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28.3。

本期文献导读将呈现2024年6月至2024年8月三个月内的主要刊物内容。

2024年6月，第25卷，第6期

《Nature immunology》2024年6月刊共发表article 12篇。

1. Affinity gaps among B cells in germinal centers drive the selection of MPER precursors

生发中心B细胞之间的亲和力差距驱动了MPER前体的选择

美国麻省理工学院、剑桥大学、哈佛大学拉根研究所

Current prophylactic human immunodeficiency virus 1 (HIV-1) vaccine research aims to elicit broadly neutralizing antibodies (bnAbs). Membrane-proximal external region (MPER)-targeting bnAbs, such as 10E8, provide exceptionally broad neutralization, but some are autoreactive. Here, we generated humanized B cell antigen receptor knock-in mouse models to test whether a series of germline-targeting immunogens could drive MPER-specific precursors toward bnAbs. We found that recruitment of 10E8 precursors to germinal centers (GCs) required a minimum affinity for germline-targeting immunogens, but the GC residency of MPER precursors was brief due to displacement by higher-affinity endogenous B cell competitors. Higher-affinity germline-targeting immunogens extended the GC residency of MPER precursors, but robust long-term GC residency and maturation were only observed for MPER-HuGL18, an MPER precursor cl908-777onotype able to close the affinity gap with endogenous B cell competitors in the GC. Thus, germline-targeting immunogens could induce MPER-targeting antibodies, and B cell residency in the GC may be regulated by a precursor–competitor affinity gap.

当前人类免疫缺陷病毒1型（HIV - 1）预防性疫苗的研究旨在诱导广泛中和抗体（bnAbs）。靶向膜近端外部区域（MPER）的 bnAbs，例如10E8，具有极其广泛的中和作用，但有些具有自身反应性。本研究利用人源化 B 细胞抗原受体敲入小鼠模型，以测试一系列胚系靶向的免疫原是否能驱动MPER特异性前体细胞向bnAbs转化。研究发现，10E8前体细胞募集到生发中心（GCs）需要对胚系靶向的免疫原具有最低亲和力，但由于被更高亲和力的内源性B细胞竞争者取代，MPER前体细胞在生发中心的停留时间短暂。更高亲和力的胚系靶向免疫原延长了 MPER 前体细胞在生发中心的停留时间，但只观察到MPER - HuGL18（一种能够在生发中心中缩小与内源性 B 细胞竞争者亲和力差距的MPER前体克隆型）显示出显著的长期GC驻留和成熟。因此，胚系靶向免疫原可以诱导针对MPER的抗体，并且B细胞在生发中心的停留可能受前体细胞 - 竞争者亲和力差距的调节。

2.Temporal dynamics and genomic programming of plasma cell fates

浆细胞命运的时间动态和基因组编程

美国宾夕法尼亚州匹兹堡大学系统免疫学中心

Affinity-matured plasma cells (PCs) of varying lifespans are generated through a germinal center (GC) response. The developmental dynamics and genomic programs of antigen-specific PC precursors remain to be elucidated. Here, using a model antigen in mice, we demonstrate biphasic generation of PC precursors, with those generating long-lived bone marrow PCs preferentially produced in the late phase of GC response. Clonal tracing using single-cell RNA sequencing and B cell antigen receptor sequencing in spleen and bone marrow compartments, coupled with adoptive transfer experiments, reveals a new PC transition state that gives rise to functionally competent PC precursors. The latter undergo clonal expansion, dependent on inducible expression of TIGIT. We propose a model for the proliferation and programming of precursors of long-lived PCs, based on extended antigen encounters in the GC.

通过生发中心（GC）反应会产生不同寿命的亲和成熟浆细胞（PCs）。抗原特异性PC前体细胞的发育动态和基因组程序仍有待阐明。本研究在小鼠中使用模型抗原，证明了PC前体细胞的双相生成，在GC反应的晚期，产生较长寿命骨髓PC的前体细胞比例较高。利用单细胞RNA测序和B细胞抗原受体测序在脾脏和骨髓中进行克隆追踪，以及体外转移实验，揭示了一种新的PC过渡状态，该状态产生了功能健全的PC前体细胞。后者依赖于TIGIT的诱导表达，经历克隆扩增。基于在GC中的延长抗原接触，本研究提出了一个长寿PC前体细胞增殖和编程的模型。

3.Cytokine polarized, alternatively activated bone marrow neutrophils drive axon regeneration

细胞因子极化激活骨髓中的中性粒细胞转化为激活状态从而促进轴突再生。

美国俄亥俄州立大学韦克斯纳医学中心神经内科

The adult central nervous system (CNS) possesses a limited capacity for self-repair. Severed CNS axons typically fail to regrow. There is an unmet need for treatments designed to enhance neuronal viability, facilitate axon regeneration and ultimately restore lost neurological functions to individuals affected by traumatic CNS injury, multiple sclerosis, stroke and other neurological disorders. Here we demonstrate that both mouse and human bone marrow neutrophils, when polarized with a combination of recombinant interleukin-4 (IL-4) and granulocyte colony-stimulating factor (G-CSF), upregulate alternative activation markers and produce an array of growth factors, thereby gaining the capacity to promote neurite outgrowth. Moreover, adoptive transfer of IL-4/G-CSF-polarized bone marrow neutrophils into experimental models of CNS injury triggered substantial axon regeneration within the optic nerve and spinal cord. These findings have far-reaching implications for the future development of autologous myeloid cell-based therapies that may bring us closer to effective solutions for reversing CNS damage.

成年中枢神经系统（CNS）的自我修复能力有限。通常情况下，被切断的CNS轴突无法再生。因此，迫切需要开发能够增强神经元存活能力、促进轴突再生并最终恢复因创伤性CNS损伤、多发性硬化症、中风和其他神经疾病而受损的神经功能的治疗方法。本研究发现，当小鼠和人类骨髓中性粒细胞被重组白细胞介素-4（IL-4）和粒细胞集落刺激因子（G-CSF）极化时，它们会上调替代激活标记并产生一系列生长因子，从而获得促进神经突起生长的能力。此外，将IL-4/G-CSF极化的骨髓中性粒细胞移植到CNS损伤的动物模型中，可诱导视神经和脊髓内大量轴突再生。这些发现对于未来开发自体髓系细胞疗法具有深远意义，可能更接近于开发出有效逆转CNS损伤的治疗方法。

4.Genetic variants in UNC93B1 predispose to childhood-onset systemic lupus erythematosus

UNC93b1的遗传变异易导致儿童发生系统性红斑狼疮

广州医科大学呼吸疾病国家重点实验室

Rare genetic variants in toll-like receptor 7 (TLR7) are known to cause lupus in humans and mice. UNC93B1 is a transmembrane protein that regulates TLR7 localization into endosomes. In the present study, we identify two new variants in UNC93B1 (T314A, located proximally to the TLR7 transmembrane domain, and V117L) in a cohort of east Asian patients with childhood-onset systemic lupus erythematosus. The V117L variant was associated with increased expression of type I interferons and NF-κB-dependent cytokines in patient plasma and immortalized B cells. THP-1 cells expressing the variant UNC93B1 alleles exhibited exaggerated responses to stimulation of TLR7/-8, but not TLR3 or TLR9, which could be inhibited by targeting the downstream signaling molecules, IRAK1/-4. Heterozygous mice expressing the orthologous Unc93b1V117L variant developed a spontaneous lupus-like disease that was more severe in homozygotes and again hyperresponsive to TLR7 stimulation. Together, this work formally identifies genetic variants in UNC93B1 that can predispose to childhood-onset systemic lupus erythematosus.

已知toll样受体7（TLR7）中的罕见遗传变异会导致人类和小鼠患狼疮。UNC93B1是一种调节TLR7定位到体内的跨膜蛋白。本研究在一组东亚儿童期发病的系统性红斑狼疮患者中鉴定出UNC93B1的两个新变异（T314A，位于TLR7跨膜结构域附近，以及 V117L）。V117L变异与患者血浆和永生化B细胞中I型干扰素和NF-κB依赖性细胞因子的表达增加有关。表达变异UNC93B1等位基因的THP-1细胞对TLR7 / -8的刺激表现出过度反应，但对TLR3或TLR9则无反应。这种过度反应可通过靶向下游信号分子IRAK1 / -4来抑制。表达同源Unc93b1V117L变异的杂合子小鼠出现了自发性狼疮样疾病，纯合子的病情更严重，并且对TLR7刺激再次过度反应。总之，这项工作正式确定了UNC93B1中的遗传变异可导致儿童期发病的系统性红斑狼疮。

5.An IFNγ-dependent immune–endocrine circuit lowers blood glucose to potentiate the innate antiviral immune response

依赖于 IFNγ 的免疫内分泌回路降低血糖以增强先天性抗病毒免疫应答

里耶卡大学医学院组织学和胚胎学系

Viral infection makes us feel sick as the immune system alters systemic metabolism to better fight the pathogen. The extent of these changes is relative to the severity of disease. Whether blood glucose is subject to infection-induced modulation is mostly unknown. Here we show that strong, nonlethal infection restricts systemic glucose availability, which promotes the antiviral type I interferon (IFN-I) response. Following viral infection, we find that IFNγ produced by γδ T cells stimulates pancreatic β cells to increase glucose-induced insulin release. Subsequently, hyperinsulinemia lessens hepatic glucose output. Glucose restriction enhances IFN-I production by curtailing lactate-mediated inhibition of IRF3 and NF-κB signaling. Induced hyperglycemia constrained IFN-I production and increased mortality upon infection. Our findings identify glucose restriction as a physiological mechanism to bring the body into a heightened state of responsiveness to viral pathogens. This immune–endocrine circuit is disrupted in hyperglycemia, possibly explaining why patients with diabetes are more susceptible to viral infection.

