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【Nature immunology】2025年1-4月论文导读

期刊介绍：

Nature Immunology是Nature杂志的免疫学分册，创刊于2000年，也是该领域经由同行评审的权威科学期刊。该杂志由NATURE RESEARCH出版集团按每月一期出版。该期刊是一本以医学-免疫学综合研究为特色的国际期刊，其涵盖的领域包括但不限于先天免疫和炎症、发育、免疫受体、信号传导和凋亡、抗原呈递、基因调控和重组、细胞和全身免疫、疫苗、免疫耐受、自身免疫、肿瘤免疫学和微生物免疫病理学。最新影响因子指数为28.3。

本期文献导读将呈现2025年1月至2025年4月四个月内的主要刊物内容。

Volume 26, Issue 1

本期共发表论著7篇。

1.A stromal inflammasome Ras safeguard against Myc-driven lymphomagenesis

基质炎症小体Ras通路可抑制Myc驱动的淋巴瘤发生

美国宾夕法尼亚州费城托马斯杰斐逊大学西德尼金梅尔医学院生命科学学院

The inflammasome plays multifaceted roles in cancer, but less is known about its function during premalignancy upon initial cell transformation. We report a homeostatic function of the inflammasome in suppressing malignant transformation through Ras inhibition. We identified increased hematopoietic stem cell (HSC) proliferation within the bone marrow of inflammasome-deficient mice. HSCs within an inflammasome-deficient stroma expressed a Ras signature associated with increased Ras pathway- and cancer-related transcripts and heightened levels of cytokine, chemokine and growth factor receptors. Stromal inflammasome deficiency established a poised Ras-dependent mitogenic state within HSCs, which fueled progeny B cell lymphomagenesis upon Myc deregulation in a spontaneous model of B cell lymphoma, and shortened its premalignant stage leading to faster onset of malignancy. Thus, the stromal inflammasome preserves tissue balance by restraining Ras to disrupt the most common oncogenic Myc–Ras cooperation and establish a natural defense against transition to malignancy. These findings should inform preventative therapies against hematological malignancies.

炎症小体在癌症中具有多重作用，但其在细胞初始转化阶段的癌前病变中的功能尚不清楚。本研究发现炎症小体通过抑制Ras通路发挥维持稳态、抑制恶性转化的作用。研究者在炎症小体缺陷小鼠的骨髓中，观察到造血干细胞（HSC）增殖活性增强。这些在炎症小体缺陷基质中生长的HSC表现出Ras信号特征：Ras通路相关转录本和癌相关转录本增加，细胞因子、趋化因子及生长因子受体表达水平升高。基质炎症小体缺陷使HSC处于一种Ras依赖的促有丝分裂预备状态，在B细胞淋巴瘤自发模型中，一旦Myc调控失常，便会加速子代B细胞的淋巴瘤发生进程，缩短癌前病变阶段，促使恶性肿瘤更早发生。因此，基质炎症小体通过抑制Ras通路来破坏最常见的Myc-Ras致癌协同效应，从而维持组织稳态，建立起抵御恶性转化的天然屏障。这些发现将为血液系统恶性肿瘤的预防性治疗提供新思路。

2.Antigen experience history directs distinct functional states of CD8+ CAR T cells during the antileukemia response

抗原经历差异决定CD8+ CAR-T细胞抗白血病反应中的功能状态分化

美国科罗拉多州奥罗拉市科罗拉多大学安舒茨医学院免疫学系

Although chimeric antigen receptor (CAR) T cells are effective against B-lineage malignancies, post-CAR relapse is common, and efficacy in other tumors is limited. These challenges may be addressed through rational manipulations to control CAR T cell function. Here we examine the impact of cognate T cell antigen experience on subsequent CD8+ CAR T cell activity. Prior antigen encounter resulted in superior effector function against leukemia expressing low target antigen density at the expense of reduced proliferative capacity and susceptibility to dysfunction at limiting CAR doses. Distinctive temporal transcriptomic and epigenetic profiles in naive-derived and memory-derived CAR T cells identified RUNX family transcription factors as potential targets to augment the function of naive-derived CD8+ CAR T cells. RUNX2 overexpression enhanced antitumor efficacy of mouse CAR T cells, dependent on prior cell state, and heightened human CAR T cell functions. Our data demonstrate that prior antigen experience of CAR T cells determines functional attributes and amenability to transcription factor-mediated functional enhancement.

