【Nature Immunology】2025年10-11月刊论文导读

期刊介绍：

《Nature Immunology》是国际顶级出版集团Springer Nature旗下专注免疫学领域的旗舰期刊。自2000年创刊以来，始终致力于发表免疫学领域内具有最高原创性、突破性及广泛影响力的研究成果。其办刊宗旨“揭示免疫系统运作的核心机制，推动基础发现向临床转化”，优先刊载能提供深刻转化医学见解或根本性科学原理的研究。影响因子27.6。

本期文献导读将呈现10月下旬至11月医学及生物学相关的主要刊物内容。

Volume 26 Issue 10, October 2025

1. Damage-induced IL-18 stimulates thymic NK cells limiting endogenous tissue regeneration

损伤诱导的IL-18刺激胸腺NK细胞从而抑制内源性组织再生

华盛顿大学医学院，弗雷德·哈钦森癌症中心，翻译科学与治疗学部及免疫治疗综合研究中心

Abstract

Interleukin-18 (IL-18) is an acute-phase proinflammatory molecule crucial for mediating viral clearance by activating T helper 1 CD4+ T cells, cytotoxic CD8+ T cells and natural killer (NK) cells. Here, we show that mature IL-18 is generated in the thymus following numerous distinct forms of tissue damage, all of which cause caspase-1-mediated immunogenic cell death. We report that IL-18-stimulated cytotoxic NK cells limit endogenous thymic regeneration, a critical process that ensures the restoration of immune competence after acute insults such as stress, infection, chemotherapy and radiation. NK cells suppress thymus recovery by aberrantly targeting thymic epithelial cells, which act as the master regulators of organ function and regeneration. Together, our data reveal a new pathway regulating tissue regeneration in the thymus and suggest IL-18 as a potential therapeutic target to boost thymic function. Moreover, given the enthusiasm for IL-18 as a cancer immunotherapy due to its capacity to elicit a type 1 immune response, these findings also offer insight into potential off-target effects.

白介素-18（IL-18）是一种急性期促炎因子，在抗病毒免疫中发挥关键作用，主要通过激活1型辅助CD4+T细胞、细胞毒性CD8+ T细胞和自然杀伤（NK）细胞来介导病毒清除。该研究发现，在多种不同类型的组织损伤后，胸腺内均可生成成熟的IL-18，这些损伤均引发了半胱天冬酶-1（caspase-1）介导的免疫原性细胞死亡。IL-18激活的细胞毒性NK细胞可限制胸腺的内源性再生过程，而该过程对于机体在应激、感染、化疗或辐射等急性损伤后恢复免疫功能至关重要。NK细胞通过异常靶向胸腺上皮细胞——一种调控胸腺功能与再生的核心细胞类型，从而抑制胸腺的自我修复。综上所述，该研究揭示了一条调控胸腺组织再生的新通路，提示IL-18或可成为促进胸腺功能恢复的潜在治疗靶点。此外，鉴于IL-18因其激发1型免疫应答的能力而在肿瘤免疫治疗领域备受关注，该研究结果也为深入理解其潜在脱靶效应提供了重要参考。

2. Lymph nodes fuel KLF2-dependent effector CD8+ T cell differentiation during chronic infection and checkpoint blockade

淋巴结在慢性感染与检查点阻断中驱动KLF2依赖性效应CD8+ T细胞分化

澳大利亚墨尔本大学，彼得·杜赫提感染与免疫研究所，微生物与免疫学系；德国波恩大学医院

Abstract

Exhausted CD8+ T (TEX) cell responses are maintained by precursors of exhausted T (TPEX) cells that possess high self-renewal and developmental potential. TPEX cells also drive the proliferative burst of effector T cells upon therapeutic immune checkpoint blockade (ICB). However, the spatial context and signals that regulate their differentiation and function are not well defined. Here we identify developmental and functional compartmentalization of TPEX and TEX cells across secondary lymphoid organs during chronic infection. We show that stem-like CD62L+ TPEX and effector-like CX3CR1+ TEX cells constitute a distinct developmental lineage that is promoted by the lymph node (LN) microenvironment and dependent on the transcription factor KLF2. LNs act as a niche in which migratory dendritic cells provide antigen and costimulatory signals to maintain the proliferative fitness of CD62L+ TPEX cells and generation of CX3CR1+ TEX cells. Moreover, LNs exclusively drive the proliferative burst and systemic dissemination of CX3CR1+ TEX cells during ICB. Thus, our findings identify a unique role for LNs in the maintenance of T cell differentiation and function during systemic chronic infection and ICB therapy.