病毒感染会让我们感到不适，因为免疫系统会改变全身代谢，以更好地对抗病原体。这些变化的程度与疾病的严重程度有关。血糖是否受到感染诱导的调节在很大程度上尚不清楚。本研究发现强烈的、非致命性的感染会限制全身葡萄糖的可用性，这会促进抗病毒的I型干扰素（IFN-I）反应。在病毒感染后，由γδT细胞产生的 IFNγ会刺激胰腺β细胞增加葡萄糖诱导的胰岛素释放。随后，高胰岛素血症会减少肝脏的葡萄糖输出。葡萄糖限制通过减少乳酸对IRF3和 NF-κB信号的抑制来增强IFN-I的产生。诱导的高血糖会限制IFN-I的产生，并增加感染后的死亡率。研究结果确定了葡萄糖限制作为一种生理机制，可以使身体对病毒病原体的反应性增强。这种免疫－内分泌回路在高血糖状态下被破坏，这可能解释了为什么糖尿病患者更容易感染病毒。

6.Apolipoprotein E controls Dectin-1-dependent development of monocyte-derived alveolar macrophages upon pulmonary β-glucan-induced inflammatory adaptation

APOE控制着在肺部β-葡聚糖诱导的炎症适应过程中单核细胞衍生的肺泡巨噬细胞的发育，这种发育依赖于Dectin-1 。

德国波恩大学生命与医学科学研究所定量系统生物学

The lung is constantly exposed to the outside world and optimal adaptation of immune responses is crucial for efficient pathogen clearance. However, mechanisms that lead to lung-associated macrophages’ functional and developmental adaptation remain elusive. To reveal such mechanisms, we developed a reductionist model of environmental intranasal β-glucan exposure, allowing for the detailed interrogation of molecular mechanisms of pulmonary macrophage adaptation. Employing single-cell transcriptomics, high-dimensional imaging and flow cytometric characterization paired with in vivo and ex vivo challenge models, we reveal that pulmonary low-grade inflammation results in the development of apolipoprotein E (ApoE)-dependent monocyte-derived alveolar macrophages (ApoE+CD11b+ AMs). ApoE+CD11b+ AMs expressed high levels of CD11b, ApoE, Gpnmb and Ccl6, were glycolytic, highly phagocytic and produced large amounts of interleukin-6 upon restimulation. Functional differences were cell intrinsic, and myeloid cell-specific ApoE ablation inhibited Ly6c+ monocyte to ApoE+CD11b+ AM differentiation dependent on macrophage colony-stimulating factor secretion, promoting ApoE+CD11b+ AM cell death and thus impeding ApoE+CD11b+ AM maintenance. In vivo, β-glucan-elicited ApoE+CD11b+ AMs limited the bacterial burden of Legionella pneumophilia after infection and improved the disease outcome in vivo and ex vivo in a murine lung fibrosis model. Collectively these data identify ApoE+CD11b+ AMs generated upon environmental cues, under the control of ApoE signaling, as an essential determinant for lung adaptation enhancing tissue resilience.

肺始终暴露于外界环境，因此肺部免疫反应的最佳适应对于有效清除病原体至关重要。然而，导致肺相关巨噬细胞功能和发育适应的机制仍不清楚。为揭示此类机制，本研究开发了一种鼻内环境β-葡聚糖暴露的还原模型，以便详细探究肺巨噬细胞适应的分子机制。通过单细胞转录组学、高维成像和流式细胞术，结合体内和体外模型，发现肺部低度炎症影响载脂蛋白 E（ApoE）依赖性单核细胞衍生肺泡巨噬细胞（ApoE⁺ CD11b ⁺ AMs）的发育。ApoE ⁺ CD11b ⁺ AMs 表达高水平的CD11b、ApoE、Gpnmb和Ccl6，具有糖酵解能力，吞噬能力强，再次刺激时产生大量白细胞介素- 6。功能差异是细胞固有的，并且通过消除巨噬细胞特异性的ApoE，可以抑制Ly6c⁺单核细胞向ApoE⁺CD11b⁺ AM的分化，这依赖于巨噬细胞集落刺激因子的分泌，促进ApoE⁺CD11b⁺ AM细胞死亡，从而阻碍ApoE⁺CD11b⁺ AM的维持。体内实验表明，β-葡聚糖诱导的ApoE ⁺ CD11b ⁺ AMs 在感染后限制了嗜肺军团菌的细菌负荷，并在体内和体外小鼠肺纤维化模型中得到改善。总的来说，这些数据表明在环境线索下产生的、受ApoE信号控制的ApoE ⁺ CD11b ⁺ AMs 是增强肺适应和组织恢复力的关键决定因素。

7.Alternative platelet differentiation pathways initiated by nonhierarchically related hematopoietic stem cells

非等级相关造血干细胞启动的另类血小板分化途径

英国牛津大学造血干细胞生物学实验室

Rare multipotent stem cells replenish millions of blood cells per second through a time-consuming process, passing through multiple stages of increasingly lineage-restricted progenitors. Although insults to the blood-forming system highlight the need for more rapid blood replenishment from stem cells, established models of hematopoiesis implicate only one mandatory differentiation pathway for each blood cell lineage. Here, we establish a nonhierarchical relationship between distinct stem cells that replenish all blood cell lineages and stem cells that replenish almost exclusively platelets, a lineage essential for hemostasis and with important roles in both the innate and adaptive immune systems. These distinct stem cells use cellularly, molecularly and functionally separate pathways for the replenishment of molecularly distinct megakaryocyte-restricted progenitors: a slower steady-state multipotent pathway and a fast-track emergency-activated platelet-restricted pathway. These findings provide a framework for enhancing platelet replenishment in settings in which slow recovery of platelets remains a major clinical challenge.

罕见的多能干细胞通过一个耗时的过程每秒补充数百万个血细胞，要经历多个阶段，逐渐成为谱系受限的祖细胞。尽管造血系统受到的损害凸显了需要更快地从干细胞中补充血细胞的需求，但已建立的造血模型表明，每种血细胞谱系只有一种强制的分化途径。本研究确定了两种不同的干细胞之间的非等级关系：一种干细胞可以补充所有血细胞谱系，另一种干细胞几乎只补充血小板，血小板这一谱系对于止血至关重要，在先天和适应性免疫系统中都具有重要作用。这些不同的干细胞在细胞、分子和功能上采用不同的途径来补充分子上不同的巨核细胞祖细胞：一种是较慢的稳态多能途径，另一种是快速的紧急激活血小板受限途径。这些发现为在血小板恢复缓慢仍是主要临床挑战的情况下加强血小板补充提供了一个框架。

8.The BTLA–HVEM axis restricts CAR T cell efficacy in cancer

BTLA-HVEM 轴限制 CAR T 细胞在癌症中的功效

美国宾夕法尼亚州费城宾夕法尼亚大学生物工程系

The efficacy of T cell-based immunotherapies is limited by immunosuppressive pressures in the tumor microenvironment. Here we show a predominant role for the interaction between BTLA on effector T cells and HVEM (TNFRSF14) on immunosuppressive tumor microenvironment cells, namely regulatory T cells. High BTLA expression in chimeric antigen receptor (CAR) T cells correlated with poor clinical response to treatment. Therefore, we deleted BTLA in CAR T cells and show improved tumor control and persistence in models of lymphoma and solid malignancies. Mechanistically, BTLA inhibits CAR T cells via recruitment of tyrosine phosphatases SHP-1 and SHP-2, upon trans engagement with HVEM. BTLA knockout thus promotes CAR signaling and subsequently enhances effector function. Overall, these data indicate that the BTLA–HVEM axis is a crucial immune checkpoint in CAR T cell immunotherapy and warrants the use of strategies to overcome this barrier.

