华西耳鼻喉前沿学术速递—文献导读（第52期）
【Nature Immunology】2024年9-10月刊论文导读
期刊介绍：
Nature Immunology是Nature杂志的免疫学分册，创刊于2000年，也是该领域经由同行评审的权威科学期刊。该杂志由NATURE RESEARCH出版集团按每月一期出版。该期刊是一本以医学-免疫学综合研究为特色的国际期刊，其涵盖的领域包括但不限于先天免疫和炎症，发育，免疫受体，信号传导和凋亡，抗原呈递，基因调控和重组，细胞和全身免疫，疫苗，免疫耐受，自身免疫，肿瘤免疫学和微生物免疫病理学，最新影响因子指数为30.5。
Volume 25 Issue 9, September 2024
2024年9月，第25卷第9期共发表29篇文章，其中3篇Research Highlights；6篇News & Views；3篇Research Briefings；1篇Review Articles；2篇Letters；12篇Articles以及2篇Resource。
Nucleophosmin 1 promotes mucosal immunity by supporting mitochondrial oxidative phosphorylation and ILC3 activity
Nucleophosmin 1 （NPM1）核蛋白通过支持线粒体氧化磷酸化和三型先天性淋巴样细胞（ILC3）活性来促进黏膜免疫
中国科学技术大学生命科学与医学部苏州生物医学工程学院等研究中心联合发表
Abstract
Nucleophosmin 1 (NPM1) is commonly mutated in myelodysplastic syndrome (MDS) and acute myeloid leukemia. Concurrent inflammatory bowel diseases (IBD) and MDS are common, indicating a close relationship between IBD and MDS. Here we examined the function of NPM1 in IBD and colitis-associated colorectal cancer (CAC). NPM1 expression was reduced in patients with IBD. Npm1+/− mice were more susceptible to acute colitis and experimentally induced CAC than littermate controls. Npm1 deficiency impaired the function of interleukin-22 (IL-22)-producing group three innate lymphoid cells (ILC3s). Mice lacking Npm1 in ILC3s exhibited decreased IL-22 production and accelerated development of colitis. NPM1 was important for mitochondrial biogenesis and metabolism by oxidative phosphorylation in ILC3s. Further experiments revealed that NPM1 cooperates with p65 to promote mitochondrial transcription factor A (TFAM) transcription in ILC3s. Overexpression of Npm1 in mice enhanced ILC3 function and reduced the severity of dextran sulfate sodium-induced colitis. Thus, our findings indicate that NPM1 in ILC3s protects against IBD by regulating mitochondrial metabolism through a p65-TFAM axis.
摘要
该研究探讨了Nucleophosmin 1（NPM1）在炎症性肠病（IBD）和结肠炎相关的结直肠癌（CAC）中的作用。研究发现，NPM1在IBD患者中的表达水平下降，且Npm1基因部分缺失的小鼠比正常小鼠更容易患急性结肠炎和实验诱导的CAC。此外，Npm1缺陷会导致产生白介素-22（IL-22）的第三类先天淋巴细胞（ILC3s）功能受损。缺乏Npm1的小鼠表现出IL-22减少的现象，并且其结肠炎也会加速进展。NPM1被证实在ILC3s中通过调控氧化磷酸化影响线粒体的生物发生和代谢，其与p65协同作用，促进线粒体转录因子A（TFAM）的转录。研究发现，过表达Npm1的小鼠表现出增强的ILC3功能，并减轻了葡聚糖硫酸钠（DSS）诱导的结肠炎严重程度。这些结果表明，NPM1通过激活p65-TFAM通路调控线粒体代谢，在ILC3s中发挥保护作用，从而防止IBD的发生和恶化。
Mechanism for controlled assembly of transcriptional condensates by Aire
Aire（全称：Autoimmune Regulator，自身免疫调节因子）控制转录凝聚体组装的机制
美国麻省波士顿，哈佛医学院，生物化学与分子药理学系等研究中心联合发表
Abstract
Transcriptional condensates play a crucial role in gene expression and regulation, yet their assembly mechanisms remain poorly understood. Here, we report a multi-layered mechanism for condensate assembly by autoimmune regulator (Aire), an essential transcriptional regulator that orchestrates gene expression reprogramming for central T cell tolerance. Aire condensates assemble on enhancers, stimulating local transcriptional activities and connecting disparate inter-chromosomal loci. This functional condensate formation hinges upon the coordination between three Aire domains: polymerization domain caspase activation recruitment domain (CARD), histone-binding domain (first plant homeodomain (PHD1)), and C-terminal tail (CTT). Specifically, CTT binds coactivators CBP/p300, recruiting Aire to CBP/p300-rich enhancers and promoting CARD-mediated condensate assembly. Conversely, PHD1 binds to the ubiquitous histone mark H3K4me0, keeping Aire dispersed throughout the genome until Aire nucleates on enhancers. Our findings showed that the balance between PHD1-mediated suppression and CTT-mediated stimulation of Aire polymerization is crucial to form transcriptionally active condensates at target sites, providing new insights into controlled polymerization of transcriptional regulators.
摘要
该研究揭示了自身免疫调节因子（Aire）通过形成转录凝聚体来调控基因表达的多层机制。转录凝聚体在基因表达和调控中起关键作用，但其组装机制尚不完全清楚。研究表明，Aire 在基因组增强子上组装凝聚体，促进局部转录活动，并连接染色体间的不同位点。这种功能性凝聚体的形成依赖于Aire的三个关键结构域的协调作用：聚合结构域（CARD）、组蛋白结合结构域（PHD1）和C端尾部（CTT）。具体来说，Aire的C端尾部（CTT）通过与共激活因子CBP/p300结合，将Aire招募到富含CBP/p300的增强子处，促进CARD介导的凝聚体组装。相反，PHD1通过结合组蛋白标记H3K4me0，在全基因组范围内抑制Aire的非特异性聚集，直到Aire在增强子上开始凝聚。研究进一步表明，PHD1的抑制作用与CTT的刺激作用之间的平衡，对于在特定靶点形成具有转录活性的凝聚体至关重要。该研究为转录调节因子的受控聚合提供了新的见解，进一步拓展了我们对基因表达调控机制的认识。
3.Age-related epithelial defects limit thymic function and regeneration
年龄相关的胸腺上皮缺陷限制了胸腺功能及其再生能力
美国加利福尼亚州杜阿尔特洛杉矶希望之城国家医疗中心等研究中心联合发表
Abstract
The thymus is essential for establishing adaptive immunity yet undergoes age-related involution that leads to compromised immune responsiveness. The thymus is also extremely sensitive to acute insult and although capable of regeneration, this capacity declines with age for unknown reasons. We applied single-cell and spatial transcriptomics, lineage-tracing and advanced imaging to define age-related changes in nonhematopoietic stromal cells and discovered the emergence of two atypical thymic epithelial cell (TEC) states. These age-associated TECs (aaTECs) formed high-density peri-medullary epithelial clusters that were devoid of thymocytes; an accretion of nonproductive thymic tissue that worsened with age, exhibited features of epithelial-to-mesenchymal transition and was associated with downregulation of FOXN1. Interaction analysis revealed that the emergence of aaTECs drew tonic signals from other functional TEC populations at baseline acting as a sink for TEC growth factors. Following acute injury, aaTECs expanded substantially, further perturbing trophic regeneration pathways and correlating with defective repair of the involuted thymus. These findings therefore define a unique feature of thymic involution linked to immune aging and could have implications for developing immune-boosting therapies in older individuals.
