
When the filtrate of the glomerulus flows through the renal tubular system, various microscopic sediment particles, including mineral crystals, are generated. Dislodging these particles is critical to ensuring the free flow of filtrate, whereas failure to remove them will result in kidney stone formation and obstruction. However, the underlying mechanism for the clearance is unclear. Here, using high-resolution microscopy, we found that the juxtatubular macrophages in the renal medulla constitutively formed transepithelial protrusions and “sampled” urine contents. They efficiently sequestered and phagocytosed intraluminal sediment particles and occasionally transmigrated to the tubule lumen to escort the excretion of urine particles. Mice with decreased renal macrophage numbers were prone to developing various intratubular sediments, including kidney stones. Mechanistically, the transepithelial behaviors of medulla macrophages required integrin β1-mediated ligation to the tubular epithelium. These findings indicate that medulla macrophages sample urine content and remove intratubular particles to keep the tubular system unobstructed. 肾小球的滤液流经肾小管系统时，会产生各种微小的沉淀颗粒，包括矿物晶体。清除这些微粒对于确保滤液的自由流动至关重要，而如果不能清除这些微粒，会导致肾结石的形成和梗阻。然而，清除的基本机制尚不清楚。在这里，我们利用高分辨率显微镜发现，肾髓质中的管旁巨噬细胞会连续形成跨上皮突起，并对尿液内容物进行 "取样"。它们能有效地吸附和吞噬管腔内的沉积物颗粒，并偶尔转移到肾小管腔内，为尿液颗粒的排泄保驾护航。肾脏巨噬细胞数量减少的小鼠容易出现各种肾小管内沉积物，包括肾结石。从机制上讲，髓质巨噬细胞的跨上皮行为需要整合素β1介导的与肾小管上皮细胞的连接。这些研究结果表明，髓质巨噬细胞会对尿液内容物进行采样，并清除管内颗粒，以保持肾小管系统畅通无阻。 6. Circulating NK cells establish tissue residency upon acute infection of skin and mediate accelerated effector responses to secondary infection 循环 NK 细胞在皮肤急性感染时组织驻留并介导对继发感染的加速效应反应
维尔茨堡系统免疫学研究所
Summary
Natural killer (NK) cells are present in the circulation and can also be found residing in tissues, and these populations exhibit distinct developmental requirements and are thought to differ in terms of ontogeny. Here, we investigate whether circulating conventional NK (cNK) cells can develop into long-lived tissue-resident NK (trNK) cells following acute infections. We found that viral and bacterial infections of the skin triggered the recruitment of cNK cells and their differentiation into Tcf1hiCD69hi trNK cells that share transcriptional similarity with CD56brightTCF1hi NK cells in human tissues. Skin trNK cells arose from interferon (IFN)-γ-producing effector cells and required restricted expression of the transcriptional regulator Blimp1 to optimize Tcf1-dependent trNK cell formation. Upon secondary infection, trNK cells rapidly gained effector function and mediated an accelerated NK cell response. Thus, cNK cells redistribute and permanently position at sites of previous infection via a mechanism promoting tissue residency that is distinct from Hobit-dependent developmental paths of NK cells and ILC1 seeding tissues during ontogeny. 自然杀伤（NK）细胞存在于血液循环中，也可驻留在组织中，这些细胞群表现出不同的发育要求，并被认为在个体发育方面存在差异。