T细胞免疫疗法的疗效受到肿瘤微环境中的免疫抑制的限制。本研究揭示了一种主要作用机制，即效应T细胞上的 BTLA 与免疫抑制性肿瘤微环境细胞（即调节性T细胞）上的HVEM（TNFRSF14）之间的相互作用。嵌合抗原受体（CAR）T细胞中高 BTLA表达与对治疗的临床反应不佳相关。因此，本研究在CAR T细胞中敲除了BTLA，并在淋巴瘤和实体恶性肿瘤模型中观察到肿瘤控制效果和持久性得到改善。从机制上讲，BTLA 在与 HVEM 进行反式结合时，通过招募酪氨酸磷酸酶SHP-1和SHP-2来抑制CAR T细胞。因此，BTLA敲除促进了CAR信号传导，并增强了效应功能。总体而言，这些数据表明BTLA-HVEM轴是 CAR T 细胞免疫治疗中的关键免疫检查点，有必要采用策略来克服这一障碍。

9.The aged tumor microenvironment limits T cell control of cancer

老年肿瘤微环境限制了T细胞对肿瘤的控制

美国马萨诸塞州波士顿麻省总医院癌症研究中心

The etiology and effect of age-related immune dysfunction in cancer is not completely understood. Here we show that limited priming of CD8+ T cells in the aged tumor microenvironment (TME) outweighs cell-intrinsic defects in limiting tumor control. Increased tumor growth in aging is associated with reduced CD8+ T cell infiltration and function. Transfer of T cells from young mice does not restore tumor control in aged mice owing to rapid induction of T cell dysfunction. Cell-extrinsic signals in the aged TME drive a tumor-infiltrating age-associated dysfunctional (TTAD) cell state that is functionally, transcriptionally and epigenetically distinct from canonical T cell exhaustion. Altered natural killer cell–dendritic cell–CD8+ T cell cross-talk in aged tumors impairs T cell priming by conventional type 1 dendritic cells and promotes TTAD cell formation. Aged mice are thereby unable to benefit from therapeutic tumor vaccination. Critically, myeloid-targeted therapy to reinvigorate conventional type 1 dendritic cells can improve tumor control and restore CD8+ T cell immunity in aging.

与年龄相关的癌症免疫功能障碍的病因和影响尚未完全阐明。本研究发现老年肿瘤微环境（TME）中CD8⁺ T细胞的激活在限制肿瘤控制方面超过了细胞内在缺陷。衰老过程中肿瘤生长的增加与CD8⁺ T细胞浸润和功能的降低有关。由于快速诱导T细胞功能障碍，将年轻小鼠的T细胞转移到老年小鼠体内并不能恢复对肿瘤的控制。老年TME中的细胞外信号驱动了一种肿瘤浸润性与年龄相关的功能障碍（TTAD）细胞状态，其在功能、转录和表观遗传方面均不同于典型的T细胞耗竭。老年肿瘤中自然杀伤细胞 - 树突状细胞 - CD8⁺ T 细胞的互作变化，削弱了常规1型树突状细胞对T细胞的激活，并促进了TTAD细胞的形成。因此，老年小鼠无法从治疗性肿瘤疫苗接种中获益。关键是，针对髓系细胞的靶向治疗以重新激活常规1型树突状细胞，能够改善衰老过程中的肿瘤控制并恢复CD8⁺ T细胞免疫功能。

10.Antitumor progenitor exhausted CD8+ T cells are sustained by TCR engagement

抗肿瘤祖细胞耗竭CD8+ T细胞由TCR参与维持

美国田纳西州孟菲斯市圣犹大儿童研究医院免疫学系

The durability of an antitumor immune response is mediated in part by the persistence of progenitor exhausted CD8+ T cells (Tpex). Tpex serve as a resource for replenishing effector T cells and preserve their quantity through self-renewal. However, it is unknown how T cell receptor (TCR) engagement affects the self-renewal capacity of Tpex in settings of continued antigen exposure. Here we use a Lewis lung carcinoma model that elicits either optimal or attenuated TCR signaling in CD8+ T cells to show that formation of Tpex in tumor-draining lymph nodes and their intratumoral persistence is dependent on optimal TCR engagement. Notably, attenuated TCR stimulation accelerates the terminal differentiation of optimally primed Tpex. This TCR-reinforced Tpex development and self-renewal is coupled to proximal positioning to dendritic cells and epigenetic imprinting involving increased chromatin accessibility at Egr2 and Tcf1 target loci. Collectively, this study highlights the critical function of TCR engagement in sustaining Tpex during tumor progression.

抗肿瘤免疫反应的持久性在一定程度上由祖细胞耗竭型CD8⁺ T 细胞（Tpex）的持久性介导。Tpex作为补充效应T细胞的资源，并通过自我更新来维持其数量。然而，在持续抗原暴露的情况下，T细胞受体（TCR）的结合如何影响Tpex的自我更新能力尚不清楚。本研究使用一种Lewis肺癌模型，该模型在CD8⁺ T细胞中引发最佳或减弱的TCR信号，表明肿瘤引流淋巴结中Tpex的形成及其在肿瘤内的持久性取决于最佳的TCR激活。值得注意的是，减弱的TCR刺激会加速最佳激活的Tpex的终末分化。这种TCR强化的 Tpex 发育和自我更新与靠近树突状细胞的近端定位以及涉及Egr2 和Tcf1 靶基因座染色质可及性增加的表观遗传印记相关。总的来说，这项研究强调了TCR激活在肿瘤进展过程中维持 Tpex 的关键作用。

11.A single infusion of engineered long-lived and multifunctional T cells confers durable remission of asthma in mice

单次输注经工程改造的长寿且多功能的T细胞可使小鼠的哮喘持久缓解

清华大学基础医学院免疫学研究所分子肿瘤学国家重点实验室

Asthma, the most prevalent respiratory disease, affects more than 300 million people and causes more than 250,000 deaths annually. Type 2-high asthma is characterized by interleukin (IL)-5-driven eosinophilia, along with airway inflammation and remodeling caused by IL-4 and IL-13. Here we utilize IL-5 as the targeting domain and deplete BCOR and ZC3H12A to engineer long-lived chimeric antigen receptor (CAR) T cells that can eradicate eosinophils. We call these cells immortal-like and functional IL-5 CAR T cells (5T_IF) cells. 5T_IF cells were further modified to secrete an IL-4 mutein that blocks IL-4 and IL-13 signaling, designated as 5T_IF4 cells. In asthma models, a single infusion of 5T_IF4 cells in fully immunocompetent mice, without any conditioning regimen, led to sustained repression of lung inflammation and alleviation of asthmatic symptoms. These data show that asthma, a common chronic disease, can be pushed into long-term remission with a single dose of long-lived CAR T cells.

哮喘是最常见的呼吸系统疾病，影响着超过3亿人，每年导致超过25万人死亡。2型高哮喘的特征是由白细胞介素（IL）-5驱动的嗜酸性粒细胞增多，以及由IL - 4和IL - 13引起的气道炎症和重塑。本研究利用IL - 5作为靶向域，并通过去除BCOR和ZC3H12A来设计出能够根除嗜酸性粒细胞的长寿命嵌合抗原受体（CAR）T细胞。将这些细胞称为永生样功能性IL - 5 CAR T细胞（5TIF）细胞。5TIF细胞进一步被修饰为分泌一种能阻断IL - 4和IL - 13信号的IL - 4突变体，被命名为5TIF4细胞。在哮喘模型中，在免疫功能完全健全的小鼠中无需任何预处理方案，仅单次输注5TIF4细胞，就能持续抑制肺部炎症并减轻哮喘症状。这些数据表明，哮喘这种常见的慢性疾病，只需通过一次长寿CAR T细胞治疗就能进入长期缓解状态。

12.Vaccination induces broadly neutralizing antibody precursors to HIV gp41

疫苗接种诱导出针对HIV gp41的广泛中和抗体前体

加利福尼亚州免疫学和微生物学系

A key barrier to the development of vaccines that induce broadly neutralizing antibodies (bnAbs) against human immunodeficiency virus (HIV) and other viruses of high antigenic diversity is the design of priming immunogens that induce rare bnAb-precursor B cells. The high neutralization breadth of the HIV bnAb 10E8 makes elicitation of 10E8-class bnAbs desirable; however, the recessed epitope within gp41 makes envelope trimers poor priming immunogens and requires that 10E8-class bnAbs possess a long heavy chain complementarity determining region 3 (HCDR3) with a specific binding motif. We developed germline-targeting epitope scaffolds with affinity for 10E8-class precursors and engineered nanoparticles for multivalent display. Scaffolds exhibited epitope structural mimicry and bound bnAb-precursor human naive B cells in ex vivo screens, protein nanoparticles induced bnAb-precursor responses in stringent mouse models and rhesus macaques, and mRNA-encoded nanoparticles triggered similar responses in mice. Thus, germline-targeting epitope scaffold nanoparticles can elicit rare bnAb-precursor B cells with predefined binding specificities and HCDR3 features.