尽管嵌合抗原受体（CAR）T细胞对B系恶性肿瘤具有疗效，但CAR治疗后复发较为常见，且对其他肿瘤的疗效有限。这些挑战或可通过合理调控CAR T细胞功能来解决。本研究探讨了T细胞既往抗原经历对CD8+ CAR T细胞活性的影响。研究发现，具有抗原暴露史的CAR T细胞对低靶抗原密度白血病表现出更强的效应功能，但其增殖能力降低，且在CAR剂量不足时更易出现功能失调。通过对比初始T细胞来源与记忆T细胞来源CAR T细胞的时序转录组和表观遗传特征，鉴定出RUNX家族转录因子可作为增强初始T细胞来源CD8+ CAR T细胞功能的潜在靶点。RUNX2过表达能提升小鼠CAR T细胞的抗肿瘤效力（该效应具有细胞状态依赖性），并增强人CAR T细胞功能。数据表明，CAR T细胞的既往抗原经历不仅决定其功能特性，更影响其对转录因子介导的功能增强的响应能力。

3.Circulating tumor-reactive KIR+CD8+ T cells suppress anti-tumor immunity in patients with melanoma

循环性肿瘤反应性KIR+CD8+ T细胞在黑色素瘤患者中抑制抗肿瘤免疫应答

耶鲁大学医学院、肿瘤内科及神经病学科

Effective anti-tumor immunity is driven by cytotoxic CD8+ T cells with specificity for tumor antigens. However, the factors that control successful tumor rejection are not well understood. Here we identify a subpopulation of CD8+ T cells that are tumor-antigen-specific and can be identified by KIR expression but paradoxically impair anti-tumor immunity in patients with melanoma. These tumor-antigen-specific KIR+CD8+ regulatory T cells target other tumor-antigen-specific CD8+ T cells, can be detected in both the tumor and the blood, have a conserved transcriptional program and are associated with a poor overall survival. These findings broaden our understanding of the transcriptional and functional heterogeneity of human CD8+ T cells and implicate KIR+CD8+ regulatory T cells as a cellular mediator of immune evasion in human cancer.

有效的抗肿瘤免疫依赖于对肿瘤抗原具有特异性的细胞毒性CD8+ T细胞。然而，肿瘤成功清除的关键调控因素尚未明确。本研究在黑色素瘤患者中发现了一类特殊的CD8+ T细胞亚群：这些细胞虽表达肿瘤抗原特异性受体，却可通过KIR分子的表达抑制抗肿瘤免疫应答。在肿瘤组织和外周血中均可检测到这类肿瘤抗原特异性KIR+CD8+调节性T细胞能够靶向攻击其他肿瘤抗原特异性CD8+ T细胞，具有保守的转录特征，并与患者不良预后显著相关。该发现不仅拓展了目前对人类CD8+ T细胞转录和功能异质性的认知，更揭示了KIR+CD8+调节性T细胞作为人类癌症免疫逃逸的关键效应细胞。

4.Efficacy of CTLA-4 checkpoint therapy is dependent on IL-21 signaling to mediate cytotoxic reprogramming of PD-1+CD8+ T cells

