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Functional differences between rodent and human PD-1 linked to evolutionary divergence 啮齿类动物和人类PD-1的功能差异与进化分化有关
IF 17.6 1区 医学 Q1 IMMUNOLOGY Pub Date : 2025-01-03 DOI: 10.1126/sciimmunol.ads6295
Takeya Masubuchi, Lin Chen, Nimi Marcel, George A. Wen, Christine Caron, Jibin Zhang, Yunlong Zhao, Gerald P. Morris, Xu Chen, Stephen M. Hedrick, Li-Fan Lu, Chuan Wu, Zhengting Zou, Jack D. Bui, Enfu Hui
Mechanistic understanding of the inhibitory immunoreceptor PD-1 is largely based on mouse models, but human and mouse PD-1 share only 59.6% amino acid identity. Here, we found that human PD-1 is more inhibitory than mouse PD-1, owing to stronger interactions with the ligands PD-L1 and PD-L2 and more efficient recruitment of the effector phosphatase Shp2. In a mouse melanoma model with adoptively transferred T cells, humanization of a PD-1 intracellular domain disrupted the antitumor activity of CD8+ T cells and increased the magnitude of anti–PD-1 response. We identified a motif highly conserved across vertebrate PD-1 orthologs, absent in rodents, as a key determinant for differential Shp2 recruitment. Evolutionary analysis suggested that PD-1 underwent a rodent lineage–specific functional attenuation during evolution. Together, our study uncovers species-specific features of the PD-1 pathway, with implications for PD-1 evolution and differential anti–PD-(L)1 responses in mouse models and human patients.
对抑制性免疫受体PD-1的机制理解主要基于小鼠模型,但人和小鼠PD-1只有59.6%的氨基酸相同。在这里,我们发现人类PD-1比小鼠PD-1具有更强的抑制作用,这是因为人类PD-1与配体PD-L1和PD-L2的相互作用更强,并且更有效地募集了效应磷酸酶Shp2。在过继性转移T细胞的小鼠黑色素瘤模型中,PD-1细胞内结构域的人源化破坏了CD8 + T细胞的抗肿瘤活性,并增加了抗PD-1反应的强度。我们发现了一个在脊椎动物PD-1同源体中高度保守的基序,在啮齿动物中不存在,这是差异Shp2募集的关键决定因素。进化分析表明,PD-1在进化过程中经历了啮齿动物谱系特异性的功能衰减。总之,我们的研究揭示了PD-1通路的物种特异性特征,对PD-1进化和小鼠模型和人类患者的不同抗pd -(L)1反应具有重要意义。
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引用次数: 0
Extrasinusoidal macrophages are a distinct subset of immunologically active dural macrophages 窦外巨噬细胞是免疫活性硬膜巨噬细胞的一个独特亚群
IF 17.6 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-12-20 DOI: 10.1126/sciimmunol.adh1129
Lukas Amann, Amelie Fell, Gianni Monaco, Roman Sankowski, Huang Zie Quann Wu, Marta Joana Costa Jordão, Katharina Borst, Maximilian Fliegauf, Takahiro Masuda, Alberto Ardura-Fabregat, Neil Paterson, Elisa Nent, James Cook, Ori Staszewski, Omar Mossad, Thorsten Falk, Antoine Louveau, Igor Smirnov, Jonathan Kipnis, Tim Lämmermann, Marco Prinz
Although macrophages in the meningeal compartments of the central nervous system (CNS) have been comprehensively characterized under steady state, studying their contribution to physiological and pathological processes has been hindered by the lack of specific targeting tools in vivo. Recent findings have shown that the dural sinus and its adjacent lymphatic vessels act as a neuroimmune interface. However, the cellular and functional heterogeneity of extrasinusoidal dural macrophages outside this immune hub is not fully understood. Therefore, we comprehensively characterized these cells using single-cell transcriptomics, fate mapping, confocal imaging, clonal analysis, and transgenic mouse lines. Extrasinusoidal dural macrophages were distinct from leptomeningeal and CNS parenchymal macrophages in terms of their origin, expansion kinetics, and transcriptional profiles. During autoimmune neuroinflammation, extrasinusoidal dural macrophages performed efferocytosis of apoptotic granulocytes. Our results highlight a previously unappreciated myeloid cell diversity and provide insights into the brain’s innate immune system.