诱导广泛中和抗体（bnAbs）对抗人类免疫缺陷病毒（HIV）和其他高抗原多样性病毒的疫苗开发的一个关键障碍是设计能够诱导罕见的bnAbs前体B细胞的启动免疫原的。HIV bnAb 10E8的高中和广度使得诱导10E8类bnAbs成为理想选择。然而，gp41内的隐性表位使得包膜三聚体不适合启动免疫原，并且需要10E8类bnAbs具有特定结合位点的长重链互补决定区3 (HCDR3)。本研究开发了对10E8类前体细胞具有亲和力的种系靶向表位支架，并设计了用于多价展示的纳米颗粒。支架在体外筛选中表现出表位结构模拟，并结合bnAb前体人类初始B细胞，蛋白质纳米颗粒在小鼠模型和恒河猴中诱导bnAb前体反应，而mRNA编码的纳米颗粒在小鼠中引发类似反应。因此，种系靶向表位支架纳米颗粒能够引发具有预先定义的结合特异性和HCDR3特征的罕见bnAb前体B细胞。

2024年7月，第25卷，第7期

《Nature immunology》2024年7月刊共发表review 1 篇；article 12篇。

1.Nociceptor-immune interactomes reveal insult-specific immune signatures of pain

伤害感受器-免疫相互作用体揭示疼痛的损伤特异性免疫特征

美国马萨诸塞州波士顿哈佛医学院系统药理学实验室

Inflammatory pain results from the heightened sensitivity and reduced threshold of nociceptor sensory neurons due to exposure to inflammatory mediators. However, the cellular and transcriptional diversity of immune cell and sensory neuron types makes it challenging to decipher the immune mechanisms underlying pain. Here we used single-cell transcriptomics to determine the immune gene signatures associated with pain development in three skin inflammatory pain models in mice: zymosan injection, skin incision and ultraviolet burn. We found that macrophage and neutrophil recruitment closely mirrored the kinetics of pain development and identified cell-type-specific transcriptional programs associated with pain and its resolution. Using a comprehensive list of potential interactions mediated by receptors, ligands, ion channels and metabolites to generate injury-specific neuroimmune interactomes, we also uncovered that thrombospondin-1 upregulated by immune cells upon injury inhibited nociceptor sensitization. This study lays the groundwork for identifying the neuroimmune axes that modulate pain in diverse disease contexts.

炎症性疼痛是由于炎症介质的作用导致伤害感受器感觉神经元的敏感性增加和阈值降低。然而，免疫细胞和感觉神经元类型的细胞和转录多样性使得解析疼痛背后的免疫机制变得具有挑战性。本研究使用单细胞转录组学在小鼠三种皮肤炎症性疼痛模型（酵母聚糖注射、皮肤切口和紫外线烧伤）中确定与疼痛发展相关的免疫基因特征。结果发现，巨噬细胞和中性粒细胞的募集与疼痛发展的动态紧密对应，并识别了与疼痛及其消退相关的细胞类型特异性转录程序。利用由受体、配体、离子通道和代谢物介导的潜在相互作用的全面列表来生成损伤特异性的神经免疫互作组，本研究还发现损伤后免疫细胞上调的血小板反应蛋白-1抑制了伤害感受器的敏感化。这项研究为识别在多种疾病背景下调节疼痛的神经免疫轴奠定了基础。

2.Vaccination reduces central nervous system IL-1βIL-1 and memory deficits after COVID-19 in mice

疫苗接种可减少小鼠COVID-19后中枢神经系统IL-1βIL-1和记忆缺陷

华盛顿大学医学院神经免疫学和神经传染病中心

Up to 25% of individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibit postacute cognitive sequelae. Although millions of cases of coronavirus disease 2019 (COVID-19)-mediated memory dysfunction are accumulating worldwide, the underlying mechanisms and how vaccination lowers risk are unknown. Interleukin-1 (IL-1), a key component of innate immune defense against SARS-CoV-2 infection, is elevated in the hippocampi of individuals with COVID-19. Here we show that intranasal infection of C57BL/6J mice with SARS-CoV-2 Beta variant leads to central nervous system infiltration of Ly6Chi monocytes and microglial activation. Accordingly, SARS-CoV-2, but not H1N1 influenza virus, increases levels of brain IL-1β and induces persistent IL-1R1-mediated loss of hippocampal neurogenesis, which promotes postacute cognitive deficits. Vaccination with a low dose of adenoviral-vectored spike protein prevents hippocampal production of IL-1β during breakthrough SARS-CoV-2 infection, loss of neurogenesis and subsequent memory deficits. Our study identifies IL-1β as one potential mechanism driving SARS-CoV-2-induced cognitive impairment in a new mouse model that is prevented by vaccination.

多达25%感染严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的个体表现出急性后期认知后遗症。尽管全球范围内有数百万例由COVID-19引起的记忆功能障碍病例，但潜在机制以及疫苗如何降低风险尚不清楚。白细胞介素-1（IL-1）是针对SARS-CoV-2感染的先天免疫防御的关键组成部分，在COVID-19患者的海马体中升高。本研究用SARS-CoV-2 Beta 变体对C57BL/6J小鼠进行鼻内感染会导致中枢神经系统中Ly6C^hi单核细胞浸润和小胶质细胞活化。相应地，SARS-CoV-2，而非H1N1流感病毒，会增加大脑中IL-1β的水平，并诱导持续的IL-1R1介导的海马神经发生缺失，从而促进急性后期认知缺陷。用低剂量腺病毒载体刺突蛋白疫苗接种可防止突破性SARS-CoV-2感染期间海马体产生IL-1β、神经发生缺失以及随后的记忆缺陷。本研究在一个新的小鼠模型中确定IL-1β是驱动 SARS-CoV-2引起认知障碍的一种潜在机制，并可通过疫苗接种来预防。

3.Eomes expression identifies the early bone marrow precursor to classical NK cells

Eomes表达鉴定了经典NK细胞的早期骨髓前体

美国伊利诺伊州芝加哥大学免疫学委员会

Natural killer (NK) cells traffic through the blood and mount cytolytic and interferon-γ (IFNγ)-focused responses to intracellular pathogens and tumors. Type 1 innate lymphoid cells (ILC1s) also produce type 1 cytokines but reside in tissues and are not cytotoxic. Whether these differences reflect discrete lineages or distinct states of a common cell type is not understood. Using single-cell RNA sequencing and flow cytometry, we focused on populations of TCF7+ cells that contained precursors for NK cells and ILC1s and identified a subset of bone marrow lineage-negative NK receptor-negative cells that expressed the transcription factor Eomes, termed EomeshiNKneg cells. Transfer of EomeshiNKneg cells into Rag2−/−Il2rg−/− recipients generated functional NK cells capable of preventing metastatic disease. By contrast, transfer of PLZF+ ILC precursors generated a mixture of ILC1s, ILC2s and ILC3s that lacked cytotoxic potential. These findings identified EomeshiNKneg cells as the bone marrow precursor to classical NK cells and demonstrated that the NK and ILC1 lineages diverged early during development.

自然杀伤（NK）细胞在血液中迁移，并对细胞内病原体和肿瘤发起细胞溶解和以干扰素－γ（IFNγ）为重点的反应。1型固有淋巴样细胞（ILC1s）也产生1型细胞因子，但存在于组织中且无细胞毒性。这些差异是反映不同的谱系还是同一细胞类型的不同状态尚不清楚。通过单细胞RNA测序和流式细胞术，本研究重点关注包含NK细胞和ILC1s前体细胞的TCF7⁺ 细胞群，并鉴定了一个骨髓谱系阴性、NK受体阴性、表达转录因子Eomes的细胞子集，称为 Eomes^hiNK_neg 细胞。将 Eomes^hiNK_neg 细胞过继到Rag2−/−Il2rg−/−受体中，产生了能够预防转移性疾病的功能性NK细胞。相比之下，将PLZF⁺ ILC前体细胞转移后产生了缺乏细胞毒性潜能的ILC1s、ILC2s和ILC3s的混合物。这些发现确定了Eomes^hiNK_neg细胞是经典 NK细胞的骨髓前体细胞，并表明NK和ILC1谱系在发育早期就出现了分化。

4.Distinct developmental pathways generate functionally distinct populations of natural killer cells

不同的发育途径产生功能不同的自然杀伤细胞群

美国国家癌症研究中心基因组完整性实验室

Natural killer (NK) cells function by eliminating virus-infected or tumor cells. Here we identified an NK-lineage-biased progenitor population, referred to as early NK progenitors (ENKPs), which developed into NK cells independently of common precursors for innate lymphoid cells (ILCPs). ENKP-derived NK cells (ENKP_NK cells) and ILCP-derived NK cells (ILCP_NK cells) were transcriptionally different. We devised combinations of surface markers that identified highly enriched ENKP_NK and ILCP_NK cell populations in wild-type mice. Furthermore, Ly49H+ NK cells that responded to mouse cytomegalovirus infection primarily developed from ENKPs, whereas ILCP_NK cells were better IFNγ producers after infection with Salmonella and herpes simplex virus. Human CD56dim and CD56bright NK cells were transcriptionally similar to ENKP_NK cells and ILCP_NK cells, respectively. Our findings establish the existence of two pathways of NK cell development that generate functionally distinct NK cell subsets in mice and further suggest these pathways may be conserved in humans.