CTLA-4检查点抑制剂的疗效依赖于IL-21信号通路介导的PD-1+CD8+ T细胞毒性重编程作用

德国弗莱堡大学医学中心医学院

The mechanisms underlying the efficacy of anti-programmed cell death protein 1 (PD-1) and anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) therapy are incompletely understood. Here, by immune profiling responding PD-1+CD8+ T (TResp) cell populations from patients with advanced melanoma, we identified differential programming of TResp cells in response to combination therapy, from an exhausted toward a more cytotoxic effector program. This effect does not occur with anti-PD-1 monotherapy. Single-cell transcriptome and T cell receptor repertoire analysis was used to identify altered effector programming of expanding PD-1+CD8+ T cell clones with distinct regulon usage, STAT1 and STAT3 utilization and antitumor specificity connected to interleukin (IL)-21 signaling in combination and anti-CTLA-4 monotherapy. Therapeutic efficacy of CTLA-4 blockade was lost in B16F10 melanoma models with either Il21r− deficiency or anti-IL-21 receptor blockade. Together, these results show how IL-21 signaling to TResp is critical for anti-CTLA-4-based checkpoint therapies and highlight major signaling differences to anti-PD-1 monotherapy.

抗程序性细胞死亡蛋白1（PD-1）和抗细胞毒性T淋巴细胞相关蛋白4（CTLA-4）疗法的疗效机制尚未完全阐明。本研究通过对晚期黑色素瘤患者产生应答的PD-1+CD8+ T细胞（TResp细胞）群体进行免疫特征分析，发现联合治疗可诱导TResp细胞从耗竭状态向更具细胞毒性的效应程序分化，而这一现象在PD-1单药治疗中并未出现。通过单细胞转录组和T细胞受体谱分析证实，联合治疗和CTLA-4单药治疗中，扩增的PD-1+CD8+ T细胞克隆通过独特的调控子利用模式、STAT1/STAT3信号通路激活及白介素（IL）-21信号依赖的抗肿瘤特异性，实现了效应程序的重编程。在B16F10黑色素瘤模型中，Il21r基因缺失或IL-21受体阻断均会导致CTLA-4阻断疗法失效。这些结果共同揭示了IL-21信号对TResp细胞的调控是CTLA-4检查点疗法的关键机制，同时凸显了其与PD-1单药治疗在信号传导层面的显著差异。

5.PD-1 and CD73 on naive CD4+ T cells synergistically limit responses to self

PD-1与CD73在初始CD4+ T细胞上的协同作用抑制自身反应性应答

美国佐治亚州奥古斯塔大学佐治亚免疫学中心

Vaccination with self- and foreign peptides induces weak and strong expansion of antigen-specific CD4+ T cells, respectively, but the mechanism is not known. In the present study, we used computational analysis of the entire mouse major histocompatibility complex class II peptidome to test how much of the naive CD4+ T cell repertoire specific for self-antigens was shaped by negative selection in the thymus and found that negative selection only partially explained the difference between responses to self and foreign. In naive uninfected and unimmunized mice, we identified higher expression of programmed cell death protein 1 (PD-1) and CD73 mRNA and protein on self-specific CD4+ T cells compared with foreign-specific CD4+ T cells. Pharmacological or genetic blockade of PD-1 and CD73 significantly increased the vaccine-induced expansion of self-specific CD4+ T cells and their transcriptomes were similar to those of foreign-specific CD4+ T cells. We concluded that PD-1 and CD73 synergistically limited CD4+ T cell responses to self. These observations have implications for the development of tolerogenic vaccines and cancer immunotherapy.

使用自身肽段和异源肽段进行疫苗接种可分别诱导抗原特异性CD4+ T细胞的弱扩增和强扩增，但其机制尚不明确。本研究通过对小鼠主要组织相容性复合体II类全肽组进行计算机分析，评估了胸腺阴性选择对自身抗原特异性初始CD4+ T细胞库的塑造程度，发现阴性选择仅能部分解释自身与异源免疫应答的差异。在未感染、未免疫的初始状态小鼠中，研究发现与异源特异性CD4+ T细胞相比，自身特异性CD4+ T细胞中PD-1和CD73的mRNA及蛋白表达水平更高。通过药理学或遗传学手段阻断PD-1和CD73后，疫苗诱导的自身特异性CD4+ T细胞扩增显著增强，其转录组特征与异源特异性CD4+ T细胞趋于一致。研究得出结论：PD-1与CD73通过协同作用限制CD4+ T细胞对自身抗原的应答。这些发现对耐受性疫苗研发和癌症免疫治疗具有重要启示意义。