耗竭CD8+T细胞（TEX）的免疫应答由具有强大自我更新与发育潜能的耗竭前体T细胞（TPEX）维持。在治疗性免疫检查点阻断（ICB）后，TPEX细胞同样能够驱动效应T细胞的增殖爆发。然而，调控这些细胞分化与功能的空间分布特征及信号机制尚未明确。该研究揭示了在慢性感染过程中，TPEX与TEX细胞在次级淋巴器官中呈现明显的发育与功能分区现象。证实了干细胞样CD62L+TPEX细胞与效应样CX3CR1+TEX细胞构成了一个独特的发育谱系，该谱系的建立受到淋巴结（LN）微环境的促进，并依赖于转录因子KLF2。淋巴结作为关键微环境，通过其内的迁移性树突状细胞提供抗原与共刺激信号，维持CD62L+TPEX细胞的增殖适应性，并促进CX3CR1+TEX细胞的生成。此外，在ICB治疗过程中，淋巴结特异性驱动CX3CR1+TEX细胞的增殖爆发与系统性分布。该研究明确了淋巴结在系统性慢性感染与ICB治疗过程中维持T细胞分化与功能的独特作用。

3. Epigenetic imprinting in innate lymphoid cell precursors directs the lineage segregation of innate lymphoid cells

先天淋巴细胞前体中的表观遗传印记指导先天淋巴细胞的谱系分化方向

中国科学院微生物研究所，病原微生物与免疫学实验室

Abstract

Innate lymphoid cells (ILCs) are essential for mucosal homeostasis, but the epigenetic regulation of their lineage segregation remains elusive. Here we simultaneously profiled the single-cell DNA methylome, chromatin accessibility and transcriptome of ILC subsets and ILC precursors (ILCPs) and found that ILCPs could be divided into two subgroups (ILCP1 and ILCP2). ILCP2s had highly heterogeneous DNA methylation profiles and could be divided into three groups according to their DNA methylation characteristics, which matched those of ILC subsets. We identified the signature methylation regions (SMRs) of each ILC subset and traced the DNA methylation imprinting during ILCP differentiation. ILCP2s with hypomethylated SMRs characteristic of ILC subsets differentiated into those subsets. DNA methylation editing of SMRs suppressed ILC lineage segregation, while deletion of Dnmt1 in ILCPs abrogated the heterogeneous distribution of SMRs and resulted in ILC differentiation defects. These findings provide evidence that epigenetic imprinting determines lineage segregation during immune cell development.

先天淋巴细胞（ILCs）在维持黏膜稳态中发挥关键作用，然而其谱系分化过程中的表观遗传调控机制尚不清晰。该研究同步检测ILC各亚群及其前体细胞（ILCPs）的单细胞DNA甲基化组、染色质可及性及转录组，发现ILCP可分为两个亚群（ILCP1与ILCP2）。其中，ILCP2表现出高度异质性的DNA甲基化模式，并可依据其甲基化特征划分为三个群体，分别对应不同的ILC亚群。对各ILC亚群特有的特征性甲基化区域（SMR）进行鉴定，并系统追踪ILCP在分化过程中DNA甲基化印记的动态变化，结果显示，那些携带特定ILC亚群特征性低甲基化SMR的ILCP2细胞，能够定向分化为相应的ILC亚群。进一步功能实验表明，对SMR进行DNA甲基化编辑可抑制ILC的谱系分化；而在ILCPs中敲除Dnmt1则破坏了SMR的异质分布，并导致ILC分化障碍。该研究为“表观遗传印记决定免疫细胞发育过程中的谱系分化”这一机制提供了直接证据。

Volume 26 Issue 11, November 2025

1. Spatiotemporal interaction of immune and renal cells controls glomerular crescent formation in autoimmune kidney disease

免疫细胞与肾脏细胞的时空互作调控自身免疫性肾病中肾小球新月体形成

德国汉堡大学医学中心，汉堡转化免疫学中心 ，汉堡肾脏健康中心

Abstract

Rapidly progressive glomerulonephritis (RPGN) is the most aggressive group of autoimmune kidney diseases and is characterized by glomerular crescent formation with proliferation of parietal epithelial cells (PECs). However, the underlying mechanisms of glomerular crescent formation are incompletely understood. Here we provide a high-resolution spatial kidney cell atlas of 57 samples from patients with RPGN (ANCA-associated GN, lupus nephritis and anti-glomerular basement membrane-GN) to characterize the cell signaling pathways in glomerular crescent development. Early platelet-derived growth factor (PDGF) signaling from epithelial and mesangial cells caused PEC activation and proliferation in glomerular crescents, whereas later transforming growth factor (TGF)-β signaling from macrophages, T cells and epithelial and mesangial cells triggered expression of extracellular matrix components in PECs associated with glomerulosclerosis and disease progression. These findings were similar across the different GNs and were functionally validated in experimental GN by PDGF and TGFβ blockade. These results highlight a spatiotemporally conserved progression program into glomerular crescents and sclerosis and indicate new treatment options for autoimmune kidney disease.

快速进展性肾小球肾炎（RPGN）是自身免疫性肾病中进展最为迅猛的疾病类型，典型特征为肾小球新月体形成。然而，新月体形成的潜在机制尚未完全阐明。该研究通过分析57例RPGN患者样本（包括ANCA相关性肾炎、狼疮性肾炎及抗肾小球基底膜肾炎），建立了高分辨率肾脏空间细胞图谱，系统解析了新月体发育过程中的细胞信号通路。研究发现，早期阶段上皮细胞和系膜细胞来源的血小板衍生生长因子（PDGF）信号驱动壁层上皮细胞活化与增殖，促进新月体形成；而在后期阶段，巨噬细胞、T细胞、上皮细胞及系膜细胞来源的转化生长因子（TGF）-β信号则诱导壁层上皮细胞表达细胞外基质成分，推动肾小球硬化及疾病进展。这一机制在不同类型肾小球肾炎中表现高度保守，并通过PDGF与TGF-β阻断实验在肾病模型中得以功能验证。研究结果揭示了肾小球新月体向硬化发展的时空保守性程序，为自身免疫性肾病提供了新的靶向干预策略。