在这里，我们研究了循环中的常规 NK（cNK）细胞是否能在急性感染后发育成长寿命的组织驻留 NK（trNK）细胞。我们发现，皮肤的病毒和细菌感染会引发 cNK 细胞的招募，并分化成 Tcf1hiCD69hi trNK 细胞，这些细胞与人体组织中的 CD56brightTCF1hi NK 细胞在转录上具有相似性。皮肤trNK细胞来自产生干扰素（IFN）-γ的效应细胞，需要限制转录调节因子Blimp1的表达，以优化Tcf1依赖性trNK细胞的形成。继发感染后，trNK 细胞迅速获得效应功能，并介导加速的 NK 细胞反应。因此，cNK 细胞通过一种促进组织驻留的机制重新分布并永久驻留在先前感染的部位，这种机制不同于 NK 细胞和 ILC1 在本体发育过程中接种组织的 Hobit 依赖性发育路径。 7. Immunomodulatory leptin receptor+ sympathetic perineurial barrier cells protect against obesity by facilitating brown adipose tissue thermogenesis 具有免疫调节作用的瘦素受体+交感神经周围屏障细胞通过促进棕色脂肪组织产热来预防肥胖症
牛津大学生理学、解剖学和遗传学系
Summary
Adipose tissues (ATs) are innervated by sympathetic nerves, which drive reduction of fat mass via lipolysis and thermogenesis. Here, we report a population of immunomodulatory leptin receptor-positive (LepR+) sympathetic perineurial barrier cells (SPCs) present in mice and humans, which uniquely co-express Lepr and interleukin-33 (Il33) and ensheath AT sympathetic axon bundles. Brown ATs (BATs) of mice lacking IL-33 in SPCs (SPCΔIl33) had fewer regulatory T (Treg) cells and eosinophils, resulting in increased BAT inflammation. SPCΔIl33 mice were more susceptible to diet-induced obesity, independently of food intake. Furthermore, SPCΔIl33 mice had impaired adaptive thermogenesis and were unresponsive to leptin-induced rescue of metabolic adaptation. We therefore identify LepR+ SPCs as a source of IL-33, which orchestrate an anti-inflammatory BAT environment, preserving sympathetic-mediated thermogenesis and body weight homeostasis. LepR+IL-33+ SPCs provide a cellular link between leptin and immune regulation of body weight, unifying neuroendocrinology and immunometabolism as previously disconnected fields of obesity research. 脂肪组织（AT）受交感神经支配，交感神经通过脂肪分解和产热来减少脂肪量。在这里，我们报告了存在于小鼠和人体内的一群免疫调节瘦素受体阳性（LepR+）交感神经周围屏障细胞（SPCs），它们独特地共同表达 Lepr 和白细胞介素-33（Il33），并包被交感神经轴突束。在SPCs（SPCΔIl33）中缺乏IL-33的小鼠棕色交感神经节（BAT）中，调节性T（Treg）细胞和嗜酸性粒细胞较少，导致BAT炎症加剧。SPCΔIl33 小鼠更容易受到饮食诱发肥胖的影响，这与食物摄入量无关。此外，SPCΔIl33 小鼠的适应性产热功能受损，对瘦素诱导的代谢适应性拯救反应迟钝。因此，我们将 LepR+ SPCs 鉴定为 IL-33 的来源，IL-33 可协调 BAT 的抗炎环境，保护交感神经介导的产热和体重平衡。LepR+IL-33+ SPCs 提供了瘦素和体重免疫调节之间的细胞联系，将神经内分泌学和免疫代谢学这两个以前互不关联的肥胖研究领域统一起来。 8. An exhausted-like microglial population accumulates in aged and APOE4 genotype Alzheimer’s brains 耗竭样小胶质细胞群在老年和 APOE4 基因型阿尔茨海默氏症患者大脑中聚集
洛克菲勒大学系统癌症生物学实验室
Summary
The dominant risk factors for late-onset Alzheimer’s disease (AD) are advanced age and the APOE4 genetic variant. To examine how these factors alter neuroimmune function, we generated an integrative, longitudinal single-cell atlas of brain immune cells in AD model mice bearing the three common human APOE alleles. Transcriptomic and chromatin accessibility analyses identified a reactive microglial population defined by the concomitant expression of inflammatory signals and cell-intrinsic stress markers whose frequency increased with