自然杀伤（NK）细胞通过清除病毒感染或肿瘤细胞发挥作用。本研究鉴定出了一种偏向NK 谱系的祖细胞群，称为早期NK祖细胞（ENKPs），其独立于先天性淋巴细胞（ILCPs）的共同前体发育为NK细胞。ENKP衍生的NK细胞（ENKP_NK细胞）和ILCP衍生的NK细胞（ILCP_NK细胞）在转录水平上有所不同。本研究设计了表面标志物的组合，以在野生型小鼠中鉴定出高度富集的ENKP_NK和ILCP_NK细胞群体。此外，对小鼠巨细胞病毒感染起主要应答作用的Ly49H⁺ NK细胞主要由ENKPs 发育而来，而ILCP_NK细胞在感染沙门氏菌和单纯疱疹病毒后能更好地产生IFNγ。人类的 CD56^dim 和 CD56^bright NK细胞在转录上分别类似于 ENKP_NK细胞和 ILCP_NK细胞。研究结果确立了在小鼠中存在两种NK细胞发育途径，它们产生功能不同的NK细胞亚群，并进一步表明这些途径在人类中可能是保守的。

5.Cell shape sensing licenses dendritic cells for homeostatic migration to lymph nodes

细胞形状感应促使树突状细胞向淋巴结的稳态迁移

法国巴黎大学居里研究所免疫与癌症中心

Immune cells experience large cell shape changes during environmental patrolling because of the physical constraints that they encounter while migrating through tissues. These cells can adapt to such deformation events using dedicated shape-sensing pathways. However, how shape sensing affects immune cell function is mostly unknown. Here, we identify a shape-sensing mechanism that increases the expression of the chemokine receptor CCR7 and guides dendritic cell migration from peripheral tissues to lymph nodes at steady state. This mechanism relies on the lipid metabolism enzyme cPLA2, requires nuclear envelope tensioning and is finely tuned by the ARP2/3 actin nucleation complex. We also show that this shape-sensing axis reprograms dendritic cell transcription by activating an IKKβ–NF-κB-dependent pathway known to control their tolerogenic potential. These results indicate that cell shape changes experienced by immune cells can define their migratory behavior and immunoregulatory properties and reveal a contribution of the physical properties of tissues to adaptive immunity.

在环境巡逻期间，免疫细胞由于在通过组织迁移时遇到的物理限制而经历大的细胞形状变化。这些细胞可以利用专门的形状感应途径适应此类变形事件。然而，形状感应如何影响免疫细胞功能在很大程度上是未知的。本研究确定了一种形状感应机制，该机制增加了趋化因子受体CCR7的表达，并在稳态下引导树突状细胞从外周组织迁移到淋巴结。这种机制依赖于脂质代谢酶cPLA2，需要核膜张力，并由ARP2/3肌动蛋白成核复合物精细调节。本研究还发现，这种形状感应轴通过激活已知控制树突状细胞免疫耐受潜力的IKKβ-NF-κB依赖性途径来重新编程树突状细胞的转录。这些结果表明，免疫细胞经历的细胞形状变化可以定义其迁移行为和免疫调节特性，并揭示了组织的物理特性对适应性免疫的贡献。

6.Perinatal thymic-derived CD8αβ-expressing γδ T cells are innate IFN-γ producers that expand in IL-7R–STAT5B-driven neoplasms

围产期胸腺源性达CD8αβ的γδT细胞是先天性IFN-γ产生细胞，在IL-7R-STAT5B驱动的肿瘤中扩增

英国伦敦玛丽皇后大学巴兹和医学院

The contribution of γδ T cells to immune responses is associated with rapid secretion of interferon-γ (IFN-γ). Here, we show a perinatal thymic wave of innate IFN-γ-producing γδ T cells that express CD8αβ heterodimers and expand in preclinical models of infection and cancer. Optimal CD8αβ+ γδ T cell development is directed by low T cell receptor signaling and through provision of interleukin (IL)-4 and IL-7. This population is pathologically relevant as overactive, or constitutive, IL-7R–STAT5B signaling promotes a supraphysiological accumulation of CD8αβ+ γδ T cells in the thymus and peripheral lymphoid organs in two mouse models of T cell neoplasia. Likewise, CD8αβ+ γδ T cells define a distinct subset of human T cell acute lymphoblastic leukemia pediatric patients. This work characterizes the normal and malignant development of CD8αβ+ γδ T cells that are enriched in early life and contribute to innate IFN-γ responses to infection and cancer.

γδT细胞对免疫反应的贡献与干扰素－γ（IFN-γ）快速分泌有关。本研究展示了一种围产期胸腺内先天性产生IFN-γ的γδT细胞，它们表达CD8αβ异二聚体，并在感染和癌症的临床前模型中扩增。最佳的CD8αβ⁺ γδT细胞发育由低T细胞受体信号传导引导，并通过提供白细胞介素（IL）-4 和 IL-7 实现。这一群体在病理学上具有相关性，因为过度活跃或组成性的IL-7R–STAT5B信号传导在两种T细胞肿瘤小鼠模型中促进了胸腺和外周淋巴器官中 CD8αβ⁺ γδT细胞的超生理积累。同样，CD8αβ⁺ γδT细胞定义了人类 T 细胞急性淋巴细胞白血病儿童患者的一个独特子集。这项工作描述了在生命早期丰富且有助于对感染和癌症的先天性 IFN-γ应答的 CD8αβ+ γδT 细胞的正常和恶性发育情况。

7.Transcriptomic analysis of intestine following administration of a transglutaminase 2 inhibitor to prevent gluten-induced intestinal damage in celiac disease

肠道转录组学分析：使用转谷氨酰胺酶2抑制剂预防乳糜泻中麸质诱导的肠道损伤

芬兰坦佩雷大学医院医学与健康技术学院的乳糜泻疾病研究中心

Transglutaminase 2 (TG2) plays a pivotal role in the pathogenesis of celiac disease (CeD) by deamidating dietary gluten peptides, which facilitates antigenic presentation and a strong anti-gluten T cell response. Here, we elucidate the molecular mechanisms underlying the efficacy of the TG2 inhibitor ZED1227 by performing transcriptional analysis of duodenal biopsies from individuals with CeD on a long-term gluten-free diet before and after a 6-week gluten challenge combined with 100 mg per day ZED1227 or placebo. At the transcriptome level, orally administered ZED1227 effectively prevented gluten-induced intestinal damage and inflammation, providing molecular-level evidence that TG2 inhibition is an effective strategy for treating CeD. ZED1227 treatment preserved transcriptome signatures associated with mucosal morphology, inflammation, cell differentiation and nutrient absorption to the level of the gluten-free diet group. Nearly half of the gluten-induced gene expression changes in CeD were associated with the epithelial interferon-γ response. Moreover, data suggest that deamidated gluten-induced adaptive immunity is a sufficient step to set the stage for CeD pathogenesis. Our results, with the limited sample size, also suggest that individuals with CeD might benefit from an HLA-DQ2/HLA-DQ8 stratification based on gene doses to maximally eliminate the interferon-γ-induced mucosal damage triggered by gluten.

转谷氨酰胺酶 2（TG2）通过对膳食中的谷蛋白肽进行脱酰胺作用，促进了抗原呈递和强烈的抗谷蛋白 T 细胞反应，在乳糜泻（CeD）的发病机制中发挥关键作用。本研究通过对长期采用无麸质饮食的乳糜泻患者在进行为期 6 周的麸质激发（同时每日服用 100 毫克 ZED1227 或安慰剂）前后的十二指肠活检样本进行转录分析，阐明了TG2抑制剂 ZED1227的疗效背后的分子机制。在转录组水平上，口服ZED1227有效地预防了麸质诱导的肠道损伤和炎症，提供了分子水平的证据，表明抑制TG2是治疗CeD的有效策略。ZED1227 治疗将与黏膜形态、炎症、细胞分化和营养吸收相关的转录组特征维持在无麸质饮食组的水平。CeD中近一半的麸质诱导的基因表达变化与上皮干扰素－γ反应有关。此外，数据表明，脱酰胺化的麸质诱导的适应性免疫是为CeD发病机制奠定基础的充分步骤。研究结果（样本量有限）还表明，CeD患者可能受益于基于基因剂量的 HLA-DQ2/HLA-DQ8 分层，以最大程度地消除麸质触发的干扰素-γ诱导的黏膜损伤。

8. Title: Stem-like T cells are associated with the pathogenesis of ulcerative colitis in humans

干细胞样T细胞与人类溃疡性结肠炎的发病机制有关

美国纽约爱因斯坦医学院病理学系

To understand the role of T cells in the pathogenesis of ulcerative colitis (UC), we analyzed colonic T cells isolated from patients with UC and controls. Here we identified colonic CD4+ and CD8+ T lymphocyte subsets with gene expression profiles resembling stem-like progenitors, previously reported in several mouse models of autoimmune disease. Stem-like T cells were increased in inflamed areas compared to non-inflamed regions from the same patients. Furthermore, TCR sequence analysis indicated stem-like T cells were clonally related to proinflammatory T cells, suggesting their involvement in sustaining effectors that drive inflammation. Using an adoptive transfer colitis model in mice, we demonstrated that CD4+ T cells deficient in either BCL-6 or TCF1, transcription factors that promote T cell stemness, had decreased colon T cells and diminished pathogenicity. Our results establish a strong association between stem-like T cell populations and UC pathogenesis, highlighting the potential of targeting this population to improve clinical outcomes.