6.System vaccinology analysis of predictors and mechanisms of antibody response durability to multiple vaccines in humans

人类多疫苗抗体应答持久性的预测因子与作用机制：系统疫苗学分析

美国斯坦福大学医学院免疫、移植和感染研究所

We performed a systems vaccinology analysis to investigate immune responses in humans to an H5N1 influenza vaccine, with and without the AS03 adjuvant, to identify factors influencing antibody response magnitude and durability. Our findings revealed a platelet and adhesion-related blood transcriptional signature on day 7 that predicted the longevity of the antibody response, suggesting a potential role for platelets in modulating antibody response durability. As platelets originate from megakaryocytes, we explored the effect of thrombopoietin (TPO)-mediated megakaryocyte activation on antibody response longevity. We found that TPO administration enhanced the durability of vaccine-induced antibody responses. TPO-activated megakaryocytes also promoted survival of human bone-marrow plasma cells through integrin β1/β2-mediated cell–cell interactions, along with survival factors APRIL and the MIF–CD74 axis. Using machine learning, we developed a classifier based on this platelet-associated signature, which predicted antibody response longevity across six vaccines from seven independent trials, highlighting a conserved mechanism for vaccine durability.

通过系统疫苗学分析方法，研究了人类对H5N1流感疫苗（含AS03佐剂与不含佐剂）的免疫应答，以揭示影响抗体反应强度与持久性的关键因素。研究发现，接种后第7天出现的血小板及黏附相关血液转录特征可预测抗体应答的持久性，提示血小板可能参与调控抗体应答的持续时间。鉴于血小板源自巨核细胞，研究者进一步探究了血小板生成素（TPO）介导的巨核细胞活化对抗体应答持久性的影响。实验证实，TPO给药能显著增强疫苗诱导抗体应答的持久性。TPO激活的巨核细胞还能通过整合素β1/β2介导的细胞间相互作用，连同生存因子APRIL及MIF-CD74轴，促进人类骨髓浆细胞的存活。基于此血小板相关特征，利用机器学习构建了预测模型，该分类器在七项独立临床试验的六种疫苗中均能预测抗体应答持久性，从而揭示了一种保守的疫苗持久性调控机制。

7.Disease-associated B cells and immune endotypes shape adaptive immune responses to SARS-CoV-2 mRNA vaccination in human SLE

疾病相关B细胞与免疫内型塑造SLE患者对SARS-CoV-2 mRNA疫苗的适应性免疫应答

埃默里大学埃默里自身免疫卓越中心

Severe acute respiratory syndrome coronavirus 2 mRNA vaccination has reduced effectiveness in certain immunocompromised individuals. However, the cellular mechanisms underlying these defects, as well as the contribution of disease-induced cellular abnormalities, remain largely unexplored. In this study, we conducted a comprehensive serological and cellular analysis of patients with autoimmune systemic lupus erythematosus (SLE) who received the Wuhan-Hu-1 monovalent mRNA coronavirus disease 2019 vaccine. Our findings revealed that patients with SLE exhibited reduced avidity of anti-receptor-binding domain antibodies, leading to decreased neutralization potency and breadth. We also observed a sustained anti-spike response in IgD−CD27− ‘double-negative (DN)’ DN2/DN3 B cell populations persisting during memory responses and with greater representation in the SLE cohort. Additionally, patients with SLE displayed compromised anti-spike T cell immunity. Notably, low vaccine efficacy strongly correlated with higher values of a newly developed extrafollicular B and T cell score, supporting the importance of distinct B cell endotypes. Finally, we found that anti-BAFF blockade through belimumab treatment was associated with poor vaccine immunogenicity due to inhibition of naive B cell priming and an unexpected impact on circulating T follicular helper cells.