2.STING signals to NF-κB from late endolysosomal compartments using IRF3 as an adaptor

STING利用IRF3为衔接子，从晚期内体溶酶体区室向NF-κB传递信号

丹麦奥胡斯大学生物医学系，病毒免疫中心

Abstract

NF-κB is central for activation of immune responses. Cytosolic DNA activates the cGAS–STING pathway to induce type I interferons (IFNs) and signaling through NF-κB, thus instigating host defenses and pathological inflammation. However, the mechanism underlying STING-induced NF-κB activation is unknown. Here we report that STING activates NF-κB in a delayed manner, following exit from the Golgi to endolysosomal compartments. Activation of NF-κB is dependent on the IFN-inducing transcription factor IRF3 but is independent of type I IFN signaling. This activation pattern is evolutionarily conserved in tetrapods. Mechanistically, the monomer IRF3 is recruited to STING pS358, with delayed kinetics relative to IRF3 recruitment to STING pS366, which promotes type I IFN responses. IRF3 engagement with STING pS358 induces trafficking to late endolysosomal compartments, supporting recruitment of TRAF6 and activation of NF-κB. We identify a TRAF6 binding motif in IRF3 that facilitates recruitment of TRAF6. This work defines a signaling surface on STING and a function for IRF3 as an adaptor in immune signaling. These findings indicate that STING signaling to NF-κB is enabled only within a short time window between exit from the Golgi and lysosomal degradation, possibly limiting inflammation under homeostatic and danger-sensing conditions.

NF-κB在免疫应答激活中发挥核心作用。胞质DNA通过激活cGAS–STING通路，不仅能诱导I型干扰素产生，也经由NF-κB信号传导启动宿主防御及病理性炎症反应。然而，STING诱导NF-κB激活的具体机制尚未明确。该研究揭示，STING在离开高尔基体并转位至内体溶酶体区室后，会以延迟方式激活NF-κB。该过程依赖于干扰素诱导转录因子IRF3，但不依赖于I型干扰素信号传导，且这一模式在四足动物中进化保守。在机制层面，单体IRF3被招募至STING pS358位点的动力学过程，相较于其向STING pS366位点（促进I型干扰素应答）的招募更为缓慢。IRF3与STING pS358的结合进一步诱导其转运至晚期内体溶酶体区室，进而支持TRAF6的招募及NF-κB的激活。该研究在IRF3中鉴定出一个负责促进TRAF6招募的结合模体。该研究不仅明确了STING上一个关键信号传导界面，也揭示了IRF3作为免疫信号衔接子的新功能。这些发现表明，STING向NF-κB的信号传导仅在其离开高尔基体后至溶酶体降解前的短暂时间窗口内发生，这一特性可能有助于在稳态与危险感知条件下限制过度炎症反应。

3. Spatial and functional diversity of innate lymphoid cells in the human female genital tract may contribute to antiviral responses to HIV

人类女性生殖道中先天淋巴细胞的空间与功能多样性可能有助于对HIV的抗病毒反应

美国塔夫茨大学医学院，韦恩州立大学医学院生物化学、微生物学与免疫学系

Abstract

Innate lymphoid cells (ILCs) are tissue-resident lymphocytes specialized in cytokine secretion that lack antigen-specific receptors. The contribution of ILCs to antiviral mucosal immunity in humans, particularly in the female genital tract (FGT), remains unexplored. Here we resolved human FGT ILC diversity by spectral flow cytometry and CITE-seq, spatial location within genital anatomical regions using ChipCytometry, and determined homeostatic function and antiviral responses. We uncovered spatial and functional specializations of genital ILC subsets under homeostasis, with compartmentalized age-related and pregnancy-related changes. CD161 expression differentially discriminated ILC subsets preloaded with cytokines at steady state. We identified a unique NKp44+CCR6+ ILC3 subset in the endometrium that actively degranulated at homeostasis and was located in lymphoid aggregates surrounded by B cells and T cells. By contrast, ILC1s were found scattered, enriched in the ectocervix and located close to the epithelium. Following in vitro HIV stimulation, genital ILCs displayed rapid subset-specific antiviral responses. These findings reveal distinct tissue and subset-specific features of FGT ILCs and their capacity to immediately respond to viral stimuli, providing a foundation for future studies to determine the potential role of ILCs in mucosal immune protection in the FGT.