age and APOE4 burden. An analogous population was detectable in the brains of human AD patients, including in the cortical tissue, using multiplexed spatial transcriptomics. This population, which we designate as terminally inflammatory microglia (TIM), exhibited defects in amyloid-β clearance and altered cell-cell communication during aducanumab treatment. TIM may represent an exhausted-like state for inflammatory microglia in the AD milieu that contributes to AD risk and pathology in APOE4 carriers and the elderly, thus presenting a potential therapeutic target for AD. 晚期阿尔茨海默病（AD）的主要风险因素是高龄和 APOE4 基因变异。为了研究这些因素如何改变神经免疫功能，我们在携带三种常见人类 APOE 等位基因的阿兹海默病模型小鼠中绘制了大脑免疫细胞的综合纵向单细胞图谱。转录组和染色质可及性分析确定了一个反应性小胶质细胞群体，该群体同时表达炎症信号和细胞内在压力标记物，其频率随年龄和 APOE4 负荷的增加而增加。利用多重空间转录组学，在人类 AD 患者的大脑（包括皮质组织）中检测到了类似的群体。我们将这一群体命名为终末炎性小胶质细胞（TIM），它在阿杜那单抗治疗期间表现出淀粉样蛋白-β清除缺陷和细胞间通讯改变。TIM可能代表了AD环境中炎症性小胶质细胞的一种耗竭样状态，这种状态导致了APOE4携带者和老年人的AD风险和病理变化，从而为AD提供了一个潜在的治疗靶点。 《Immunity》2024年2月刊共发表article 8篇。 1. Antibody agonists trigger immune receptor signaling through local exclusion of receptor-type protein tyrosine phosphatases 抗体激动剂通过局部排斥受体型蛋白酪氨酸磷酸酶触发免疫受体信号传导 英国牛津大学约翰·拉德克利夫医院拉德克利夫医学系 Summary Antibodies can block immune receptor engagement or trigger the receptor machinery to initiate signaling. We hypothesized that antibody agonists trigger signaling by sterically excluding large receptor-type protein tyrosine phosphatases (RPTPs) such as CD45 from sites of receptor engagement. An agonist targeting the costimulatory receptor CD28 produced signals that depended on antibody immobilization and were sensitive to the sizes of the receptor, the RPTPs, and the antibody itself. Although both the agonist and a non-agonistic anti-CD28 antibody locally excluded CD45, the agonistic antibody was more effective. An anti-PD-1 antibody that bound membrane proximally excluded CD45, triggered Src homology 2 domain-containing phosphatase 2 recruitment, and suppressed systemic lupus erythematosus and delayed-type hypersensitivity in experimental models. Paradoxically, nivolumab and pembrolizumab, anti-PD-1-blocking antibodies used clinically, also excluded CD45 and were agonistic in certain settings. Reducing these agonistic effects using antibody engineering improved PD-1 blockade. These findings establish a framework for developing new and improved therapies for autoimmunity and cancer. 抗体可以阻断免疫受体的接合，也可以激活受体机制启动信号传导。我们假设，抗体激动剂通过位阻效应将CD45等大型受体型蛋白酪氨酸磷酸酶（RPTPs）从受体结合位点排斥开，从而触发信号传导。靶向共刺激受体 CD28 的激动剂产生的信号取决于抗体的固定情况，并对受体、RPTPs 和抗体本身的大小敏感。虽然激动型和非激动型的抗 CD28 抗体都能在局部排斥CD45，但激动型抗体更有效。一种与膜结合的抗 PD-1 抗体可在近端排斥 CD45，引发 Src 同源区2 含磷酸酶 2 的招募，并在实验模型中抑制系统性红斑狼疮和迟发型超敏反应。矛盾的是，临床上使用的抗 PD-1 阻断抗体 纳武单抗 和帕博利珠单抗在某些情况下也会排斥 CD45 并产生激动作用。利用抗体工程技术减少这些激动效应可改善 PD-1 阻断效果。这些发现为开发新的、更好的自身免疫和癌症疗法建立了一个框架。 