尽管中枢神经系统(CNS)脑膜室中的巨噬细胞已经在稳态下得到了全面的表征,但由于缺乏体内特异性靶向工具,研究它们对生理和病理过程的贡献一直受到阻碍。最近的研究结果表明,硬脑膜窦及其邻近的淋巴管作为神经免疫界面。然而,在这个免疫中枢外的窦外硬膜巨噬细胞的细胞和功能异质性尚不完全清楚。因此,我们使用单细胞转录组学、命运图谱、共聚焦成像、克隆分析和转基因小鼠系来全面表征这些细胞。脑膜窦外巨噬细胞在起源、扩张动力学和转录谱方面不同于脑膜轻脑膜和中枢神经系统实质巨噬细胞。在自身免疫性神经炎症期间,硬膜窦外巨噬细胞对凋亡的粒细胞进行efferocytic作用。我们的结果强调了以前未被认识到的骨髓细胞多样性,并提供了对大脑先天免疫系统的见解。
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引用次数: 0
NK cells restrain cytotoxic CD8+ T cells in the submandibular gland via PD-1–PD-L1 NK细胞通过PD-1-PD-L1抑制颌下腺细胞毒性CD8 + T细胞
IF 17.6 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-12-20 DOI: 10.1126/sciimmunol.adl2967
Samantha M. Borys, Shanelle P. Reilly, Ian Magill, David Zemmour, Laurent Brossay
The increasing use of anti–programmed cell death 1 (PD-1) immune checkpoint blockade has led to the emergence of immune-related adverse events (irAEs), including dysfunction of the submandibular gland (SMG). In this study, we investigated the immunoregulatory mechanism contributing to the susceptibility of the SMG to irAEs. We found that the SMGs of PD-1–deficient mice and anti–programmed cell death ligand 1 (PD-L1)–treated mice harbor an expanded population of CD8+ T cells. We demonstrate that natural killer (NK) cells expressing PD-L1 tightly regulate CD8+ T cells in the SMG. When this immunoregulation is disrupted, CD8+ T cells clonally expand and acquire a unique transcriptional profile consistent with T cell receptor (TCR) activation. These clonally expanded cells phenotypically overlapped with cytotoxic GzmK+ CD8+ T autoimmune cells identified in patients with primary Sjögren’s syndrome. Understanding how NK cells modulate CD8+ T cell activity in the SMG opens new avenues for preventing irAEs in patients undergoing checkpoint blockade therapies.
越来越多地使用抗程序性细胞死亡1 (PD-1)免疫检查点阻断导致免疫相关不良事件(irAEs)的出现,包括颌下腺(SMG)功能障碍。在这项研究中,我们研究了影响SMG对irAEs易感性的免疫调节机制。我们发现pd -1缺陷小鼠和抗程序性细胞死亡配体1 (PD-L1)处理小鼠的smg中含有更多的CD8 + T细胞。我们证明了表达PD-L1的自然杀伤细胞(NK)在SMG中紧密调节CD8 + T细胞。当这种免疫调节被破坏时,CD8 + T细胞克隆扩增并获得与T细胞受体(TCR)激活一致的独特转录谱。这些克隆扩增的细胞在表型上与原发性Sjögren综合征患者中发现的细胞毒性GzmK + CD8 + T自身免疫细胞重叠。了解NK细胞如何调节SMG中CD8 + T细胞的活性,为接受检查点阻断治疗的患者预防irae开辟了新的途径。
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引用次数: 0
Meeting report: Hidden links in autoimmunity 会议报告:自身免疫的隐藏联系
IF 17.6 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-12-20 DOI: 10.1126/sciimmunol.ads5884
Mireia Guerau-de-Arellano, Margaret A. Morris, Matthew A. Sherman, Thomas R. Esch
A NIAID-sponsored workshop was held in September 2024, where challenges to understanding common mechanisms in autoimmune disease were discussed as opportunities to advance research.
在2024年9月举行的niaid赞助的研讨会上,了解自身免疫性疾病常见机制的挑战被视为推进研究的机会。
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引用次数: 0
Erratum for the Research Article “GGNBP2 regulates MDA5 sensing triggered by self double-stranded RNA following loss of ADAR1 editing” by J. E. Heraud-Farlow et al. J. E. Heraud-Farlow等人的研究文章“GGNBP2调控ADAR1编辑缺失后自双链RNA触发的MDA5传感”的勘误。
IF 17.6 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-12-20 DOI: 10.1126/sciimmunol.adv0928
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引用次数: 0
Antigen-presenting cell activation requires intrinsic and extrinsic STING signaling after the phagocytosis of DNA-damaged cells 抗原呈递细胞的激活需要dna受损细胞吞噬后的内源性和外源性STING信号
IF 17.6 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-12-20 DOI: 10.1126/sciimmunol.adk7812
Seongji Park, Jeonghyun Ahn, Glen N. Barber
Antigen-presenting cells (APCs) are readily activated after phagocytosing infected or DNA-damaged cells but not normal apoptotic cells for reasons that are not well understood. Here, we demonstrate that after DNA damage events, cytosolic dsDNA species trigger intrinsic STING signaling and the production of key immunogenic proteins, including CCL5, which renders such cells capable of APC activation upon phagocytosis. These events involve the generation of immunogenic STING-inducible endosomal vesicles (SIEVEs) additionally comprising critical autophagy-associated proteins associated with cytosolic DNA species. After phagocytosis, extrinsic cGAS-STING signaling is triggered via engulfed, immunogenic transactivating DNA vesicles resulting in APC stimulation. These results help explain how APCs are predominantly activated by DNA-damaged or infected cells in contrast with normal apoptotic cells and suggest that reconstitution of STING signaling or key inducible genes in cGAS-STING–defective malignancies could substantially augment cancer immunotherapies.