先天淋巴细胞（ILCs）是缺乏抗原特异性受体、专门分泌细胞因子的组织驻留淋巴细胞。ILCs对人类抗病毒黏膜免疫（特别是女性生殖道（FGT）中）的贡献仍有待探索。该研究通过光谱流式细胞术和CITE-seq解析了人类FGT ILC的多样性，使用ChipCytometry技术确定了其在生殖道解剖区域内的空间位置及功能特征。该研究发现了稳态条件下生殖器ILC亚群的空间和功能特化，以及与年龄和妊娠相关的区域特异性变化。CD161表达差异性地区分了在稳态下预载细胞因子的ILC亚群。在子宫内膜中发现了一个独特的 NKp44+CCR6+ ILC3亚群，该亚群在稳态下活跃脱颗粒，并位于被B细胞和T细胞包围的淋巴聚集体中。相比之下，ILC1s呈分散分布，在宫颈外部富集并靠近上皮定位。在体外HIV刺激后，生殖器ILCs表现出快速的亚群特异性抗病毒反应。这些发现揭示了FGT ILCs独特的组织和亚群特异性特征及其对病毒刺激立即反应的能力，为未来研究ILCs在FGT黏膜免疫保护中的潜在作用奠定了基础。

4. Chemotherapy-induced CA-repeat DNA fragments in breast cancer trigger antitumor immune responses

乳腺癌中化疗诱导的CA重复DNA片段触发抗肿瘤免疫反应

中山大学孙逸仙纪念医院乳腺肿瘤中心；广东省恶性肿瘤表观遗传与基因调控重点实验室

Abstract

Damage-associated molecular patterns generated by cancer treatment can modulate antitumor immunity, but the underlying mechanisms of this effect are unclear. Here we show that CA-enriched DNA fragments resulting from DNA-damaging chemotherapy in MSH2-low tumors preferentially bind cGAS with strong affinity and form biomolecular condensates by phase separation in the cytoplasm, resulting in antitumor immunity. However, classical CA-poor DNAs released from MSH2-high tumor cells engage AIM2, resulting in immunosuppression by upregulating PD-L1 and IDO. Intratumoral administration of CA-rich DNA fragments enhanced antitumor immunity in syngrafted PyMT tumors. Clinically, CA-rich DNA abundance in breast cancer following chemotherapy was associated with increased tumor-antigen-reactive T cells and better chemotherapeutic responses. Therefore, different tumor DNA fragments can trigger opposing immune responses depending on their preference for differential sensors. This study highlights another mechanistic link between genome instability and immune modulation and the therapeutic potential of CA-rich DNAs to enhance antitumor immunity.

癌症治疗过程中产生的损伤相关分子模式可调控抗肿瘤免疫，但其具体作用机制尚未明确。该研究发现在MSH2低表达肿瘤中，DNA损伤性化疗产生的富含CA的DNA片段能够优先结合cGAS并显示高亲和性，通过胞质内的相分离过程形成生物分子凝聚体，从而激活抗肿瘤免疫反应。相比之下，MSH2高表达肿瘤细胞释放的CA缺失型DNA则通过激活AIM2感应器，上调PD-L1和IDO表达，导致免疫抑制状态。动物实验表明，瘤内注射富含CA的DNA片段可显著增强同种移植PyMT肿瘤模型的抗肿瘤免疫。临床数据分析显示，乳腺癌患者化疗后组织中富含CA的DNA片段丰度与肿瘤抗原特异性T细胞数量增加及更优的化疗疗效呈正相关。这些发现表明，不同特性的肿瘤DNA片段通过选择性激活特定感应器可引发截然相反的免疫应答。该研究不仅揭示了基因组不稳定与免疫调控之间存在新的机制联系，同时展现了富含CA的DNA片段在增强抗肿瘤免疫方面的治疗潜力。

5.Plasmacytoid dendritic cells are dispensable or detrimental in murine systemic or respiratory viral infections

浆细胞样树突状细胞在小鼠全身性与呼吸道病毒感染中非必需且可能有害

法国艾克斯-马赛大学，马赛免疫学中心，图灵生命系统中心

Abstract

Plasmacytoid dendritic cells (pDCs) are major producers of type I/III interferons. As interferons are crucial for antiviral defense, pDCs are assumed to play an essential role in this process; however, robust evidence supporting this dogma is scarce. Genetic or pharmacological manipulations that eliminate pDCs or disrupt their interferon production often affect other cells, confounding interpretation. Here, to overcome this issue, we engineered pDC-less mice that are specifically and constitutively devoid of pDCs by expressing diphtheria toxin under coordinated control of the Siglech and Pacsin1 genes, uniquely coexpressed in pDCs. pDC-less mice mounted protective immunity against systemic infection with mouse cytomegalovirus and showed higher survival and less lung immunopathology to intranasal infection with influenza virus and SARS-CoV-2. Thus, contrary to the prevailing dogma, we revealed that pDCs and their interferons are dispensable or deleterious during several viral infections. pDC-less mice will enable rigorously reassessing the roles of pDCs in health and disease.