2. Reversible, tunable epigenetic silencing of TCF1 generates flexibility in the T cell memory decision 可逆、可调的表观遗传学沉默TCF1使T细胞记忆选择具有灵活性 华盛顿大学西雅图分校生物工程系 Summary The immune system encodes information about the severity of a pathogenic threat in the quantity and type of memory cells it forms. This encoding emerges from lymphocyte decisions to maintain or lose self-renewal and memory potential during a challenge. By tracking CD8+ T cells at the single-cell and clonal lineage level using time-resolved transcriptomics, quantitative live imaging, and an acute infection model, we find that T cells will maintain or lose memory potential early after antigen recognition. However, following pathogen clearance, T cells may regain memory potential if initially lost. Mechanistically, this flexibility is implemented by a stochastic cis-epigenetic switch that tunably and reversibly silences the memory regulator, TCF1, in response to stimulation. Mathematical modeling shows how this flexibility allows memory T cell numbers to scale robustly with pathogen virulence and immune response magnitudes. We propose that flexibility and stochasticity in cellular decisions ensure optimal immune responses against diverse threats. 免疫系统将病原体威胁严重程度的信息编码在其形成的记忆细胞数量和类型中。这种编码产生于淋巴细胞在面临病原体时保持或丧失自我更新和记忆潜能的选择。通过使用时间分辨转录组学、定量活体成像和急性感染模型在单细胞和克隆系水平追踪 CD8+ T 细胞，我们发现 T 细胞在识别抗原后早期会保持或丧失记忆潜能。然而，在病原体被清除后，T 细胞可能会重新获得最初丧失的记忆潜能。从机理上讲，这种灵活性是通过随机顺式表观遗传开关实现的，该开关可调且可逆地沉默记忆调节因子 TCF1，以应对刺激。数学建模显示了这种灵活性是如何使记忆 T 细胞的数量随着病原体毒力和免疫反应的大小而稳健地调整。我们认为，细胞选择的灵活性和随机性确保了针对各种威胁的最佳免疫反应。 3. Signaling via a CD27-TRAF2-SHP-1 axis during naive T cell activation promotes memory-associated gene regulatory networks 在幼稚 T 细胞活化过程中通过 CD27-TRAF2-SHP-1 轴发出信号，促进记忆相关基因调控网络的形成 华盛顿大学医学系 Summary The interaction of the tumor necrosis factor receptor (TNFR) family member CD27 on naive CD8+ T (Tn) cells with homotrimeric CD70 on antigen-presenting cells (APCs) is necessary for T cell memory fate determination. Here, we examined CD27 signaling during Tn cell activation and differentiation. In conjunction with T cell receptor (TCR) stimulation, ligation of CD27 by a synthetic trimeric CD70 ligand triggered CD27 internalization and degradation, suggesting active regulation of this signaling axis. Internalized CD27 recruited the signaling adaptor TRAF2 and the phosphatase SHP-1, thereby modulating TCR and CD28 signals. CD27-mediated modulation of TCR signals promoted transcription factor circuits that induced memory rather than effector associated gene programs, which are induced by CD28 costimulation. CD27-costimulated chimeric antigen receptor (CAR)-engineered T cells exhibited improved tumor control compared with CD28-costimulated CAR-T cells. Thus, CD27 signaling during Tn cell activation promotes memory properties with relevance to T cell immunotherapy. 幼稚 CD8+ T（Tn）细胞上的肿瘤坏死因子受体（TNFR）家族成员 CD27 与抗原递呈细胞（APC）上的同源三聚体 CD70 的相互作用是 T 细胞记忆选择的必要条件。在此，我们研究了 Tn 细胞活化和分化过程中的 CD27 信号传导。在T细胞受体（TCR）活化的同时，CD27与合成三聚体CD70配体的结合引发了CD27的内化和降解，这表明这一信号轴受到了主动调控。