摘要
胸腺对于建立适应性免疫至关重要，但随着年龄的增长，胸腺会发生退化，导致免疫反应能力下降。尽管胸腺对急性损伤非常敏感，并且具有再生能力，但这种能力随着年龄的增长而下降，具体原因尚不清楚。该研究运用了单细胞和空间转录组学、谱系追踪和先进成像技术，深入研究了与年龄相关的非造血基质细胞的变化，发现了两种非典型的胸腺上皮细胞（TEC）状态。这些与年龄相关的TEC（aaTEC）在髓质周围形成了高密度的上皮细胞聚集区，这些区域缺乏胸腺细胞，形成了随着年龄增长而恶化的无功能胸腺组织，表现出上皮-间质转化的特征，并伴随着FOXN1的下调。进一步相互作用分析显示，aaTEC通过吸收其他功能性TEC群体的稳定信号，起到了TEC生长因子的“汇集”作用，从而进一步加剧了胸腺功能的退化。在急性损伤后，aaTEC会大量扩增，进一步扰乱了营养再生通路，这与退化胸腺的修复缺陷相关。这些发现定义了与免疫老化相关的胸腺退化的独特特征，可能对增强老年人免疫疗法的开发具有重要意义。
4.Distinctive evolution of alveolar T cell responses is associated with clinical outcomes in unvaccinated patients with SARS-CoV-2 pneumonia
未接种疫苗的SARS-CoV-2肺炎患者中，肺泡T细胞反应的独特演变与临床结局相关
美国伊利诺伊州芝加哥，西北大学范伯格医学院，辛普森·奎里肺部转化科学研究所等研究中心联合发表
Abstract
The evolution of T cell molecular signatures in the distal lung of patients with severe pneumonia is understudied. Here, we analyzed T cell subsets in longitudinal bronchoalveolar lavage fluid samples from 273 patients with severe pneumonia, including unvaccinated patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or with respiratory failure not linked to pneumonia. In patients with SARS-CoV-2 pneumonia, activation of interferon signaling pathways, low activation of the NF-κB pathway and preferential targeting of spike and nucleocapsid proteins early after intubation were associated with favorable outcomes, whereas loss of interferon signaling, activation of NF-κB-driven programs and specificity for the ORF1ab complex late in disease were associated with mortality. These results suggest that in patients with severe SARS-CoV-2 pneumonia, alveolar T cell interferon responses targeting structural SARS-CoV-2 proteins characterize individuals who recover, whereas responses against nonstructural proteins and activation of NF-κB are associated with poor outcomes.
摘要
该研究探讨了严重肺炎患者远端肺泡T细胞分子特征的演变，尤其是在SARS-CoV-2感染者中的变化。研究分析了273例严重肺炎患者的支气管肺泡灌洗液样本，其中包括未接种疫苗的SARS-CoV-2感染患者以及因其他原因导致呼吸衰竭的患者。结果显示，在SARS-CoV-2肺炎患者中，早期干扰素信号通路的激活、NF-κB通路的低水平激活，以及对病毒刺突蛋白和核衣壳蛋白的靶向免疫反应与良好临床结局相关。而随着疾病进展，干扰素信号的丧失、NF-κB驱动的免疫程序激活，以及晚期针对ORF1ab复合体的特异性免疫反应与较高的死亡率相关。因此，结果表明，在重症SARS-CoV-2肺炎患者中，肺泡T细胞的早期干扰素反应，特别是针对SARS-CoV-2结构蛋白的免疫应答，是临床康复的关键特征，而针对非结构蛋白的免疫反应和NF-κB的激活与不良预后相关。
5.Targeting p97-Npl4 interaction inhibits tumor Treg cell development to enhance tumor immunity
靶向抑制p97–Npl4相互作用可阻止肿瘤调节性T细胞（Treg细胞）的发育，从而增强肿瘤免疫力
复旦大学生命科学学院，遗传工程国家重点实验室等研究中心联合发表
Abstract
Targeting tumor-infiltrating regulatory T (TI-Treg) cells is a potential strategy for cancer therapy. The ATPase p97 in complex with cofactors (such as Npl4) has been investigated as an antitumor drug target; however, it is unclear whether p97 has a function in immune cells or immunotherapy. Here we show that thonzonium bromide is an inhibitor of the interaction of p97 and Npl4 and that this p97–Npl4 complex has a critical function in TI-Treg cells. Thonzonium bromide boosts antitumor immunity without affecting peripheral Treg cell homeostasis. The p97–Npl4 complex bridges Stat3 with E3 ligases PDLIM2 and PDLIM5, thereby promoting Stat3 degradation and enabling TI-Treg cell development. Collectively, this work shows an important role for the p97–Npl4 complex in controlling Treg–TH17 cell balance in tumors and identifies possible targets for immunotherapy.
摘要
该研究探讨了靶向肿瘤浸润性调节性T细胞（TI-Treg）作为癌症治疗策略的潜力。研究表明，ATP酶p97与其辅因子（如Npl4）形成的复合体是抗肿瘤药物的一个重要靶点，但尚不清楚p97是否在免疫细胞或免疫治疗中发挥作用。研究发现，溴化硫胺（thonzonium bromide）是一种p97和Npl4相互作用的抑制剂，并且p97–Npl4复合体在TI-Treg细胞中发挥关键作用。具体而言，溴化硫胺增强了抗肿瘤免疫反应，同时不会影响外周Treg细胞的稳态。机制上，该复合体通过连接Stat3和E3泛素连接酶PDLIM2、PDLIM5，促进Stat3的降解，从而推动TI-Treg细胞的发育。总体而言，研究揭示了p97–Npl4复合体在调控肿瘤中Treg和TH17细胞平衡中的重要作用，并提出了潜在的免疫治疗靶点。
6.An intestinal TH17 cell-derived subset can initiate cancer
肠道来源的TH17细胞亚群可以启动癌症
法国里昂癌症研究中心等研究中心联合发表
Abstract
Approximately 25% of cancers are preceded by chronic inflammation that occurs at the site of tumor development. However, whether this multifactorial oncogenic process, which commonly occurs in the intestines, can be initiated by a specific immune cell population is unclear. Here, we show that an intestinal T cell subset, derived from interleukin-17 (IL-17)-producing helper T (TH17) cells, induces the spontaneous transformation of the intestinal epithelium. This subset produces inflammatory cytokines, and its tumorigenic potential is not dependent on IL-17 production but on the transcription factors KLF6 and T-BET and interferon-γ. The development of this cell type is inhibited by transforming growth factor-β1 (TGFβ1) produced by intestinal epithelial cells. TGFβ signaling acts on the pretumorigenic TH17 cell subset, preventing its progression to the tumorigenic stage by inhibiting KLF6-dependent T-BET expression. This study therefore identifies an intestinal T cell subset initiating cancer.