浆细胞样树突状细胞（pDC）是I型与III型干扰素的主要来源。尽管干扰素在抗病毒防御中具有关键作用，且pDC常被认为在此过程中不可或缺，但支持这一传统观点的实证依据却相当有限。既往通过遗传或药理学手段清除pDC或干扰其干扰素产生的尝试，往往因同时影响其他细胞类型而使结果解读存在争议。为解决这一局限，该研究通过在白喉毒素中引入由pDC特异性共表达基因Siglech与Pacsin1协同调控的表达系统，成功构建了可持续、特异性缺失pDC的小鼠模型（即pDC缺失小鼠）。在系统性小鼠巨细胞病毒感染模型中，pDC缺失小鼠仍能建立有效的保护性免疫应答；而在甲型流感病毒与SARS-CoV-2鼻腔感染实验中，该模型小鼠不仅存活率更高，肺部免疫病理损伤也显著减轻。综上所述，该研究突破了当前认知框架，证实pDC及其干扰素在多种病毒感染过程中不仅非必需，甚至可能加剧病理损害。这一pDC缺失小鼠模型将为深入重新评估pDC在机体稳态与疾病状态中的功能提供关键实验工具。

6.Profiling of HIV-1 elite neutralizer cohort reveals a CD4bs bnAb for HIV-1 prevention and therapy

HIV-1精英中和者队列分析揭示靶向CD4结合位点的广谱中和抗体在HIV-1预防与治疗中的应用潜力

德国科隆大学医学院，实验免疫学实验室，病毒学研究所

Abstract

Administration of HIV-1 neutralizing antibodies can suppress viremia and prevent infection in vivo. However, clinical use is challenged by envelope diversity and rapid viral escape. Here, we performed single B cell profiling of 32 top HIV-1 elite neutralizers to identify broadly neutralizing antibodies with highest antiviral activity. From 831 expressed monoclonal antibodies, we identified 04_A06, a VH1-2-encoded broadly neutralizing antibody to the CD4 binding site with remarkable breadth and potency against multiclade pseudovirus panels (geometric mean half-maximal inhibitory concentration = 0.059 µg ml−1, breadth = 98.5%, 332 strains). Moreover, 04_A06 was not susceptible to classic CD4 binding site escape variants and maintained full viral suppression in HIV-1-infected humanized mice. Structural analyses revealed an unusually long 11-amino-acid heavy chain insertion that facilitates interprotomer contacts with highly conserved residues on the adjacent gp120 protomer. Finally, 04_A06 demonstrated high activity against contemporaneously circulating viruses from the Antibody-Mediated Prevention trials (geometric mean half-maximal inhibitory concentration = 0.082 µg ml−1, breadth = 98.4%, 191 virus strains), and in silico modeling for 04_A06LS predicted prevention efficacy of >93%. Thus, 04_A06 will provide unique opportunities for effective treatment and prevention of HIV-1 infection.

HIV-1中和抗体能够在体内有效抑制病毒血症并预防感染，然而病毒包膜蛋白的多样性及快速逃逸特性限制了其临床应用。该研究通过对32名顶级HIV-1精英中和者进行单B细胞分析，系统筛选具有最优抗病毒活性的广谱中和抗体。从831个表达的单克隆抗体中成功鉴定出04_A06——一种由VH1-2基因编码的靶向CD4结合位点的广谱中和抗体。该抗体对多亚型假病毒库展现出卓越的中和广度与效力（几何平均半抑制浓度=0.059µg/ml，中和广度98.5%，覆盖332株病毒）。值得注意的是，04_A06不受经典CD4结合位点逃逸变异的影响，并在HIV-1感染的人源化小鼠模型中实现完全病毒抑制。结构解析表明，其重链中一段独特的11个氨基酸插入片段，可与相邻gp120原体上的高度保守残基形成原体间相互作用。最终验证显示，04_A06对抗体介导预防试验中的当期流行毒株保持高效活性（几何平均半抑制浓度=0.082 µg/ml，中和广度98.4%，覆盖191株病毒），且04_A06LS的计算机模拟预测其预防效能超过93%。这些发现表明，04_A06为HIV-1感染的有效防治提供了新的突破性方案。

7.Temporal and context-dependent requirements for the transcription factor Foxp3 expression in regulatory T cells

调节性T细胞中转录因子Foxp3表达的时间性与情境依赖性需求

美国纪念斯隆凯特琳癌症中心，免疫学项目，斯隆凯特琳研究所

Abstract

Regulatory T (Treg) cells, expressing the transcription factor Foxp3, are obligatory gatekeepers of immune responsiveness, yet the mechanisms by which Foxp3 governs the Treg transcriptional network remain incompletely understood. Using a novel chemogenetic system of inducible Foxp3 protein degradation in vivo, we found that while Foxp3 was indispensable for the establishment of transcriptional and functional programs of newly generated Treg cells, Foxp3 loss in mature Treg cells resulted in minimal functional and transcriptional changes under steady state. This resilience of the Foxp3-dependent program in mature Treg cells was acquired over an unexpectedly long timescale; however, in settings of severe inflammation, Foxp3 loss led to a pronounced perturbation of Treg cell transcriptome and fitness. Furthermore, tumoral Treg cells were uniquely sensitive to Foxp3 degradation, which led to impairment in their suppressive function and tumor shrinkage in the absence of pronounced adverse effects. These studies demonstrate a context-dependent differential requirement for Foxp3 for Treg transcriptional and functional programs.