内化的 CD27 招募了信号适配体 TRAF2 和磷酸酶 SHP-1，从而调节了 TCR 和 CD28 信号。CD27 介导的 TCR 信号调节促进了转录因子回路，从而诱导了记忆相关基因程序。而效应相关基因程序则是由 CD28 共刺激诱导的。与 CD28 共刺激的 CAR-T 细胞相比，CD27 共刺激CART 细胞能更好地控制肿瘤。因此，Tn细胞活化过程中的CD27信号传导促进了T细胞免疫疗法的记忆特性。 4. Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis 调节性 T 细胞产生的双调蛋白促进非酒精性脂肪肝患者的肝纤维化和胰岛素抵抗 哥伦比亚大学微生物学与免疫学系 Summary Production of amphiregulin (Areg) by regulatory T (Treg) cells promotes repair after acute tissue injury. Here, we examined the function of Treg cells in non-alcoholic steatohepatitis (NASH), a setting of chronic liver injury. Areg-producing Treg cells were enriched in the livers of mice and humans with NASH. Deletion of Areg in Treg cells, but not in myeloid cells, reduced NASH-induced liver fibrosis. Chronic liver damage induced transcriptional changes associated with Treg cell activation. Mechanistically, Treg cell-derived Areg activated pro-fibrotic transcriptional programs in hepatic stellate cells via epidermal growth factor receptor (EGFR) signaling. Deletion of Areg in Treg cells protected mice from NASH-dependent glucose intolerance, which also was dependent on EGFR signaling on hepatic stellate cells. Areg from Treg cells promoted hepatocyte gluconeogenesis through hepatocyte detection of hepatic stellate cell-derived interleukin-6. Our findings reveal a maladaptive role for Treg cell-mediated tissue repair functions in chronic liver disease and link liver damage to NASH-dependent glucose intolerance. 调节性 T（Treg）细胞产生的双调蛋白（Areg）可促进急性组织损伤后的修复。在这里，我们研究了Treg细胞在非酒精性脂肪性肝炎（NASH）（一种慢性肝损伤）中的功能。在患有非酒精性脂肪性肝炎的小鼠和人类肝脏中富集了产生Areg的Treg细胞。在Treg细胞中清除Areg，而不是在髓系细胞中清除Areg，可减少NASH诱发的肝纤维化。慢性肝损伤诱导了与Treg细胞活化相关的转录变化。从机制上讲，Treg细胞衍生的Areg通过表皮生长因子受体（EGFR）信号激活了肝星状细胞中的促纤维化转录程序。清除Treg细胞中的Areg可保护小鼠免受NASH依赖性葡萄糖耐受不良的影响，这种耐受不良也依赖于肝星状细胞上的表皮生长因子受体信号转导。Treg细胞中的Areg通过肝细胞检测肝星状细胞衍生的白细胞介素-6促进肝细胞葡萄糖生成。我们的研究结果揭示了 Treg 细胞介导的组织修复功能在慢性肝病中的不良作用，并揭示了肝损伤与 NASH 依赖性糖耐量减低的关联。 5. Microbiota-derived butyrate restricts tuft cell differentiation via histone deacetylase 3 to modulate intestinal type 2 immunity 源于微生物的丁酸盐通过组蛋白去乙酰化酶3限制簇细胞分化，从而调节肠道2型免疫 辛辛那提儿童医院医学中心免疫生物学部 Summary Tuft cells in mucosal tissues are key regulators of type 2 immunity. Here, we examined the impact of the microbiota on tuft cell biology in the intestine. Succinate induction of tuft cells and type 2 innate lymphoid cells was elevated with loss of gut microbiota. Colonization with butyrate-producing bacteria or treatment with butyrate suppressed this effect and reduced intestinal histone deacetylase activity. Epithelial-intrinsic deletion of the epigenetic-modifying enzyme histone deacetylase 3 (HDAC3) inhibited tuft cell expansion in vivo and impaired type 2 immune responses during helminth infection. Butyrate restricted stem cell differentiation into tuft cells, and inhibition of HDAC3 in adult mice and human intestinal organoids blocked tuft cell expansion. Collectively, these data define a HDAC3 mechanism in stem cells for tuft cell differentiation that is dampened by a commensal metabolite, revealing a pathway whereby the microbiota calibrate intestinal type 2 immunity. 