为了解T细胞在溃疡性结肠炎（UC）发病机制中的作用，本研究分析了来自UC患者和对照组的结肠T细胞，鉴定出了结肠CD4⁺和CD8⁺ T淋巴细胞亚群，其基因表达谱类似于先前在几种自身免疫性疾病小鼠模型中报道的干细胞样祖细胞。与同一患者的非炎症区域相比，炎症区域的干细胞样T细胞有所增加。此外，TCR序列分析表明，干细胞样T细胞与促炎性T细胞克隆相关，这表明它们参与了维持驱动炎症的效应细胞。在小鼠过继转移结肠炎模型中，本研究证明了缺乏促进 T 细胞干性的转录因子BCL-6或TCF1的CD4⁺ T细胞，其结肠T细胞减少且致病性降低。研究结果确立了干细胞样T细胞群与UC发病机制之间的紧密关联，突出了针对这一群体以改善临床结果的潜力。

9.Distinct SIV-specific CD8+ T cells in the lymph node exhibit simultaneous effector and stem-like profiles and are associated with limited SIV persistence

淋巴结中不同的SIV特异性CD8+ T细胞同时表现出效应和干性特征，并与有限的SIV持久性相关。

美国埃默里国家灵长类动物研究中心微生物学和免疫学

Human immunodeficiency virus (HIV) cure efforts are increasingly focused on harnessing CD8+ T cell functions, which requires a deeper understanding of CD8+ T cells promoting HIV control. Here we identifiy an antigen-responsive TOXhiTCF1+CD39+CD8+ T cell population with high expression of inhibitory receptors and low expression of canonical cytolytic molecules. Transcriptional analysis of simian immunodeficiency virus (SIV)-specific CD8+ T cells and proteomic analysis of purified CD8+ T cell subsets identified TOXhiTCF1+CD39+CD8+ T cells as intermediate effectors that retained stem-like features with a lineage relationship with terminal effector T cells. TOXhiTCF1+CD39+CD8+ T cells were found at higher frequency than TCF1−CD39+CD8+ T cells in follicular microenvironments and were preferentially located in proximity of SIV-RNA+ cells. Their frequency was associated with reduced plasma viremia and lower SIV reservoir size. Highly similar TOXhiTCF1+CD39+CD8+ T cells were detected in lymph nodes from antiretroviral therapy-naive and antiretroviral therapy-suppressed people living with HIV, suggesting this population of CD8+ T cells contributes to limiting SIV and HIV persistence.

人类免疫缺陷病毒（HIV）的治愈工作越来越侧重于利用CD8⁺ T细胞的功能，这需要更深入地了解促进HIV控制的CD8⁺ T细胞。本研究鉴定出一种抗原反应性的TOX^hiTCF1⁺ CD39⁺ CD8⁺ T细胞群体，其抑制性受体高表达，典型的细胞溶解分子低表达。对猴免疫缺陷病毒（SIV）特异性CD8⁺ T细胞的转录分析以及对纯化的CD8⁺ T细胞亚群的蛋白质组学分析发现，TOX^hiTCF1⁺ CD39⁺ CD8⁺ T细胞为保留了干细胞样特征的中间效应细胞，与终末效应T细胞存在谱系关系。在滤泡微环境中，TOX^hiTCF1⁺ CD39⁺ CD8⁺ T细胞的频率高于 TCF1^- CD39⁺ CD8⁺ T 细胞，并且优先位于SIV^- RNA ⁺细胞附近。它们的频率与血浆病毒血症的降低和SIV病毒库规模的缩小有关。在未经抗逆转录病毒治疗和接受抗逆转录病毒治疗抑制的HIV感染者的淋巴结中检测到高度相似的TOX^hiTCF1⁺ CD39⁺ CD8⁺ T细胞，表明这一CD8⁺ T细胞群体有助于限制SIV和HIV的持续存在。

10.Circadian control of tumor immunosuppression affects efficacy of immune checkpoint blockade

肿瘤免疫抑制的昼夜节律控制影响免疫检查点封锁的效果

美国加州大学欧文分校生物化学系

The circadian clock is a critical regulator of immunity, and this circadian control of immune modulation has an essential function in host defense and tumor immunosurveillance. Here we use a single-cell RNA sequencing approach and a genetic model of colorectal cancer to identify clock-dependent changes to the immune landscape that control the abundance of immunosuppressive cells and consequent suppression of cytotoxic CD8+ T cells. Of these immunosuppressive cell types, PD-L1-expressing myeloid-derived suppressor cells (MDSCs) peak in abundance in a rhythmic manner. Disruption of the epithelial cell clock regulates the secretion of cytokines that promote heightened inflammation, recruitment of neutrophils and the subsequent development of MDSCs. We also show that time-of-day anti-PD-L1 delivery is most effective when synchronized with the abundance of immunosuppressive MDSCs. Collectively, these data indicate that circadian gating of tumor immunosuppression informs the timing and efficacy of immune checkpoint inhibitors.

生物钟是免疫的关键调节器，生物钟对免疫调节的控制在宿主防御和肿瘤免疫监视中具有重要作用。本研究使用单细胞RNA测序方法和结直肠癌的遗传模型，来确定生物钟控制的免疫图谱变化，这些变化控制着免疫抑制细胞的丰度以及随之而来的细胞毒性CD8⁺ T细胞的抑制。在这些免疫抑制细胞类型中，表达PD - L1的髓源性抑制细胞（MDSCs）的丰度呈节律性高峰。上皮细胞生物钟的破坏调节了细胞因子的分泌，促进了炎症加剧、中性粒细胞的募集以及随后MDSCs的发展。当与免疫抑制性MDSCs的丰度同步时，每日不同时间给予抗PD - L1治疗最有效。总的来说，这些数据表明肿瘤免疫抑制的生物钟调控为免疫检查点抑制剂的给药时间和疗效提供了信息。

11.Genetic and environmental interactions contribute to immune variation in rewilded mice

遗传和环境的相互作用导致了野生小鼠的免疫变异

美国国立卫生研究院国家过敏与传染病研究所寄生虫病实验室

The relative and synergistic contributions of genetics and environment to interindividual immune response variation remain unclear, despite implications in evolutionary biology and medicine. Here we quantify interactive effects of genotype and environment on immune traits by investigating C57BL/6, 129S1 and PWK/PhJ inbred mice, rewilded in an outdoor enclosure and infected with the parasite Trichuris muris. Whereas cellular composition was shaped by interactions between genotype and environment, cytokine response heterogeneity including IFNγ concentrations was primarily driven by genotype with consequence on worm burden. In addition, we show that other traits, such as expression of CD44, were explained mostly by genetics on T cells, whereas expression of CD44 on B cells was explained more by environment across all strains. Notably, genetic differences under laboratory conditions were decreased following rewilding. These results indicate that nonheritable influences interact with genetic factors to shape immune variation and parasite burden.

尽管在进化生物学和医学中具有重要意义，但遗传学和环境对个体间免疫反应变异的相对和协同作用仍不清楚。本研究通过探索C57BL/6、129S1 和 PWK/PhJ 近交系小鼠来量化基因型和环境对免疫特征的相互作用，这些小鼠在户外围栏中野化并感染了寄生虫鼠鞭虫。细胞组成由基因型和环境之间的相互作用塑造，包括IFNγ浓度在内的细胞因子反应异质性主要由基因型驱动，并对蠕虫负担产生影响。此外，其他特征，如CD44的表达，在T细胞中主要由遗传学解释，而在所有品系中，B细胞上CD44的表达更多地由环境解释。值得注意的是，野化后实验室条件下的遗传差异减小。这些结果表明，不可遗传的影响与遗传因素相互作用，塑造了免疫变异和寄生虫负担。

12.IL-12 induces a B cell-intrinsic IL-12/IFNγ feed-forward loop promoting extrafollicular B cell responses

IL-12诱导 B 细胞内源性 IL-12/IFNγ 前馈回路促进滤泡外B细胞应答

美国宾夕法尼亚州匹兹堡大学免疫学系

While some infections elicit germinal centers, others produce only extrafollicular responses. The mechanisms controlling these dichotomous fates are poorly understood. We identify IL-12 as a cytokine switch, acting directly on B cells to promote extrafollicular and suppress germinal center responses. IL-12 initiates a B cell-intrinsic feed-forward loop between IL-12 and IFNγ, amplifying IFNγ production, which promotes proliferation and plasmablast differentiation from mouse and human B cells, in synergy with IL-12. IL-12 sustains the expression of a portion of IFNγ-inducible genes. Together, they also induce unique gene changes, reflecting both IFNγ amplification and cooperative effects between both cytokines. In vivo, cells lacking both IL-12 and IFNγ receptors are more impaired in plasmablast production than those lacking either receptor alone. Further, B cell-derived IL-12 enhances both plasmablast responses and T helper 1 cell commitment. Thus, B cell-derived IL-12, acting on T and B cells, determines the immune response mode, with implications for vaccines, pathogen protection and autoimmunity.