表达Foxp3转录因子的调节性T（Treg）细胞是维持免疫稳态的关键调控者，然而Foxp3如何精确调控Treg细胞的转录网络尚不完全清楚。通过建立新型体内化学遗传学系统诱导Foxp3蛋白降解，该研究发现：虽然Foxp3对新生成Treg细胞建立转录与功能程序至关重要，但在稳态条件下，成熟Treg细胞缺失Foxp3仅引发轻微的功能和转录变化。这种Foxp3依赖性调控程序在成熟Treg细胞中的稳定性需要较长时间才能建立；然而在严重炎症环境下，Foxp3的缺失会导致Treg细胞转录组和适应性的显著紊乱。特别值得注意的是，肿瘤微环境中的Treg细胞对Foxp3降解表现独特敏感性，其抑制功能受损并引发肿瘤消退，且不伴随明显不良反应。这些发现揭示了Foxp3在调控Treg细胞转录与功能程序方面具有显著的情境依赖性差异化需求。

8.Tonic type I interferon signaling optimizes the antiviral function of plasmacytoid dendritic cells

基础型I型干扰素信号优化浆细胞样树突状细胞的抗病毒功能

纽约大学格罗斯曼医学院，病理学系 / 医学部消化内科炎症性肠病中心；

加州大学圣地亚哥分校医学院，药理学系 / 生物科学学院分子生物学系

Abstract

Plasmacytoid dendritic cells (pDCs) mount powerful antiviral type I interferon (IFN-I) responses, yet only a fraction of pDCs produces high levels of IFN-I. Here we report that peripheral pDCs in naive mice comprise three subsets (termed A, B and C) that represent progressive differentiation stages. This heterogeneity was generated by tonic IFN-I signaling elicited in part by the cGAS/STING and TLR9 DNA-sensing pathways. A small ‘IFN-I-naive’ subset (pDC-A) could give rise to other subsets; it was expanded in STING deficiency or after the IFN-I receptor blockade, but was abolished by exogenous IFN-I. In response to RNA viruses, pDC-A showed increased Bcl2-dependent survival and superior IFN-I responses, but was susceptible to virus infection. Conversely, the majority of pDCs comprised the ‘IFN-I-primed’ subsets (pDC-B/C) that showed lower IFN-I responses and poor survival, but did not support virus replication. Thus, tonic IFN-I signaling decreases the cytokine-producing capacity and survival of pDCs but increases their virus resistance, facilitating optimal antiviral responses.

浆细胞样树突状细胞（pDC）能够启动强烈的抗病毒I型干扰素（IFN-I）反应，但仅有少数pDC可产生高水平的IFN-I。该研究发现，未受刺激小鼠的外周pDC包含三个亚群（分别命名为A、B和C），代表其渐进分化阶段。这种异质性由基础型IFN-I信号驱动，该过程部分通过cGAS/STING和TLR9 DNA感知通路实现。其中较小的"IFN-I-初始"亚群（pDC-A）具有分化为其他亚群的能力：该亚群在STING缺失或IFN-I受体阻断后发生扩增，但可被外源性IFN-I消除。在应对RNA病毒时，pDC-A表现出增强的Bcl2依赖性存活能力和更优异的IFN-I反应，但对病毒感染较为易感。相反，大多数pDC属于"IFN-I-预激活"亚群（pDC-B/C），这些细胞表现出较弱的IFN-I反应和较差的存活能力，但不支持病毒复制。因此，基础型IFN-I信号在降低pDC细胞因子产生能力和存活率的同时，增强了其抗病毒能力，从而实现最佳的抗病毒反应。

9.Transient tissue residency and lymphatic egress define human CD56bright NK cell homeostasis

人类CD56bright NK细胞的稳态由短暂组织驻留与淋巴外流共同决定

瑞典卡罗林斯卡学院，胡丁格医学院，传染病医学中心

Abstract

Human tissue-resident (TR) CD56bright natural killer (NK) cells can be identified by expression of integrins and chemokine receptors inferred from murine studies, but many aspects of their homeostasis are unclear. Here we used an integrated approach of dynamic human, humanized mouse and non-human primate models and sampling of efferent lymph fluid to determine recirculation and TR patterns of human NK cells. By intravascular labeling, we showed that CD56bright NK cells access tissue niches at steady state. Furthermore, in human liver transplantation, donor-derived CD56bright NK cells represent the dominant TR NK cell population early after transplantation, but are replaced over time by infiltrating recipient NK cells that establish TR traits, a process partly regulated by Runx3. Transient TR CD56bright NK cells recirculated via lymphatics, displaying a consistent phenotype detectable in draining lymph nodes and efferent lymph fluid, and waned from peripheral blood on lymph node egress blockade. Finally, CD56dim NK cells, constrained to vasculature at steady state, entered lymph nodes upon inflammation. This study provides a mechanistic framework for the transient tissue residency and recirculation pattern of human NK cell populations.

人类组织驻留（tissue-resident, TR）CD56bright NK细胞可通过整合素和趋化因子受体的表达加以鉴定，这些特征是从小鼠研究中推断出的，但其稳态的许多方面仍不清楚。该研究综合运用动态人体模型、人源化小鼠模型和非人灵长类动物模型，并采集传出淋巴液样本，解析人类NK细胞的再循环和组织驻留模式。通过血管内标记，证明CD56bright NK细胞在稳态条件下能够进入组织微环境。在人类肝移植模型中，供体来源的CD56bright NK细胞在移植早期构成主要的组织驻留NK细胞群体，但随着时间推移，这些细胞被获得组织驻留特征的浸润性受体NK细胞所取代，该过程部分受Runx3调控。短暂组织驻留的CD56bright NK细胞通过淋巴系统进行再循环，在引流淋巴结和传出淋巴液中呈现一致的表型特征，且当淋巴结外流被阻断时，这些细胞在外周血中的数量会减少。最后，研究发现通常局限于血管系统的CD56dim NK细胞在炎症状态下能够进入淋巴结。该研究为人类NK细胞群体的短暂组织驻留和再循环模式提供了机制性解释框架。