粘膜组织中的簇细胞是 2 型免疫的关键调节因子。在这里，我们研究了微生物群对肠道簇细胞生物学的影响。随着肠道微生物群的丢失，簇细胞和2型先天性淋巴细胞的琥珀酸诱导率升高。定殖产生丁酸盐的细菌或用丁酸盐处理可抑制这种效应，并降低肠道组蛋白去乙酰化酶的活性。表观遗传修饰酶组蛋白去乙酰化酶3（HDAC3）的上皮内在缺失抑制了体内簇细胞的扩张，并损害了蠕虫感染期间的2型免疫反应。丁酸盐限制干细胞分化为簇细胞，在成年小鼠和人类肠器官组织中抑制HDAC3会阻止簇细胞的扩张。总之，这些数据确定了干细胞分化为簇细胞的一种HDAC3调节机制，这一机制可被共生代谢物抑制。这揭示了微生物群校正肠道2型免疫的途径。 6. A GPCR-neuropeptide axis dampens hyperactive neutrophils by promoting an alternative-like polarization during bacterial infection GPCR-神经肽轴通过促进细菌感染期间的替代性极化来抑制中性粒细胞的过度活跃 约翰霍普金斯大学医学院神经科学系 Summary The notion that neutrophils exist as a homogeneous population is being replaced with the knowledge that neutrophils adopt different functional states. Neutrophils can have a pro-inflammatory phenotype or an anti-inflammatory state, but how these states are regulated remains unclear. Here, we demonstrated that the neutrophil-expressed G-protein-coupled receptor (GPCR) Mrgpra1 is a negative regulator of neutrophil bactericidal functions. Mrgpra1-mediated signaling was driven by its ligand, neuropeptide FF (NPFF), which dictated the balance between pro- and anti-inflammatory programming. Specifically, the Mrgpra1-NPFF axis counter-regulated interferon (IFN) γ-mediated neutrophil polarization during acute lung infection by favoring an alternative-like polarization, suggesting that it may act to balance overzealous neutrophilic responses. Distinct, cross-regulated populations of neutrophils were the primary source of NPFF and IFNγ during infection. As a subset of neutrophils at steady state expressed NPFF, these findings could have broad implications in various infectious and inflammatory diseases. Therefore, a neutrophil-intrinsic pathway determines their cellular fate, function, and magnitude of infection. 曾经认为中性粒细胞是一个同质群体，但近年来中性粒细胞的不同功能状态逐渐被揭示。中性粒细胞可以具有促炎表型或抗炎状态，但这些状态是如何调节的仍不清楚。在这里，我们证明了中性粒细胞表达的 G 蛋白偶联受体（GPCR）Mrgpra1 是其杀菌功能的负调控因子。Mrgpra1介导的信号由其配体神经肽FF（NPFF）驱动，后者决定了促炎和抗炎程序之间的平衡。具体来说，在急性肺部感染期间，Mrgpra1-NPFF 轴通过倾向于替代性极化来反调节干扰素（IFN）γ 介导的中性粒细胞极化，这表明它可能起到平衡过度的中性粒细胞反应的作用。在感染过程中，不同的、交叉调节的中性粒细胞群是 NPFF 和 IFNγ 的主要来源。由于处于稳定状态的中性粒细胞中有一部分表达 NPFF，这些发现可能对各种感染性和炎症性疾病有广泛的影响。因此，中性粒细胞的内在通路决定了它们的细胞命运、功能和感染程度。 7. Fate mapping of Spp1 expression reveals age-dependent plasticity of disease-associated microglia-like cells after brain injury Spp1 表达的命运图谱揭示了脑损伤后与疾病相关的小胶质细胞的年龄可塑性 西湖大学生命科学学院神经血管生物学实验室 Summary Microglial reactivity to injury and disease is emerging as a heterogeneous, dynamic, and crucial determinant in neurological disorders. However, the plasticity and fate of disease-associated microglia (DAM) remain largely unknown. We established a lineage tracing system, leveraging the expression dynamics of secreted phosphoprotein 