抗原呈递细胞(APCs)在吞噬感染的或dna受损的细胞后很容易被激活,但在吞噬正常的凋亡细胞后却不被激活,原因尚不清楚。在这里,我们证明了DNA损伤事件后,细胞质dsDNA物种触发内在的STING信号和关键免疫原性蛋白的产生,包括CCL5,这使得这些细胞能够在吞噬时激活APC。这些事件涉及产生免疫原性sting诱导的内体囊泡(SIEVEs),另外包括与细胞质DNA物种相关的关键自噬相关蛋白。吞噬后,外源性cGAS-STING信号通过被吞噬的免疫原性反激活DNA囊泡触发,导致APC刺激。这些结果有助于解释与正常凋亡细胞相比,apc如何主要被dna损伤或感染细胞激活,并表明在cgas -STING缺陷恶性肿瘤中重建STING信号或关键诱导基因可以大大增强癌症免疫治疗。
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引用次数: 0
Crystal structure of the human LAG-3–HLA-DR1–peptide complex 人lag -3 - hla - dr1肽复合物的晶体结构
IF 17.6 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-12-13 DOI: 10.1126/sciimmunol.ads5122
Jan Petersen, Carmen Llerena, Bagher Golzarroshan, Camilla Faoro, Frederic Triebel, Jamie Rossjohn
T cell activity is governed by T cell receptor (TCR) signaling and constrained by immune checkpoint molecules, including programmed cell death protein 1 (PD-1), cytotoxic T lymphocyte–associated antigen 4 (CTLA-4), and lymphocyte activation gene 3 (LAG-3). The basis for how LAG-3 binds to human leukocyte antigen class II molecules (HLA-II) remains unknown. Here, we present the 3.4-angstrom crystal structure of a LAG-3–peptide–HLA-II complex and probe the energetics of the complex interface. Coincident with the HLA-II binding site of the ancestrally related, monomeric CD4 receptor, the LAG-3 homodimer laterally engages two HLA-II molecules via distal D1 domain surfaces, imposing a 38° angular offset. The LAG-3–HLA-II interface is discontinuous and lacks involvement of the D1 extra loop, a binding site for anti–LAG-3 therapeutic monoclonal antibodies. Upon HLA-II binding, intrinsically mobile loops of the LAG-3 molecule become ordered, with contact residues highly conserved across HLA-DR, DQ, and DP allomorphs. Our data provide a structural foundation for development of immunomodulatory approaches targeting LAG-3.
T细胞活性受T细胞受体(TCR)信号控制,并受免疫检查点分子的约束,包括程序性细胞死亡蛋白1 (PD-1)、细胞毒性T淋巴细胞相关抗原4 (CTLA-4)和淋巴细胞激活基因3 (LAG-3)。LAG-3如何与人类白细胞抗原II类分子(HLA-II)结合的基础仍然未知。在这里,我们展示了LAG-3-peptide-HLA-II配合物的3.4埃晶体结构,并探测了配合物界面的能量学。与祖先相关的单体CD4受体的HLA-II结合位点一致,LAG-3同二聚体通过远端D1结构域表面横向结合两个HLA-II分子,形成38°角偏移。LAG-3-HLA-II界面是不连续的,缺乏D1额外环的参与,D1额外环是抗lag -3治疗性单克隆抗体的结合位点。HLA-II结合后,LAG-3分子的内在移动环变得有序,接触残基在HLA-DR、DQ和DP异型中高度保守。我们的数据为开发针对LAG-3的免疫调节方法提供了结构基础。
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引用次数: 0
Asparagine availability controls germinal center B cell homeostasis 天冬酰胺可用性控制生发中心B细胞稳态
IF 17.6 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-12-13 DOI: 10.1126/sciimmunol.adl4613
Yavuz F. Yazicioglu, Eros Marin, Hana F. Andrew, Karolina Bentkowska, Julia C. Johnstone, Robert Mitchell, Zhi Yi Wong, Kristina Zec, Joannah Fergusson, Mariana Borsa, Iwan G. A. Raza, Moustafa Attar, Mohammad Ali, Barbara Kronsteiner, Izadora L. Furlani, James I. MacRae, Michael J. Devine, Mark Coles, Christopher D. Buckley, Susanna J. Dunachie, Alexander J. Clarke
The rapid proliferation of germinal center (GC) B cells requires metabolic reprogramming to meet energy demands, yet these metabolic processes are poorly understood. By integrating metabolomic and transcriptomic profiling of GC B cells, we identified that asparagine (Asn) metabolism was highly up-regulated and essential for B cell function. Asparagine synthetase (ASNS) was up-regulated after B cell activation through the integrated stress response sensor GCN2. Conditional deletion of Asns in B cells impaired survival and proliferation in low Asn conditions. Removal of environmental Asn by asparaginase or dietary restriction compromised the GC reaction, impairing affinity maturation and the humoral response to influenza infection. Furthermore, metabolic adaptation to the absence of Asn required ASNS, and oxidative phosphorylation, mitochondrial homeostasis, and synthesis of nucleotides were particularly sensitive to Asn deprivation. These findings demonstrate that Asn metabolism acts as a key regulator of B cell function and GC homeostasis.