摘要
大约25%的癌症是在肿瘤发生部位由慢性炎症引发的。然而，这种多因素致癌过程是否由特定的免疫细胞群体启动尚不明确。本研究表明，一种源自分泌白介素-17（IL-17）的辅助性T细胞（TH17）的肠道T细胞亚群能够诱导肠上皮自发转化。这类细胞群体的致瘤潜力并不依赖于IL-17的产生，而是依赖于转录因子KLF6、T-BET和干扰素-γ。研究还表明，肠道上皮细胞分泌的转化生长因子-β1（TGFβ1）能够抑制这种T细胞亚群的发育。TGFβ信号通过抑制KLF6依赖的T-BET表达，阻止该亚群从致癌前阶段发展为致癌阶段。总的来说，该研究确定了一种能够启动癌症的肠道T细胞亚群，并揭示了TGFβ信号在抑制其致瘤潜力中的关键作用。
7.Attenuated effector T cells are linked to control of chronic HBV infection
效应T细胞功能减弱与慢性乙型肝炎病毒（HBV）感染的控制有关
德国弗赖堡大学医学院等研究中心联合发表
Abstract
Hepatitis B virus (HBV)-specific CD8+ T cells play a dominant role during acute-resolving HBV infection but are functionally impaired during chronic HBV infection in humans. These functional deficits have been linked with metabolic and phenotypic heterogeneity, but it has remained unclear to what extent different subsets of HBV-specific CD8+ T cells still suppress viral replication. We addressed this issue by deep profiling, functional testing and perturbation of HBV-specific CD8+ T cells during different phases of chronic HBV infection. Our data revealed a mechanism of effector CD8+ T cell attenuation that emerges alongside classical CD8+ T cell exhaustion. Attenuated HBV-specific CD8+ T cells were characterized by cytotoxic properties and a dampened effector differentiation program, determined by antigen recognition and TGFβ signaling, and were associated with viral control during chronic HBV infection. These observations identify a distinct subset of CD8+ T cells linked with immune efficacy in the context of a chronic human viral infection with immunotherapeutic potential.
摘要
该研究探讨了乙型肝炎病毒（HBV）特异性CD8+ T细胞在慢性HBV感染中的作用。尽管，HBV特异性CD8+ T细胞在急性HBV感染的恢复期发挥了关键作用，但在人类慢性HBV感染中，这些细胞的功能却显著受损。研究发现，这种功能障碍与细胞代谢和表型的异质性有关，但不同亚群的HBV特异性CD8+ T细胞在抑制病毒复制方面的作用尚不明确。通过对不同阶段的慢性HBV感染中的CD8+ T细胞进行深入分析、功能测试和扰动研究，研究发现了一种效应CD8+ T细胞的衰减机制，与经典的CD8+ T细胞耗竭过程并存。这些衰减的HBV特异性CD8+ T细胞表现出一定的细胞毒性和减弱的效应分化程序，其特性受抗原识别和TGFβ信号调控，与慢性HBV感染中的病毒控制有关。研究结果表明，在慢性HBV感染中存在一个独特的与免疫效能相关的CD8+ T细胞亚群，这一发现为免疫治疗提供了潜在的靶点。
8.Transcriptional function of E2A, Ebf1, Pax5, Ikaros and Aiolos analyzed by in vivo acute protein degradation in early B cell development
通过体内急性蛋白降解技术，分析五种关键转录因子——E2A、Ebf1、Pax5、Ikaros和Aiolos——在早期B细胞发育过程中的转录功能
奥地利维也纳生物中心分子病理学研究所等研究中心联合发表
Abstract
Early B cell lymphopoiesis depends on E2A, Ebf1, Pax5 and Ikaros family members. In the present study, we used acute protein degradation in mice to identify direct target genes of these transcription factors in pro-B, small pre-B and immature B cells. E2A, Ebf1 and Pax5 predominantly function as transcriptional activators by inducing open chromatin at their target genes, have largely unique functions and are essential for early B cell maintenance. Ikaros and Aiolos act as dedicated repressors to cooperatively control early B cell development. The surrogate light-chain genes Igll1 and Vpreb1 are directly activated by Ebf1 and Pax5 in pro-B cells and directly repressed by Ikaros and Aiolos in small pre-B cells. Pax5 and E2A contribute to V(D)J recombination by activating Rag1, Rag2, Dntt, Irf4 and Irf8. Similar to Pax5, Ebf1 also represses the cohesin-release factor gene Wapl to mediate prolonged loop extrusion across the Igh locus. In summary, in vivo protein degradation has provided unprecedented insight into the control of early B cell lymphopoiesis by five transcription factors.
摘要
该研究探讨了E2A、Ebf1、Pax5及Ikaros家族成员在早期B细胞发育中的作用。研究人员利用小鼠体内的急性蛋白降解技术，分析了这些转录因子在前B细胞、小前B细胞和未成熟B细胞中的直接靶基因。结果显示，E2A、Ebf1和Pax5主要作为转录激活因子，通过诱导靶基因的开放染色质来发挥作用，它们各自具有独特功能，并且对于早期B细胞的维持至关重要。而Ikaros和Aiolos作为专职的转录抑制因子，协同控制早期B细胞的发育。在前B细胞中，Ebf1和Pax5直接被激活替代轻链基因Igll1和Vpreb1，而在小前B细胞中这些基因则被Ikaros和Aiolos直接抑制。此外，Pax5和E2A通过激活Rag1、Rag2、Dntt、Irf4和Irf8，促进V(D)J重组。与Pax5类似，Ebf1通过抑制cohesin释放因子基因Wapl，延长Igh基因座的环状挤出。总之，体内蛋白质降解技术为揭示这五个转录因子如何调控早期B细胞发育提供了前所未有的见解。
9.A TNIP1-driven systemic autoimmune disorder with elevated IgG4
由TNIP1驱动的伴随IgG4升高的系统性自身免疫疾病
澳大利亚国立大学约翰·柯廷医学研究院免疫学与传染病学部等研究中心联合发表
Abstract
Whole-exome sequencing of two unrelated kindreds with systemic autoimmune disease featuring antinuclear antibodies with IgG4 elevation uncovered an identical ultrarare heterozygous TNIP1Q333P variant segregating with disease. Mice with the orthologous Q346P variant developed antinuclear autoantibodies, salivary gland inflammation, elevated IgG2c, spontaneous germinal centers and expansion of age-associated B cells, plasma cells and follicular and extrafollicular helper T cells. B cell phenotypes were cell-autonomous and rescued by ablation of Toll-like receptor 7 (TLR7) or MyD88. The variant increased interferon-β without altering nuclear factor kappa-light-chain-enhancer of activated B cells signaling, and impaired MyD88 and IRAK1 recruitment to autophagosomes. Additionally, the Q333P variant impaired TNIP1 localization to damaged mitochondria and mitophagosome formation. Damaged mitochondria were abundant in the salivary epithelial cells of Tnip1Q346P mice. These findings suggest that TNIP1-mediated autoimmunity may be a consequence of increased TLR7 signaling due to impaired recruitment of downstream signaling molecules and damaged mitochondria to autophagosomes and may thus respond to TLR7-targeted therapeutics.