1（Spp1） to label and track DAM-like microglia during brain injury and recovery. Fate mapping of Spp1+ microglia during stroke in juvenile mice revealed an irreversible state of DAM-like microglia that were ultimately eliminated from the injured brain. By contrast, DAM-like microglia in the neonatal stroke models exhibited high plasticity, regaining a homeostatic signature and integrating into the microglial network after recovery. Furthermore, neonatal injury had a lasting impact on microglia, rendering them intrinsically sensitized to subsequent immune challenges. Therefore, our findings highlight the plasticity and innate immune memory of neonatal microglia, shedding light on the fate of DAM-like microglia in various neuropathological conditions. 小胶质细胞对损伤和疾病的反应正在成为神经系统疾病中一个异质性、动态和关键的决定因素。然而，疾病相关小胶质细胞（DAM）的可塑性和命运在很大程度上仍然未知。我们利用分泌型磷蛋白1（Spp1）的表达动态，建立了一个谱系追踪系统，来标记和追踪脑损伤和恢复过程中的DAM样小胶质细胞。Spp1+小胶质细胞在幼鼠中风期间的命运图谱显示了DAM样小胶质细胞的不可逆状态，它们最终会从受伤的大脑中被清除。相比之下，新生小鼠中风模型中的 DAM 样小胶质细胞表现出高度的可塑性，在恢复后能重新获得平衡特征并融入小胶质细胞网络。此外，新生小鼠损伤会对小胶质细胞产生持久影响，使它们对随后的免疫挑战产生内在敏感性。因此，我们的研究结果突显了新生儿小胶质细胞的可塑性和先天免疫记忆，揭示了 DAM 样小胶质细胞在各种神经病理学条件下的命运。 8. Small-molecule CBP/p300 histone acetyltransferase inhibition mobilizes leukocytes from the bone marrow via the endocrine stress response 小分子 CBP/p300 组蛋白乙酰转移酶抑制通过内分泌应激反应动员骨髓白细胞 德累斯顿工业大学医学院第三医学系内分泌科 Summary Mutations of the CBP/p300 histone acetyltransferase (HAT) domain can be linked to leukemic transformation in humans, suggestive of a checkpoint of leukocyte compartment sizes. Here, we examined the impact of reversible inhibition of this domain by the small-molecule A485. We found that A485 triggered acute and transient mobilization of leukocytes from the bone marrow into the blood. Leukocyte mobilization by A485 was equally potent as, but mechanistically distinct from, granulocyte colony-stimulating factor (G-CSF), which allowed for additive neutrophil mobilization when both compounds were combined. These effects were maintained in models of leukopenia and conferred augmented host defenses. Mechanistically, activation of the hypothalamus-pituitary-adrenal gland (HPA) axis by A485 relayed shifts in leukocyte distribution through corticotropin-releasing hormone receptor 1 (CRHR1) and adrenocorticotropic hormone (ACTH), but independently of glucocorticoids. Our findings identify a strategy for rapid expansion of the blood leukocyte compartment via a neuroendocrine loop, with implications for the treatment of human pathologies. CBP/p300组蛋白乙酰转移酶（HAT）结构域的突变可能与人类白血病的转化有关，提示了白细胞区室大小存在检查点。在这里，我们研究了小分子 A485 对该结构域的可逆抑制作用。我们发现，A485 会引发白细胞从骨髓向血液的急性和短暂迁移。A485 对白细胞的动员作用与粒细胞集落刺激因子（G-CSF）的作用相同，但在机理上有所不同，当两种复合物联合使用时可以增加中性粒细胞的动员。这些效应在白细胞减少症模型中得以保持，并增强了宿主防御能力。从机制上讲，A485 对下丘脑-垂体-肾上腺（HPA）轴的激活通过促肾上腺皮质激素释放激素受体 1（CRHR1）和促肾上腺皮质激素（ACTH）改变了白细胞的分布，但与糖皮质激素无关。我们的研究结果确定了一种通过神经内分泌环路快速扩大血液白细胞区室的策略，这对治疗人类病症具有重要意义。 汇报人：蒋子涵 导师：刘世喜教授 编辑：陈秋蓉 审核：任建君、吴桂儀