生殖中心(GC)B细胞的快速增殖需要进行代谢重编程以满足能量需求,但人们对这些代谢过程知之甚少。通过整合 GC B 细胞的代谢组学和转录组学图谱,我们发现天冬酰胺(Asn)代谢高度上调,并且对 B 细胞功能至关重要。天冬酰胺合成酶(ASNS)在 B 细胞激活后通过综合应激反应传感器 GCN2 上调。在低天冬酰胺条件下,B细胞中条件性缺失的天冬酰胺合成酶(ASNS)会影响其存活和增殖。通过天冬酰胺酶或饮食限制去除环境中的Asn会影响GC反应,损害亲和力成熟和对流感感染的体液反应。此外,新陈代谢对缺乏 Asn 的适应需要 ASNS,氧化磷酸化、线粒体平衡和核苷酸合成对 Asn 剥夺特别敏感。这些发现表明,Asn 代谢是 B 细胞功能和 GC 平衡的关键调节因子。
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引用次数: 0
Immunopathology in human tuberculosis 人结核的免疫病理学
IF 17.6 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-12-13 DOI: 10.1126/sciimmunol.ado5951
Thomas J. Scriba, Mahlatse Maseeme, Carly Young, Laura Taylor, Alasdair J. Leslie
Mycobacterium tuberculosis (M.tb) is a bacterial pathogen that has evolved in humans, and its interactions with the host are complex and best studied in humans. Myriad immune pathways are involved in infection control, granuloma formation, and progression to tuberculosis (TB) disease. Inflammatory cells, such as macrophages, neutrophils, conventional and unconventional T cells, B cells, NK cells, and innate lymphoid cells, interact via cytokines, cell-cell communication, and eicosanoid signaling to contain or eliminate infection but can alternatively mediate pathological changes required for pathogen transmission. Clinical manifestations include pulmonary and extrapulmonary TB, as well as post-TB lung disease. Risk factors for TB progression, in turn, largely relate to immune status and, apart from traditional chemotherapy, interventions primarily target immune mechanisms, highlighting the critical role of immunopathology in TB. Maintaining a balance between effector mechanisms to achieve protective immunity and avoid detrimental inflammation is central to the immunopathogenesis of TB. Many research gaps remain and deserve prioritization to improve our understanding of human TB immunopathogenesis.
结核分枝杆菌(M.tb)是一种在人类中进化的细菌病原体,它与宿主的相互作用很复杂,在人类中研究得最好。感染控制、肉芽肿形成和结核(TB)疾病进展涉及无数免疫途径。炎症细胞,如巨噬细胞、中性粒细胞、常规和非常规T细胞、B细胞、NK细胞和先天淋巴样细胞,通过细胞因子、细胞间通讯和类二十蛋白信号相互作用来抑制或消除感染,但也可以介导病原体传播所需的病理变化。临床表现包括肺结核和肺外结核,以及结核后肺病。反过来,结核病进展的危险因素在很大程度上与免疫状态有关,除了传统的化疗外,干预措施主要针对免疫机制,这突出了免疫病理在结核病中的关键作用。维持效应机制之间的平衡以实现保护性免疫和避免有害炎症是结核病免疫发病机制的核心。许多研究空白仍然存在,值得优先考虑,以提高我们对人类结核病免疫发病机制的理解。
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引用次数: 0
Erratum for the Research Article “Acquisition of suppressive function by conventional T cells limits antitumor immunity upon Treg depletion” by S. K. Whiteside et al. S. K. Whiteside等人的研究文章《常规T细胞获得抑制功能限制Treg耗竭时的抗肿瘤免疫》的勘误。
IF 17.6 1区 医学 Q1 IMMUNOLOGY Pub Date : 2024-12-13 DOI: 10.1126/sciimmunol.adu6398
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引用次数: 0
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Science Immunology
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