摘要
这项研究通过对两个不同家族的全外显子组测序，发现了一种非常罕见的TNIP1 Q333P变异，它与伴有抗核抗体和IgG4升高的系统性自身免疫疾病相关。研究人员进一步利用携带类似变异的Q346P小鼠模型来研究这种变异的影响。在这些小鼠中，研究人员观察到了几种异常的免疫反应特征，包括：抗核抗体的产生、唾液腺发炎、IgG2c水平升高、生发中心体内自发形成、与年龄相关的B细胞、浆细胞和辅助性T细胞的数量增加。研究发现，这些B细胞的异常行为是细胞自主的（即这些细胞本身的特性所致），并且可以通过抑制Toll样受体7（TLR7）或MyD88信号通路得到缓解。TNIP1 Q333P变异没有改变NF-κB信号通路，但增加了干扰素-β的水平，并且损害了关键信号分子MyD88和IRAK1的募集。研究还发现，这种变异会导致受损的线粒体无法正常被自噬清除，尤其是在唾液腺细胞中，损伤的线粒体数量显著增加。总结来说，该研究提出，TNIP1变异引发的自身免疫反应可能是由于线粒体损伤未能被及时清除，进而导致TLR7信号异常增强，引发免疫系统的过度反应。因此，研究者认为，针对TLR7的药物可能对这种自身免疫疾病有潜在的治疗效果。
10.A unique serum IgG glycosylation signature predicts development of Crohn’s disease and is associated with pathogenic antibodies to mannose glycan
独特的血清IgG糖基化特征可预测克罗恩病的发生，并与致病性甘露糖糖基抗体相关
葡萄牙波尔图大学健康研究与创新研究所（i3S）等研究中心联合发表
Abstract
Inflammatory bowel disease (IBD) is characterized by chronic inflammation in the gut. There is growing evidence in Crohn’s disease (CD) of the existence of a preclinical period characterized by immunological changes preceding symptom onset that starts years before diagnosis. Gaining insight into this preclinical phase will allow disease prediction and prevention. Analysis of preclinical serum samples, up to 6 years before IBD diagnosis (from the PREDICTS cohort), revealed the identification of a unique glycosylation signature on circulating antibodies (IgGs) characterized by lower galactosylation levels of the IgG fragment crystallizable (Fc) domain that remained stable until disease diagnosis. This specific IgG2 Fc glycan trait correlated with increased levels of antimicrobial antibodies, specifically anti-Saccharomyces cerevisiae (ASCA), pinpointing a glycome–ASCA hub detected in serum that predates by years the development of CD. Mechanistically, we demonstrated that this agalactosylated glycoform of ASCA IgG, detected in the preclinical phase, elicits a proinflammatory immune pathway through the activation and reprogramming of innate immune cells, such as dendritic cells and natural killer cells, via an FcγR-dependent mechanism, triggering NF-κB and CARD9 signaling and leading to inflammasome activation. This proinflammatory role of ASCA was demonstrated to be dependent on mannose glycan recognition and galactosylation levels in the IgG Fc domain. The pathogenic properties of (anti-mannose) ASCA IgG were validated in vivo. Adoptive transfer of antibodies to mannan (ASCA) to recipient wild-type mice resulted in increased susceptibility to intestinal inflammation that was recovered in recipient FcγR-deficient mice. Here we identify a glycosylation signature in circulating IgGs that precedes CD onset and pinpoint a specific glycome–ASCA pathway as a central player in the initiation of inflammation many years before CD diagnosis. This pathogenic glyco-hub may constitute a promising new serum biomarker for CD prediction and a potential target for disease prevention.
摘要
这项研究揭示了克罗恩病（CD）发病前的免疫变化，并找到了一个早期预测疾病的潜在生物标志物。研究发现，在疾病症状出现前数年（最多可达6年），患者血液中的免疫球蛋白G（IgG）糖基化模式发生了变化，特别是IgG的Fc区域缺少半乳糖（称为低半乳糖基化），这一特征在疾病发作前一直保持稳定。
此外，这种糖基化特征与抗酿酒酵母抗体（ASCA）的增加密切相关。ASCA是与克罗恩病相关的抗体，它与肠道的抗微生物反应相关。研究发现，在临床前期，这种特殊的IgG形式会通过激活先天免疫细胞（如树突状细胞和自然杀伤细胞）的特定免疫通路，引发炎症。这一过程依赖于甘露糖识别以及IgG糖基化的变化，激活了NF-κB和CARD9信号通路，进而导致了炎症小体的激活。
通过动物实验，研究验证了这些抗ASCA IgG抗体的致病性。将这些抗体注射到小鼠体内后，小鼠出现更高的肠道炎症风险，但在没有相关受体的小鼠中则不会出现这种反应。
总结来说，研究发现了一种特殊的IgG糖基化特征，这种特征可以在克罗恩病发作前数年检测到，并且与肠道炎症的启动密切相关。这个发现可能成为预测克罗恩病的血清标志物，并为疾病的预防提供了潜在的靶点。
11.Arid1a-dependent canonical BAF complex suppresses inflammatory programs to drive efficient germinal center B cell responses
Arid1a依赖的经典BAF复合体抑制炎症程序，以促进高效的生发中心B细胞反应。
美国伊利诺伊州芝加哥，西北大学，细胞与发育生物学系等研究中心联合发表
Abstract
The mammalian Brg1/Brm-associated factor (BAF) complexes are major regulators of nucleosomal remodeling that are commonly mutated in several cancers, including germinal center (GC)-derived B cell lymphomas. However, the specific roles of different BAF complexes in GC B cell biology are not well understood. Here we show that the AT-rich interaction domain 1a (Arid1a) containing canonical BAF (cBAF) complex is required for maintenance of GCs and high-affinity antibody responses. While Arid1a-deficient B cells undergo initial activation, they fail to sustain the GC program. Arid1a establishes permissive chromatin landscapes for B cell activation and is concomitantly required to suppress inflammatory gene programs. The inflammatory signatures instigated by Arid1a deficiency promoted the recruitment of neutrophils and inflammatory monocytes. Dampening of inflammatory cues through interleukin-1β blockade or glucocorticoid receptor agonist partially rescued Arid1a-deficient GCs, highlighting a critical role for inflammation in impeding GCs. Our work reveals essential functions of Arid1a-dependent cBAF in promoting efficient GC responses.