虽然有些感染会引发生发中心反应，而其他感染只会产生滤泡外反应。但控制这两种不同命运的机制尚不清楚。本研究确定了IL - 12是一种细胞因子转换开关，直接作用于B细胞，促进滤泡外反应并抑制生发中心反应。IL - 12在 IL - 12 和 IFNγ之间启动了一个B细胞内在的前馈回路，放大了 IFNγ的产生，与 IL - 12协同作用，促进小鼠和人类B细胞的增殖和浆母细胞分化。IL - 12维持了一部分 IFNγ诱导基因的表达。它们共同还诱导了独特的基因变化，反映了 IFNγ的放大以及两种细胞因子之间的协同效应。在体内，同时缺乏 IL - 12 和 IFNγ受体的细胞在浆母细胞生成方面比单独缺乏任一受体的细胞受损更严重。此外，B 细胞衍生的IL - 12增强了浆母细胞反应和Th1细胞的定型。因此，作用于T细胞和B细胞衍生的IL - 12决定了免疫反应模式，对疫苗、病原体防护和自身免疫具有影响。

2024年8月，第25卷，第8期

《Nature immunology》2024年8月刊共发表article 7篇。

1.Vγ9Vδ2 T cells recognize butyrophilin 2A1 and 3A1 heteromers

Vγ9Vδ2T 细胞识别亲丁基蛋白2A1和3A1异源体

墨尔本大学感染与免疫研究所微生物学与免疫学系

Butyrophilin (BTN) molecules are emerging as key regulators of T cell immunity; however, how they trigger cell-mediated responses is poorly understood. Here, the crystal structure of a gamma-delta T cell antigen receptor (γδTCR) in complex with BTN2A1 revealed that BTN2A1 engages the side of the γδTCR, leaving the apical TCR surface bioavailable. We reveal that a second γδTCR ligand co-engages γδTCR via binding to this accessible apical surface in a BTN3A1-dependent manner. BTN2A1 and BTN3A1 also directly interact with each other in cis, and structural analysis revealed formation of W-shaped heteromeric multimers. This BTN2A1–BTN3A1 interaction involved the same epitopes that BTN2A1 and BTN3A1 each use to mediate the γδTCR interaction; indeed, locking BTN2A1 and BTN3A1 together abrogated their interaction with γδTCR, supporting a model wherein the two γδTCR ligand-binding sites depend on accessibility to cryptic BTN epitopes. Our findings reveal a new paradigm in immune activation, whereby γδTCRs sense dual epitopes on BTN complexes.

丁酰基蛋白（BTN）分子正逐渐成为T细胞免疫的关键调节剂；然而，它们如何触发细胞介导的反应却知之甚少。在此，γ-δ T细胞抗原受体（γδTCR）与BTN2A1复合物的晶体结构显示，BTN2A1与γδTCR的侧面结合，使TCR的顶端表面保持可生物利用状态。本研究发现第二种γδTCR配体通过以BTN3A1依赖的方式与该可利用的顶端表面结合而共同与γδTCR 结合。BTN2A1和 BTN3A1在顺式中也直接相互作用，结构分析显示形成了W形的异聚多聚体。这种BTN2A1 - BTN3A1相互作用涉及BTN2A1和BTN3A1各自用于介导γδTCR相互作用的相同表位；事实上，将BTN2A1和BTN3A1锁定在一起会消除它们与γδTCR的相互作用，这支持了一种模型，即两个γδTCR配体结合位点依赖于对隐蔽BTN 表位的可及性。本研究揭示了免疫激活的一种新范式，即γδTCR感知BTN复合物上的双重表位。

2.Direct presentation of inflammation-associated self-antigens by thymic innate-like T cells induces elimination of autoreactive CD8+ thymocytes

胸腺先天样 T 细胞直接呈递炎症相关自身抗原诱导自身反应性CD8+胸腺细胞的消除

瑞典卡罗林斯大学医院免疫学与变态反应学中心

Upregulation of diverse self-antigens that constitute components of the inflammatory response overlaps spatially and temporally with the emergence of pathogen-derived foreign antigens. Therefore, discrimination between these inflammation-associated self-antigens and pathogen-derived molecules represents a unique challenge for the adaptive immune system. Here, we demonstrate that CD8+ T cell tolerance to T cell-derived inflammation-associated self-antigens is efficiently induced in the thymus and supported by redundancy in cell types expressing these molecules. In addition to thymic epithelial cells, this included thymic eosinophils and innate-like T cells, a population that expressed molecules characteristic for all major activated T cell subsets. We show that direct T cell-to-T cell antigen presentation by minute numbers of innate-like T cells was sufficient to eliminate autoreactive CD8+ thymocytes. Tolerance to such effector molecules was of critical importance, as its breach caused by decreased thymic abundance of a single model inflammation-associated self-antigen resulted in autoimmune elimination of an entire class of effector T cells.

构成炎症反应组成部分的各种自身抗原的上调在空间和时间上与病原体衍生的外来抗原的出现重叠。因此，对于适应性免疫系统来说，区分这些与炎症相关的自身抗原和病原体衍生的分子是一个独特的挑战。本研究证明CD8⁺ T细胞对T细胞衍生的炎症相关自身抗原的耐受性在胸腺中被有效诱导，并由表达这些分子的细胞类型冗余的支持。除了胸腺上皮细胞外，还包括胸腺嗜酸性粒细胞和具有所有主要激活T细胞亚群特征的先天样T细胞。研究表明，少量先天样T细胞直接进行的T细胞对T细胞的抗原呈递足以消除自身反应性CD8⁺ 胸腺细胞。对这种效应分子的耐受性至关重要，因为由于单个模型炎症相关自身抗原的胸腺丰度降低而导致其突破，会引起整个效应T细胞类群的自身免疫性消除。

3.Reciprocal regulation of T follicular helper cells and dendritic cells drives colitis development

相互调节的T滤泡辅助细胞和树突状细胞驱动结肠炎的发展

上海交通大学医学院附属仁济医院免疫治疗研究所

The immunological mechanisms underlying chronic colitis are poorly understood. T follicular helper (TFH) cells are critical in helping B cells during germinal center reactions. In a T cell transfer colitis model, a lymphoid structure composed of mature dendritic cells (DCs) and TFH cells was found within T cell zones of colonic lymphoid follicles. TFH cells were required for mature DC accumulation, the formation of DC–T cell clusters and colitis development. Moreover, DCs promoted TFH cell differentiation, contributing to colitis development. A lineage-tracing analysis showed that, following migration to the lamina propria, TFH cells transdifferentiated into long-lived pathogenic TH1 cells, promoting colitis development. Our findings have therefore demonstrated the reciprocal regulation of TFH cells and DCs in colonic lymphoid follicles, which is critical in chronic colitis pathogenesis.

慢性结肠炎潜在的免疫机制尚不清楚。滤泡辅助性 T（TFH）细胞在生发中心反应期间协助 B 细胞方面起着关键作用。在T细胞转移结肠炎模型中，在结肠淋巴滤泡的T细胞区内发现了由成熟树突状细胞（DCs）和TFH细胞组成的淋巴结构。TFH细胞对于成熟DC的积累、DC-T细胞簇的形成以及结肠炎的发展是必需的。此外，DC促进了TFH细胞的分化，从而促进了结肠炎的发展。谱系追踪分析表明，迁移到固有层后，TFH细胞转分化为长寿的致病性TH1细胞，促进了结肠炎的发展。因此，本研究结果表明，TFH细胞和DC在结肠淋巴滤泡中的相互调节在慢性结肠炎的发病机制中至关重要。

4.BACH2 regulates diversification of regulatory and proinflammatory chromatin states in TH17 cells

BACH2调节TH17细胞中调节和促炎症染色质状态的多样化

麻省理工大学和美国剑桥大学

Interleukin-17 (IL-17)-producing helper T (TH17) cells are heterogenous and consist of nonpathogenic TH17 (npTH17) cells that contribute to tissue homeostasis and pathogenic TH17 (pTH17) cells that mediate tissue inflammation. Here, we characterize regulatory pathways underlying TH17 heterogeneity and discover substantial differences in the chromatin landscape of npTH17 and pTH17 cells both in vitro and in vivo. Compared to other CD4+ T cell subsets, npTH17 cells share accessible chromatin configurations with regulatory T cells, whereas pTH17 cells exhibit features of both npTH17 cells and type 1 helper T (TH1) cells. Integrating single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) and single-cell RNA sequencing (scRNA-seq), we infer self-reinforcing and mutually exclusive regulatory networks controlling different cell states and predicted transcription factors regulating TH17 cell pathogenicity. We validate that BACH2 promotes immunomodulatory npTH17 programs and restrains proinflammatory TH1-like programs in TH17 cells in vitro and in vivo. Furthermore, human genetics implicate BACH2 in multiple sclerosis. Overall, our work identifies regulators of TH17 heterogeneity as potential targets to mitigate autoimmunity.