10.The co-inhibitory receptor TIGIT promotes tissue-protective functions in T cells

共抑制受体TIGIT促进T细胞的组织保护功能

瑞士苏黎世大学，定量生物医学系

Abstract

The co-inhibitory receptor TIGIT suppresses excessive immune responses in autoimmune conditions while also restraining antitumor immunity. In viral infections, TIGIT alone does not affect viral control but has been shown to limit tissue pathology. However, the underlying mechanisms are incompletely understood. Here we found TIGIT+ T cells to express not only an immunoregulatory gene signature but also a tissue repair gene signature. Specifically, after viral infection, TIGIT directly drives expression of the tissue growth factor amphiregulin (Areg), which is strongly reduced in the absence of TIGIT. We identified regulatory T (Treg) cells, but not CD8+ T cells, as the critical T cell subset mediating these tissue-protective effects. In Treg cells, TIGIT engagement after T cell antigen receptor stimulation induces the transcription factor Blimp-1, which then promotes Areg production and tissue repair. Thus, we uncovered a nonclassical function of the co-inhibitory receptor TIGIT, wherein it not only limits immune pathology by suppressing the immune response but also actively fosters tissue regeneration by inducing the tissue growth factor Areg in T cells.

共抑制受体TIGIT在抑制自身免疫反应的同时也会限制抗肿瘤免疫。在病毒感染过程中，虽然TIGIT本身不影响病毒清除，但已被证实可减轻组织病理损伤，其具体机制尚未明确。研究发现，TIGIT+ T细胞不仅具有免疫调节特征，还表现出独特的组织修复基因表达谱。特别是在病毒感染后，TIGIT直接诱导组织生长因子双调蛋白（Areg）的表达，而在TIGIT缺失时Areg表达显著降低。机制研究表明，调节性T细胞（Treg）——而非CD8+T细胞——是介导这种组织保护作用的关键细胞亚群。在Treg细胞中，T细胞受体激活后，TIGIT通过诱导转录因子Blimp-1表达，进而促进Areg产生并驱动组织修复进程。该研究揭示了TIGIT的非经典功能：它不仅通过抑制免疫反应来限制组织损伤，还通过在T细胞中诱导组织生长因子Areg，积极促进组织再生。

11.Influenza vaccine based on AS03-adjuvanted chimeric HA induces long-lived stalk-specific plasma cells in bone marrow and lymph nodes of nonhuman primates

基于AS03佐剂的嵌合血凝素流感疫苗可诱导非人灵长类动物骨髓及淋巴结中的长效茎部特异性浆细胞

美国埃默里大学，埃默里疫苗中心 ，埃默里国家灵长类动物研究中心，微生物与免疫学系

Abstract

Current influenza vaccines face challenges due to antigenic evolution of the circulating virus and waning immunity in humans. Here we investigated the durability of humoral immunity induced by an influenza vaccine based on AS03-adjuvanted chimeric hemagglutinin (cHA) in nonhuman primates (NHPs). Two groups of NHPs received two doses of a seasonal quadrivalent influenza vaccine, followed by sequential immunization with split virus cHA vaccines cH8/1N1, and cH5/1N1. One group received cHA immunizations with AS03 adjuvant. We monitored serum antibodies and long-lived plasma cells in bone marrow for nearly 2 years after the final vaccination. cHA vaccines induced stalk-specific antibody responses. The addition of AS03 enhanced both the magnitude and durability of humoral immunity by establishing long-lived plasma cells in the bone marrow and lymph nodes for nearly 2 years. Passive transfer of NHP serum provided protection against challenge with heterologous influenza A virus strains in mice. This study highlights the potential of the AS03-adjuvanted chimeric HA vaccine strategy to provide durable and broadly protective humoral immunity.

当前流感疫苗面临病毒抗原持续演变与人体免疫力逐渐衰减的双重挑战。该研究旨在评估基于AS03佐剂的嵌合血凝素（cHA）流感疫苗在非人灵长类动物（NHPs）中诱导的体液免疫持久性。研究人员将NHPs分为两组，均先接种两剂季节性四价流感疫苗，随后序贯免疫裂解病毒cHA疫苗cH8/1N1和cH5/1N1，其中一组全程采用AS03佐剂配伍。通过近两年的持续监测发现，cHA疫苗可有效激发针对血凝素茎部区域的特异性抗体应答。特别值得注意的是，AS03佐剂的加入显著增强了免疫反应的强度与持久性——其通过在骨髓和淋巴结中建立可维持近两年的长效浆细胞群体，实现了持久的免疫保护。被动免疫实验进一步证实，接种疫苗的NHPs血清能够为小鼠提供对抗异源甲型流感病毒株的有效保护。该研究表明，基于AS03佐剂的嵌合HA疫苗策略在诱导持久、广谱的体液免疫方面具有重要应用前景。