摘要
这项研究探讨了哺乳动物Brg1/Brm相关因子（BAF）复合体在生发中心（GC）B细胞生物学中的作用，特别是它在维持GC和高亲和力抗体反应中的功能。研究表明，含有Arid1a的经典BAF复合体（cBAF）对GC的维持和高效抗体反应是必需的。尽管Arid1a缺失的B细胞能够初步激活，但它们无法维持GC程序的持续运作。Arid1a通过调节染色质结构，促进B细胞激活，同时抑制炎症基因程序的启动。然而，Arid1a缺失会导致炎症特征的出现，促使中性粒细胞和炎症性单核细胞的募集。进一步发现，通过阻断白介素-1β或使用糖皮质激素受体激动剂来抑制炎症信号，可以部分恢复Arid1a缺失所造成的GC缺陷，表明炎症在阻碍GC反应中的关键作用。总体而言，该研究揭示了Arid1a依赖的cBAF复合体在促进有效GC反应中的重要功能，特别是在调控染色质和抑制炎症程序方面的关键作用。
12.Gα13 restricts nutrient driven proliferation in mucosal germinal centers
Gα13限制了黏膜生发中心中由营养供给引发的细胞增殖。
美国马里兰州贝塞斯达，国家癌症研究所（NCI），美国国立卫生研究院（NIH），癌症研究中心，淋巴系统恶性肿瘤分部等研究中心联合发表
Abstract
Germinal centers (GCs) that form in mucosal sites are exposed to gut-derived factors that have the potential to influence homeostasis independent of antigen receptor-driven selective processes. The G-protein Gα13 confines B cells to the GC and limits the development of GC-derived lymphoma. We discovered that Gα13-deficiency fuels the GC reaction via increased mTORC1 signaling and Myc protein expression specifically in the mesenteric lymph node (mLN). The competitive advantage of Gα13-deficient GC B cells (GCBs) in mLN was not dependent on T cell help or gut microbiota. Instead, Gα13-deficient GCBs were selectively dependent on dietary nutrients likely due to greater access to gut lymphatics. Specifically, we found that diet-derived glutamine supported proliferation and Myc expression in Gα13-deficient GCBs in the mLN. Thus, GC confinement limits the effects of dietary glutamine on GC dynamics in mucosal tissues. Gα13 pathway mutations coopt these processes to promote the gut tropism of aggressive lymphoma.
摘要
这项研究探讨了G蛋白Gα13在黏膜生发中心（GCs）中的作用，揭示其对B细胞增殖和淋巴瘤发展的影响。研究发现，Gα13限制了B细胞在黏膜生发中心内的增殖，并防止了由GC来源的淋巴瘤的发展。具体来说，Gα13缺失会通过增强mTORC1信号和Myc蛋白表达，推动生发中心反应，特别是在肠系膜淋巴结（mLN）中表现得尤为明显。
这种竞争优势并不依赖于T细胞的帮助或肠道微生物群，而是依赖于饮食中的营养物质，特别是谷氨酰胺，这可能是因为Gα13缺失的B细胞更容易进入肠道淋巴系统。研究发现，饮食中的谷氨酰胺促进了这些细胞的增殖和Myc蛋白的表达。总之，Gα13通过限制饮食谷氨酰胺对生发中心的影响，调控了黏膜组织中的生发中心反应，而Gα13信号通路的突变则会促使侵袭性淋巴瘤的肠道趋向性发展。
研究表明，Gα13信号在调控B细胞的黏膜生发中心动态和预防侵袭性淋巴瘤方面起到了关键作用。
Volume 25 Issue 10, October 2024
2024年10月，第25卷第10期共发表24篇文章，其中5篇Research Highlights；5篇News & Views；3篇Research Briefings；1篇Review Articles；1篇Letters以及9篇Articles。
1.Local delivery of cell surface-targeted immunocytokines programs systemic antitumor immunity
将免疫细胞因子（一种能调节免疫反应的蛋白质）靶向递送到肿瘤细胞表面，可以在局部产生效果，进而激活全身的抗肿瘤免疫反应。
美国麻省理工学院柯赫综合癌症研究所等研究中心联合发表
Abstract
Systemically administered cytokines are potent immunotherapeutics but can cause severe dose-limiting toxicities. To overcome this challenge, cytokines have been engineered for intratumoral retention after local delivery. However, despite inducing regression of treated lesions, tumor-localized cytokines often elicit only modest responses at distal untreated tumors. In the present study, we report a localized cytokine therapy that safely elicits systemic antitumor immunity by targeting the ubiquitous leukocyte receptor CD45. CD45-targeted immunocytokines have lower internalization rates relative to wild-type counterparts, leading to sustained downstream cis and trans signaling between lymphocytes. A single intratumoral dose of αCD45-interleukin (IL)-12 followed by a single dose of αCD45-IL-15 eradicated treated tumors and untreated distal lesions in multiple syngeneic mouse tumor models without toxicity. Mechanistically, CD45-targeted cytokines reprogrammed tumor-specific CD8+ T cells in the tumor-draining lymph nodes to have an antiviral transcriptional signature. CD45 anchoring represents a broad platform for protein retention by host immune cells for use in immunotherapy.
摘要
该研究提出了一种通过靶向白细胞受体CD45的局部细胞因子疗法，能够安全有效地引发全身性抗肿瘤免疫反应。研究发现，传统全身给药的细胞因子虽然有效，但容易引起严重的毒性问题。为了克服这一挑战，研究团队设计了能在肿瘤内保留的细胞因子，并观察到这些经过工程化的细胞因子不仅能有效消除局部肿瘤，还能产生全身免疫反应，从而抑制远处未处理的肿瘤。在多个同系小鼠肿瘤模型中，一次性肿瘤内注射αCD45-白介素（IL）-12，再辅以一次性注射αCD45-IL-15，不仅消除了注射部位的肿瘤，还消除了远端未处理的肿瘤，并且没有引发毒性。机制上，CD45靶向的细胞因子重新编程了肿瘤引流淋巴结中的肿瘤特异性CD8+ T细胞，使其具有抗病毒转录特征。这一研究表明，CD45锚定的细胞因子疗法为免疫治疗提供了新的方向，并为蛋白质在宿主免疫细胞中保留提供了广泛的平台。
2.Sodium chloride in the tumor microenvironment enhances T cell metabolic fitness and cytotoxicity
肿瘤微环境中的盐（氯化钠）可以提升T细胞的代谢状态和杀伤能力。
德国慕尼黑工业大学等研究中心联合发表
Abstract
The efficacy of antitumor immunity is associated with the metabolic state of cytotoxic T cells, which is sensitive to the tumor microenvironment. Whether ionic signals affect adaptive antitumor immune responses is unclear. In the present study, we show that there is an enrichment of sodium in solid tumors from patients with breast cancer. Sodium chloride (NaCl) enhances the activation state and effector functions of human CD8+ T cells, which is associated with enhanced metabolic fitness. These NaCl-induced effects translate into increased tumor cell killing in vitro and in vivo. Mechanistically, NaCl-induced changes in CD8+ T cells are linked to sodium-induced upregulation of Na+/K+-ATPase activity, followed by membrane hyperpolarization, which magnifies the electromotive force for T cell receptor (TCR)-induced calcium influx and downstream TCR signaling. We therefore propose that NaCl is a positive regulator of acute antitumor immunity that might be modulated for ex vivo conditioning of therapeutic T cells, such as CAR T cells.