白细胞介素17（IL-17）产生辅助性T细胞（TH17）具有异质性，由有助于组织稳态的非致病性 TH17（npTH17）细胞和介导组织炎症的致病性 TH17（pTH17）细胞组成。本研究表征了TH17异质性背后的调控途径，并发现了体外和体内npTH17和pTH17细胞染色质图谱的显著差异。与其他CD4⁺ T细胞亚群相比，npTH17细胞与调节性T细胞具有相同的染色质可及构型，而pTH17细胞则兼具npTH17细胞和1型辅助性T（TH1）细胞的特征。通过整合转座酶可及染色质测序的单细胞分析（scATAC-seq）和单细胞RNA测序（scRNA-seq），推断出控制不同细胞状态的自我强化和相互排斥的调控网络，并预测了调节TH17细胞致病性的转录因子。本研究验证了BACH2在体外和体内促进TH17细胞的免疫调节npTH17程序，并抑制TH1样促炎性程序。此外，人类遗传学表明BACH2与多发性硬化症有关。总的来说，本研究确定了TH17异质性的调节因子是减轻自身免疫的潜在靶点。

5.Specific CD4+ T cell phenotypes associate with bacterial control in people who ‘resist’ infection with Mycobacterium tuberculosis

特定的CD4+ T 细胞表型与“抵抗”结核分枝杆菌感染的人的细菌控制有关

美国加利福尼亚州斯坦福大学医学院免疫移植与感染研究所

A subset of individuals exposed to Mycobacterium tuberculosis (Mtb) that we refer to as ‘resisters’ (RSTR) show evidence of IFN-γ− T cell responses to Mtb-specific antigens despite serially negative results on clinical testing. Here we found that Mtb-specific T cells in RSTR were clonally expanded, confirming the priming of adaptive immune responses following Mtb exposure. RSTR CD4+ T cells showed enrichment of TH17 and regulatory T cell-like functional programs compared to Mtb-specific T cells from individuals with latent Mtb infection. Using public datasets, we showed that these TH17 cell-like functional programs were associated with lack of progression to active tuberculosis among South African adolescents with latent Mtb infection and with bacterial control in nonhuman primates. Our findings suggested that RSTR may successfully control Mtb following exposure and immune priming and established a set of T cell biomarkers to facilitate further study of this clinical phenotype.

一部分暴露于结核分枝杆菌（Mtb）的个体，我们将其称为“耐药者”（RSTR），尽管临床检测结果连续呈阴性，但有证据表明其对Mtb特异性抗原存在IFN-γ- T细胞反应。在此，本研究发现RSTR中的Mtb特异性T细胞呈克隆性扩增，证实了Mtb暴露后适应性免疫反应的启动。与潜伏性Mtb感染个体的Mtb特异性T细胞相比，RSTR的CD4⁺ T细胞显示出TH17和调节性T细胞样功能程序的富集。利用公共数据集，在患有潜伏性Mtb感染的南非青少年中，这些类似TH17细胞的功能程序与未发展为活动性结核病以及非人灵长类动物中的细菌控制有关。本研究结果表明，RSTR可能在暴露和免疫启动后成功控制Mtb，并建立了一组T细胞生物标志物，以促进对这种临床表型的进一步研究。

6.PI3Kγ in B cells promotes antibody responses and generation of antibody-secreting cells

B 细胞中的PI3Kγ促进抗体应答和抗体分泌细胞的产生

美国耶鲁大学医学院免疫生物学系

The differentiation of naive and memory B cells into antibody-secreting cells (ASCs) is a key feature of adaptive immunity. The requirement for phosphoinositide 3-kinase-delta (PI3Kδ) to support B cell biology has been investigated intensively; however, specific functions of the related phosphoinositide 3-kinase-gamma (PI3Kγ) complex in B lineage cells have not. In the present study, we report that PI3Kγ promotes robust antibody responses induced by T cell-dependent antigens. The inborn error of immunity caused by human deficiency in PI3Kγ results in broad humoral defects, prompting our investigation of roles for this kinase in antibody responses. Using mouse immunization models, we found that PI3Kγ functions cell intrinsically within activated B cells in a kinase activity-dependent manner to transduce signals required for the transcriptional program supporting differentiation of ASCs. Furthermore, ASC fate choice coincides with upregulation of PIK3CG expression and is impaired in the context of PI3Kγ disruption in naive B cells on in vitro CD40-/cytokine-driven activation, in memory B cells on toll-like receptor activation, or in human tonsillar organoids. Taken together, our study uncovers a fundamental role for PI3Kγ in supporting humoral immunity by integrating signals instructing commitment to the ASC fate.

幼稚B细胞和记忆B细胞分化为抗体分泌细胞（ASCs）是适应性免疫的一个关键特征。磷脂酰肌醇 3 - 激酶 - δ（PI3Kδ）对支持B细胞生物学的需求已被深入研究；然而，相关的PI3Kγ复合物在B系细胞中的特定功能尚未得到研究。本研究报告了PI3Kγ 促进了由 T 细胞依赖性抗原诱导的强大抗体反应。人类PI3Kγ缺乏导致的先天性免疫缺陷会引起广泛的体液缺陷，促使研究聚焦于这种激酶在抗体反应中的作用。利用小鼠免疫模型，本研究发现 PI3Kγ以依赖激酶活性的方式在活化的B细胞内发挥细胞内在功能，以转导支持 ASCs分化的转录程序所需的信号。此外，ASC命运选择与PIK3CG表达的上调相一致，并且在体外CD40-/细胞因子驱动的活化的幼稚B细胞、toll样受体活化中的记忆B细胞或人类扁桃体类器官中PI3Kγ破坏的情况下受到损害。综上所述，本研究揭示了PI3Kγ通过整合指示ASC命运的信号在支持体液免疫中的基本作用。

7.Epigenetic recording of stimulation history reveals BLIMP1–BACH2 balance in determining memory B cell fate upon recall challenge

刺激历史的表观遗传记录揭示了BLIMP1 - BACH2的平衡在回忆性挑战时决定记忆B细胞命运方面的作用

清华-北京生命科学中心

Memory B cells (MBCs) differentiate into plasma cells (PCs) or germinal centers (GCs) upon antigen recall. How this decision is programmed is not understood. We found that the relative strength between two antagonistic transcription factors, B lymphocyte-induced maturation protein 1 (BLIMP1) and BTB domain and CNC homolog 2 (BACH2), progressively increases in favor of BLIMP1 in antigen-responding B cells through the course of primary responses. MBC subsets that preferentially produce secondary GCs expressed comparatively higher BACH2 but lower BLIMP1 than those predisposed for PC development. Skewing the BLIMP1–BACH2 balance in otherwise fate-predisposed MBC subsets could switch their fate preferences. Underlying the changing BLIMP1-over-BACH2 balance, we observed progressively increased accessibilities at chromatin loci that are specifically opened in PCs, particularly those that contain interferon-sensitive response elements (ISREs) and are controlled by interferon regulatory factor 4 (IRF4). IRF4 is upregulated by B cell receptor, CD40 or innate receptor signaling and it induces graded levels of PC-specifying epigenetic imprints according to the strength of stimulation. By analyzing history-stamped GC B cells, we found progressively increased chromatin accessibilities at PC-specific, IRF4-controlled gene loci over time. Therefore, the cumulative stimulation history of B cells is epigenetically recorded in an IRF4-dependent manner, determines the relative strength between BLIMP1 and BACH2 in individual MBCs and dictates their probabilities to develop into GCs or PCs upon restimulation.

记忆B细胞（MBCs）在抗原召回时分化为浆细胞（PCs）或生发中心（GCs）。这个决策是如何编程的尚不清楚。本研究发现，在初级反应过程中，两种拮抗转录因子，即B淋巴细胞诱导成熟蛋白1（BLIMP1）和BTB结构域及CNC同源物 2（BACH2）之间的相对强度在抗原应答B细胞中逐渐增加，有利于BLIMP1。相较于倾向于形成浆细胞的MBC亚群，优先产生次级GCs的MBC亚群表达相对较高的BACH2但较低的BLIMP1。改变原本具有命运倾向的MBC亚群中的BLIMP1-BACH2平衡可以改变它们的命运偏好。在不断变化的 BLIMP1相对于BACH2的平衡背后，在PC中观察到特异性开放的染色质位点，特别是那些包含干扰素敏感反应元件（ISREs）并由干扰素调节因子4（IRF4）控制的位点，其可及性逐渐增加。IRF4由B细胞受体、CD40 或先天受体信号上调，并根据刺激强度诱导不同等级的PC特异性表观遗传印记。通过分析带有标记的GC B细胞，发现随着时间的推移，PC特异性、IRF4控制的基因位点的染色质可及性逐渐增加。因此，B细胞的累积刺激历史以依赖IRF4的方式在表观遗传学上被记录，决定了单个MBC中BLIMP1和BACH2之间的相对强度，并决定了它们在再次刺激时发育为GCs或PCs的概率。

汇报人：饶郁芳

合作导师：李为民、赵宇

审核：宋瑶、庞文都、任建君