12.Transcriptional and epigenetic targets of MEF2C in human microglia contribute to cellular functions related to autism risk and age-related disease

人类小胶质细胞中MEF2C的转录及表观遗传靶点可影响自闭症风险及年龄相关疾病的细胞功能

美国加州大学圣地亚哥分校，儿科／细胞与分子医学系，雷迪儿童基因组医学研究所

Abstract

MEF2C encodes a transcription factor that is critical in nervous system development. Here, to examine disease-associated functions of MEF2C in human microglia, we profiled microglia differentiated from isogenic MEF2C-haploinsufficient and MEF2C-knockout induced pluripotent stem cell lines. Complementary transcriptomic and functional analyses revealed that loss of MEF2C led to a hyperinflammatory phenotype with broad phagocytic impairment, lipid accumulation, lysosomal dysfunction and elevated basal inflammatory cytokine secretion. Genome-wide profiling of MEF2C-bound sites coupled with the active regulatory landscape enabled inference of its transcriptional functions and potential mechanisms for MEF2C-associated cellular functions. Transcriptomic and epigenetic approaches identified substantial overlap with idiopathic autism datasets, suggesting a broader role of human microglial MEF2C dysregulation in idiopathic autism. In a mouse xenotransplantation model, loss of MEF2C led to morphological, lysosomal and lipid abnormalities in human microglia in vivo. Together, these studies reveal mechanisms by which reduced microglial MEF2C could contribute to the development of neurological diseases.

MEF2C编码的转录因子在神经系统发育过程中起着关键作用。为深入探究MEF2C在人类小胶质细胞中的疾病相关功能，该研究利用等基因MEF2C单倍体不足及MEF2C敲除的诱导多能干细胞系分化获得小胶质细胞，并进行系统分析。整合转录组学与功能学研究显示，MEF2C缺失引发小胶质细胞出现过度炎症状态，表现为广泛的吞噬功能缺陷、脂质异常积聚、溶酶体功能障碍以及基础炎症因子分泌水平升高。通过全基因组范围的MEF2C结合位点分析，结合细胞活性调控图谱，揭示了MEF2C的转录调控功能及其介导细胞功能的潜在分子机制。转录组与表观遗传学分析进一步发现，MEF2C调控的靶点与特发性自闭症数据集存在显著重叠，表明人类小胶质细胞中MEF2C的功能紊乱可能在特发性自闭症中具有广泛的病理生理学意义。在小鼠异种移植模型中，MEF2C的缺失导致体内人类小胶质细胞出现明显的形态学异常、溶酶体功能紊乱和脂质代谢失调。综上所述，该研究系统阐明了小胶质细胞中MEF2C功能下降促进神经系统疾病发生发展的潜在机制，为理解自闭症风险及年龄相关疾病的细胞基础提供了新的见解。

13.Hypoxia induces histone clipping and H3K4me3 loss in neutrophil progenitors resulting in long-term impairment of neutrophil immunity

缺氧诱导中性粒细胞前体发生组蛋白剪切及H3K4me3缺失，导致中性粒细胞免疫功能长期受损

英国爱丁堡大学，炎症研究中心

Abstract

The long-term impact of systemic hypoxia resulting from acute respiratory distress syndrome (ARDS) on the function of short-lived innate immune cells is unclear. We show that patients 3–6 months after recovering from ARDS have persistently impaired circulating neutrophil effector functions and an increased susceptibility to secondary infections. These defects are linked to a widespread loss of the activating histone mark H3K4me3 in genes that are crucial for neutrophil activities. By studying healthy volunteers exposed to altitude-induced hypoxemia, we demonstrate that oxygen deprivation alone causes this long-term neutrophil reprogramming. Mechanistically, mouse models of systemic hypoxia reveal that persistent loss of H3K4me3 originates in proNeu and preNeu progenitors within the bone marrow and is linked to N-terminal histone 3 clipping, which removes the lysine residue for methylation. Thus, we present new evidence that systemic hypoxia initiates a sustained maladaptive reprogramming of neutrophil immunity by triggering histone 3 clipping and H3K4me3 loss in neutrophil progenitors.

急性呼吸窘迫综合症（ARDS）引起的全身性缺氧对短寿命先天免疫细胞功能的长期影响尚不明确。研究者发现，经历ARDS恢复后3至6个月的患者，其外周中性粒细胞效应功能持续受损，并且对继发感染的易感性增加。这些缺陷与在对中性粒细胞活动至关重要的基因中广泛丧失激活性组蛋白标记H3K4me3有关。通过研究暴露于高原引起的缺氧症的健康志愿者，研究证明仅仅是氧气剥夺就会导致这种长期的中性粒细胞重编程。从机制上看，小鼠全身性缺氧模型显示，H3K4me3的持续丧失起源于骨髓中的前中性粒细胞（proNeu）和预中性粒细胞（preNeu）前体，并且与组蛋白3 N端剪切相关，剪切去除了用于甲基化的赖氨酸残基。因此，该研究提供了新的证据，表明全身性缺氧通过触发组蛋白3剪切和H3K4me3丧失，启动了中性粒细胞前体的持续不良适应性重编程，从而导致中性粒细胞免疫功能的长期受损。

汇报人：厚媛

导师：赵宇

编辑：胡延昇、张宇阳