摘要
抗肿瘤免疫的效果与细胞毒性T细胞的代谢状态密切相关，而T细胞的代谢状态容易受到肿瘤微环境的影响。然而，离子信号是否影响适应性抗肿瘤免疫反应尚不明确。这项研究发现，乳腺癌患者的实体肿瘤中钠含量增加。氯化钠（NaCl）可以增强人类CD8+ T细胞的活化状态和效应功能，这一效应与代谢状态的提升相关。NaCl诱导的这些效应不仅在体外实验中增强了T细胞对肿瘤细胞的杀伤力，在体内实验中也有相同效果。
在机制上，NaCl引起的T细胞变化与钠离子诱导的Na+/K+-ATP酶活性上调有关，随后出现了细胞膜的超极化，这进一步增强了T细胞受体（TCR）诱导的钙离子内流和下游的TCR信号传导。因此，作者们提出NaCl是急性抗肿瘤免疫的正向调节因子，可能有助于在体外条件下优化治疗性T细胞（如CAR T细胞）的功能。
3.NaCl enhances CD8+ T cell effector functions in cancer immunotherapy
NaCl增强了癌症免疫疗法中CD8+ T细胞的效应功能
意大利米兰，IRCCS Humanitas研究医院等研究中心联合发表
Abstract
CD8+ T cells control tumors but inevitably become dysfunctional in the tumor microenvironment. Here, we show that sodium chloride (NaCl) counteracts T cell dysfunction to promote cancer regression. NaCl supplementation during CD8+ T cell culture induced effector differentiation, IFN-γ production and cytotoxicity while maintaining the gene networks responsible for stem-like plasticity. Accordingly, adoptive transfer of tumor-specific T cells resulted in superior anti-tumor immunity in a humanized mouse model. In mice, a high-salt diet reduced the growth of experimental tumors in a CD8+ T cell-dependent manner by inhibiting terminal differentiation and enhancing the effector potency of CD8+ T cells. Mechanistically, NaCl enhanced glutamine consumption, which was critical for transcriptional, epigenetic and functional reprogramming. In humans, CD8+ T cells undergoing antigen recognition in tumors and predicting favorable responses to checkpoint blockade immunotherapy resembled those induced by NaCl. Thus, NaCl metabolism is a regulator of CD8+ T cell effector function, with potential implications for cancer immunotherapy.
摘要
CD8+ T细胞可以控制肿瘤，但在肿瘤微环境中往往会功能失调。这项研究发现，氯化钠（NaCl）能够抵抗T细胞的功能失调，促进癌症的消退。在CD8+ T细胞培养过程中补充NaCl，能够诱导效应分化、IFN-γ的产生以及增强细胞毒性，同时保持与干细胞样可塑性相关的基因网络。在小鼠实验中，高盐饮食可以通过抑制CD8+ T细胞的终末分化并增强其效应功能，减少了肿瘤的生长。机制上，NaCl促进了谷氨酰胺的消耗，这一过程对于转录、表观遗传和功能的重编程至关重要。在人体中，肿瘤内识别抗原的CD8+ T细胞，与对免疫检查点抑制疗法有良好反应的CD8+ T细胞，表现出与NaCl诱导的T细胞相似的特征。因此，NaCl代谢是CD8+ T细胞效应功能的调节因子，可能对癌症免疫治疗产生重要影响。
4.Tumor editing suppresses innate and adaptive antitumor immunity and is reversed by inhibiting DNA methylation
肿瘤细胞通过改变自身的基因（称为肿瘤编辑）能够抑制先天免疫和适应性免疫的抗肿瘤功能，通过抑制DNA甲基化可以逆转这一过程。
美国哈佛医学院儿科系等研究中心联合发表
Abstract
Cancer cells edit gene expression to evade immunosurveillance. However, genome-wide studies of gene editing during early tumorigenesis are lacking. Here we used single-cell RNA sequencing in a breast cancer genetically engineered mouse model (GEMM) to identify edited genes without bias. Late tumors repressed antitumor immunity genes, reducing infiltrating immune cells and tumor–immune cell communications. Innate immune genes, especially interferon-stimulated genes, dominated the list of downregulated tumor genes, while genes that regulate cell-intrinsic malignancy were mostly unedited. Naive and activated CD8+ T cells in early tumors were replaced with exhausted or precursor-exhausted cells in late tumors. Repression of immune genes was reversed by inhibiting DNA methylation using low-dose decitabine, which suppressed tumor growth and restored immune control, increasing the number, functionality and memory of tumor-infiltrating lymphocytes and reducing the number of myeloid suppressor cells. Decitabine induced important interferon, pyroptosis and necroptosis genes, inflammatory cell death and immune control in GEMM and implanted breast and melanoma tumors.
摘要
癌细胞可以通过编辑基因表达来逃避免疫监视。这项研究使用单细胞RNA测序技术发现，晚期肿瘤通过抑制抗肿瘤免疫基因的表达，减少了免疫细胞的浸润，并削弱了肿瘤与免疫系统的沟通。特别是先天性免疫基因（如干扰素刺激基因）在晚期肿瘤中显著下调，而与肿瘤细胞内恶性转化相关的基因大多未受影响。在肿瘤的早期阶段，存在活跃的CD8+ T细胞，但随着肿瘤的进展，这些T细胞逐渐变得功能耗竭，失去了抗肿瘤的能力。研究进一步发现，通过使用地西他滨（一种DNA甲基化抑制剂），可以逆转这些抗肿瘤免疫基因的抑制状态，重新激活免疫系统。这种药物不仅抑制了肿瘤生长，还恢复了免疫系统对肿瘤的控制能力，增加了肿瘤浸润淋巴细胞的数量、功能和记忆，同时减少了髓系抑制细胞的数量。此外，地西他滨还诱导了与干扰素、细胞焦亡和坏死性凋亡相关的基因表达，促进了肿瘤中的炎症性细胞死亡和免疫反应的激活，表现出抑制乳腺癌和黑色素瘤的效果。总结来说，这项研究揭示了癌细胞通过改变自身基因表达逃避免疫监视的机制，并展示了通过抑制DNA甲基化恢复免疫控制、抑制肿瘤生长的潜在治疗策略。
5.Epigenetic tuning of PD-1 expression improves exhausted T cell function and viral control
通过调整表观遗传机制来调控PD-1的表达，可以恢复或改善功能失常的T细胞，从而增强它们对病毒的控制能力
美国哈佛医学院等研究中心联合发表
Abstract
PD-1 is a key negative regulator of CD8+ T cell activation and is highly expressed by exhausted T cells in cancer and chronic viral infection. Although PD-1 blockade can improve viral and tumor control, physiological PD-1 expression prevents immunopathology and improves memory formation. The mechanisms driving high PD-1 expression in exhaustion are not well understood and could be critical to disentangling its beneficial and detrimental effects. Here, we functionally interrogated the epigenetic regulation of PD-1 using a mouse model with deletion of an exhaustion-specific PD-1 enhancer. Enhancer deletion exclusively alters PD-1 expression in CD8+ T cells in chronic infection, creating a ‘sweet spot’ of intermediate expression where T cell function is optimized compared to wild-type and Pdcd1-knockout cells. This permits improved control of chronic infection without additional immunopathology. Together, these results demonstrate that tuning PD-1 via epigenetic editing can reduce CD8+ T cell dysfunction while avoiding excess immunopathology.
摘要
这项研究探讨了如何通过调整PD-1的表达来改善功能失调的T细胞，同时避免引发不必要的免疫反应的策略。PD-1是T细胞表面的一种抑制分子，在癌症和慢性病毒感染中，T细胞会由于PD-1的过度表达而变得“耗竭”，失去攻击肿瘤或病毒的能力。然而，适当水平的PD-1表达有助于防止免疫系统过度反应，避免T细胞攻击健康组织。研究人员通过删除PD-1基因的一种特定的基因调控区域（增强子），降低了T细胞中PD-1的表达。删除该增强子后，PD-1的表达处于一个“中间水平”，优化了T细胞的功能：既可以增强其攻击病毒或肿瘤的能力，又不会引发过度的免疫反应。
优化后的PD-1表达水平让T细胞在对抗慢性病毒感染时功能更强，而且不会引发额外的免疫系统过度活跃的问题。通过这种表观遗传调控，研究人员成功在T细胞功能失调和免疫系统过度反应之间找到了一个平衡点。研究表明，通过表观遗传手段调节PD-1的表达，可以让T细胞保持在最佳状态：既能够有效对抗病毒和肿瘤，又不会引发免疫系统攻击健康细胞的过度反应。这为免疫治疗提供了一种新的调控方式。
6.Deficiency of metabolic regulator PKM2 activates the pentose phosphate pathway and generates TCF1+ progenitor CD8+ T cells to improve immunotherapy
代谢调节因子PKM2的缺乏激活了戊糖磷酸途径，并生成TCF1+前体CD8+ T细胞，从而提升了免疫治疗效果。
美国威尔康奈尔医学院细胞与发育生物学系等研究中心联合发表
Abstract
TCF1high progenitor CD8+ T cells mediate the efficacy of immunotherapy; however, the mechanisms that govern their generation and maintenance are poorly understood. Here, we show that targeting glycolysis through deletion of pyruvate kinase muscle 2 (PKM2) results in elevated pentose phosphate pathway (PPP) activity, leading to enrichment of a TCF1high progenitor-exhausted-like phenotype and increased responsiveness to PD-1 blockade in vivo. PKM2KO CD8+ T cells showed reduced glycolytic flux, accumulation of glycolytic intermediates and PPP metabolites and increased PPP cycling as determined by 1,2-13C glucose carbon tracing. Small molecule agonism of the PPP without acute glycolytic impairment skewed CD8+ T cells toward a TCF1high population, generated a unique transcriptional landscape and adoptive transfer of agonist-treated CD8+ T cells enhanced tumor control in mice in combination with PD-1 blockade and promoted tumor killing in patient-derived tumor organoids. Our study demonstrates a new metabolic reprogramming that contributes to a progenitor-like T cell state promoting immunotherapy efficacy.
摘要
这项研究探讨了如何通过改变CD8+ T细胞的代谢状态来增强免疫治疗的效果，具体来说，是通过影响糖酵解和戊糖磷酸途径（PPP）来让T细胞变得更具抗肿瘤能力。TCF1高表达的前体CD8+ T细胞是一类在免疫疗法中非常重要的T细胞亚群，它们有助于增强免疫系统对抗肿瘤的能力。然而，这些T细胞的生成和维持机制还未完全阐明。研究人员通过敲除一种叫PKM2的基因（调控糖酵解代谢过程），观察到细胞中的PPP被激活。这种代谢变化导致CD8+ T细胞转变为一种具有前体耗竭样状态的细胞，而这种状态与更好的免疫治疗反应相关。在进一步的小鼠实验中，研究人员通过激活PPP，成功让CD8+ T细胞具备更高效的抗肿瘤能力。将这种经过PPP激活的CD8+ T细胞转移到小鼠体内，并与PD-1抑制疗法（用于癌症免疫治疗的一种疗法）结合，能显著增强对肿瘤的控制能力。这种方法在患者来源的肿瘤类器官中也表现出促进肿瘤细胞杀伤的效果。总之，通过改变CD8+ T细胞的代谢（通过抑制糖酵解并激活PPP），可以让T细胞转变为一种更有效的前体状态，从而增强免疫治疗的效果。这为开发利用代谢途径提升癌症免疫治疗效果的方法提供了新的见解。
7.Dual blockade of IL-10 and PD-1 leads to control of SIV viral rebound following analytical treatment interruption
在停止治疗后，同时阻断IL-10和PD-1这两种分子，可以帮助控制SIV病毒的再次反弹。
美国埃默里大学温希普癌症研究所等研究中心联合发表
Abstract
Human immunodeficiency virus (HIV) persistence during antiretroviral therapy (ART) is associated with heightened plasma interleukin-10 (IL-10) levels and PD-1 expression. We hypothesized that IL-10 and PD-1 blockade would lead to control of viral rebound following analytical treatment interruption (ATI). Twenty-eight ART-treated, simian immunodeficiency virus (SIV)mac239-infected rhesus macaques (RMs) were treated with anti-IL-10, anti-IL-10 plus anti-PD-1 (combo) or vehicle. ART was interrupted 12 weeks after introduction of immunotherapy. Durable control of viral rebound was observed in nine out of ten combo-treated RMs for >24 weeks post-ATI. Induction of inflammatory cytokines, proliferation of effector CD8+ T cells in lymph nodes and reduced expression of BCL-2 in CD4+ T cells pre-ATI predicted control of viral rebound. Twenty-four weeks post-ATI, lower viral load was associated with higher frequencies of memory T cells expressing TCF-1 and of SIV-specific CD4+ and CD8+ T cells in blood and lymph nodes of combo-treated RMs. These results map a path to achieve long-lasting control of HIV and/or SIV following discontinuation of ART.
摘要
这项研究旨在探索如何通过阻断IL-10和PD-1来抑制人类免疫缺陷病毒（HIV）或猴免疫缺陷病毒（SIV）在停止抗病毒药物（ART）治疗后的病毒反弹。HIV和SIV会导致免疫系统功能失调，在抗病毒治疗期间，病毒虽然被控制住，但并没有被彻底清除。IL-10和PD-1是免疫系统中的抑制分子，通常会抑制免疫反应，而在HIV感染者中，这两个分子水平较高，可能帮助病毒在免疫系统中“躲避”。研究中，研究者将感染了SIV的猕猴分为三组，分别接受：阻断IL-10（即使用抗IL-10抗体）同时阻断IL-10和PD-1（联合治疗）、对照组（没有接受免疫阻断）。在使用了12周的免疫疗法后，停止了所有猕猴的抗病毒药物治疗（ART），以观察病毒是否反弹。结果显示，在接受联合治疗（阻断IL-10和PD-1）的猕猴中，90%（9只猕猴中的9只）在停止抗病毒药物后仍然控制住了病毒，且持续了超过24周。在治疗中断前，免疫系统中的一些指标（如CD8+ T细胞的增殖、促炎细胞因子水平等）能够预测哪只猕猴能够控制病毒反弹。24周后，成功控制了病毒反弹的猕猴血液和淋巴结中，记忆T细胞的数量更多，并且这些T细胞能够有效识别和攻击病毒。总的来说，通过同时阻断IL-10和PD-1，免疫系统能够在停止药物治疗后继续控制病毒。这为未来在HIV治疗中通过免疫调节实现病毒长期控制提供了新思路。
8.Mucosal adenovirus vaccine boosting elicits IgA and durably prevents XBB.1.16 infection in nonhuman primates
黏膜腺病毒疫苗增强可诱导IgA并持久预防非人灵长类动物中的XBB.1.16感染。
美国国家过敏和传染病研究所疫苗研究中心等研究中心联合发表
Abstract
A mucosal route of vaccination could prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication at the site of infection and limit transmission. We compared protection against heterologous XBB.1.16 challenge in nonhuman primates (NHPs) ~5 months following intramuscular boosting with bivalent mRNA encoding WA1 and BA.5 spike proteins or mucosal boosting with a WA1–BA.5 bivalent chimpanzee adenoviral-vectored vaccine delivered by intranasal or aerosol device. NHPs boosted by either mucosal route had minimal virus replication in the nose and lungs, respectively. By contrast, protection by intramuscular mRNA was limited to the lower airways. The mucosally delivered vaccine elicited durable airway IgG and IgA responses and, unlike the intramuscular mRNA vaccine, induced spike-specific B cells in the lungs. IgG, IgA and T cell responses correlated with protection in the lungs, whereas mucosal IgA alone correlated with upper airway protection. This study highlights differential mucosal and serum correlates of protection and how mucosal vaccines can durably prevent infection against SARS-CoV-2.
摘要
通过黏膜途径进行疫苗接种可以在感染部位抑制严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的复制，并限制病毒传播。研究者在非人灵长类动物（NHPs）中，比较了不同疫苗增强策略在接受异源XBB.1.16病毒挑战后的保护效果（间隔约5个月）。对比的疫苗包括：肌肉注射双价mRNA疫苗（编码WA1和BA.5刺突蛋白）和通过鼻内或气雾装置黏膜增强注射的WA1–BA.5双价黑猩猩腺病毒载体疫苗。结果显示，通过黏膜途径增强（无论是鼻内或气雾方式）接种的动物，其鼻腔和肺部的病毒复制均显著减少。相比之下，肌肉注射mRNA疫苗的保护仅限于下呼吸道。此外，黏膜疫苗诱导了持久的气道IgG和IgA反应，并且与肌肉注射的mRNA疫苗不同，它在肺部诱导了刺突蛋白特异性B细胞的产生。研究进一步表明，IgG、IgA和T细胞反应与肺部的保护相关，而上呼吸道的保护主要与黏膜IgA有关。这项研究强调了黏膜和血清保护机制的差异，并表明黏膜疫苗可以持久预防SARS-CoV-2感染。
9.IRF8 defines the epigenetic landscape in postnatal microglia, thereby directing their transcriptome programs
IRF8（一种转录因子）在小胶质细胞中起着关键作用，决定了它们的表观遗传特征，进而影响这些细胞的基因表达（转录组）和功能
美国国立卫生研究院儿童健康与人类发展研究所等研究中心联合发表
Abstract
Microglia are innate immune cells in the brain. Transcription factor IRF8 (interferon regulatory factor 8) is highly expressed in microglia. However, its role in postnatal microglia development is unknown. We demonstrate that IRF8 binds stepwise to enhancer regions of postnatal microglia along with Sall1 and PU.1, reaching a maximum after day 14. IRF8 binding correlated with a stepwise increase in chromatin accessibility, which preceded the initiation of microglia-specific transcriptome. Constitutive and postnatal Irf8 deletion led to a loss of microglia identity and gain of disease-associated microglia (DAM)-like genes. Combined analysis of single-cell (sc)RNA sequencing and single-cell transposase-accessible chromatin with sequencing (scATAC–seq) revealed a correlation between chromatin accessibility and transcriptome at a single-cell level. IRF8 was also required for microglia-specific DNA methylation patterns. Last, in the 5xFAD model, constitutive and postnatal Irf8 deletion reduced the interaction of microglia with amyloidβ plaques and the size of plaques, lessening neuronal loss. Together, IRF8 sets the epigenetic landscape, which is required for postnatal microglia gene expression.
摘要
这项研究的重点是揭示IRF8（一种转录因子）在小胶质细胞发育中的作用，尤其是它如何通过调控基因表达来影响小胶质细胞的功能。小胶质细胞是大脑中的免疫细胞，主要负责清理废物、对抗感染等。IRF8是一种转录因子，通常在小胶质细胞中高表达，但它在小胶质细胞发育中的具体作用此前并不明确。研究发现，IRF8会和其他两个蛋白（Sall1和PU.1）一起结合到小胶质细胞的基因调控区域（增强子区域）。这种结合会让小胶质细胞的染色质变得更加开放，从而促进特定基因的表达。如果敲除IRF8，小胶质细胞就会失去它们正常的特性，并开始表现出一些异常的、类似疾病相关小胶质细胞的基因特征。这些异常基因变化会让小胶质细胞表现出在疾病中（比如阿尔茨海默病）常见的“病态”特征。总之，IRF8通过控制小胶质细胞的基因表达，塑造了它们的“身份”。如果缺失IRF8，小胶质细胞的正常功能会受到影响，转而变得像疾病中的小胶质细胞。这表明IRF8对于小胶质细胞的正常发育和功能是至关重要的，尤其是在出生后的发育阶段。
汇报人：冯兰
导师：任建君、赵宇
审核：夏晓旭、任建君