重症急性呼吸综合征冠状病毒2（SARS-CoV-2）mRNA疫苗在部分免疫功能低下个体中的有效性降低。然而，这些免疫缺陷背后的细胞机制以及疾病诱导的细胞异常所起的作用，目前仍不清楚。本研究对接种武汉-Hu-1单价mRNA型2019冠状病毒病疫苗的自身免疫性系统性红斑狼疮（SLE）患者进行了系统的血清学和细胞免疫分析。研究发现，SLE患者抗受体结合域抗体亲和力降低，导致中和效价和广度下降。此外，在记忆应答期间持续存在的IgD−CD27−“双阴性（DN）”B细胞亚群（DN2/DN3）中维持着抗刺突蛋白应答，且该亚群在SLE队列中比例更高。SLE患者也表现出抗刺突蛋白T细胞免疫受损。值得注意的是，疫苗低效性与新开发的滤泡外B细胞和T细胞评分升高呈强相关性，这支持了特定B细胞内型的重要性。最后，研究发现通过贝利尤单抗进行的抗BAFF阻断治疗会抑制初始B细胞启动，并对循环滤泡辅助性T细胞产生意外影响，从而导致疫苗免疫原性降低。

Volume 26, Issue 2

本期共发表论著9篇。

1.β-Glucan reprograms neutrophils to promote disease tolerance against influenza A virus

β-葡聚糖重编程中性粒细胞以增强对甲型流感病毒的疾病耐受性

麦吉尔大学医学部、病理学部、微生物学和免疫学部

   Disease tolerance is an evolutionarily conserved host defense strategy that preserves tissue integrity and physiology without affecting pathogen load. Unlike host resistance, the mechanisms underlying disease tolerance remain poorly understood. In the present study, we investigated whether an adjuvant (β-glucan) can reprogram innate immunity to provide protection against influenza A virus (IAV) infection. β-Glucan treatment reduces the morbidity and mortality against IAV infection, independent of host resistance. The enhanced survival is the result of increased recruitment of neutrophils via RoRγt+ T cells in the lung tissue. β-Glucan treatment promotes granulopoiesis in a type 1 interferon-dependent manner that leads to the generation of a unique subset of immature neutrophils utilizing a mitochondrial oxidative metabolism and producing interleukin-10. Collectively, our data indicate that β-glucan reprograms hematopoietic stem cells to generate neutrophils with a new ‘regulatory’ function, which is required for promoting disease tolerance and maintaining lung tissue integrity against viral infection.

疾病耐受性是一种进化保守的宿主防御策略，可在不影响病原体负荷的情况下维持组织完整性和生理功能。与宿主抗病性不同，疾病耐受性的作用机制至今尚未阐明。本研究探讨了佐剂（β-葡聚糖）能否通过重编程先天免疫系统来防御甲型流感病毒（IAV）感染。研究发现，β-葡聚糖治疗可降低IAV感染后的发病率和死亡率，且这一保护作用独立于宿主抗病机制。生存率的提升源于肺部组织中RoRγt+ T细胞介导的中性粒细胞募集增加。β-葡聚糖通过I型干扰素依赖性途径促进粒细胞生成，从而产生一类具有线粒体氧化代谢模式并分泌白细胞介素-10的未成熟中性粒细胞亚群。研究结果表明，β-葡聚糖能重编程造血干细胞，产生具有新型"调节"功能的中性粒细胞，这对促进疾病耐受性和维持病毒感染下的肺组织完整性至关重要。

2.Cholesterol mobilization regulates dendritic cell maturation and the immunogenic response to cancer

胆固醇动员调节树突状细胞成熟和对癌症的免疫原性反应

美国纽约州西奈山伊坎医学院蒂施癌症研究所

   Maturation of conventional dendritic cells (cDCs) is crucial for maintaining tolerogenic safeguards against auto-immunity and for promoting immunogenic responses to pathogens and cancer. The subcellular mechanism for cDC maturation remains poorly defined. We show that cDCs mature by leveraging an internal reservoir of cholesterol (harnessed from extracellular cell debris and generated by de novo synthesis) to assemble lipid nanodomains on cell surfaces of maturing cDCs, enhance expression of maturation markers and stabilize immune receptor signaling. This process is dependent on cholesterol transport through Niemann–Pick disease type C1 (NPC1) and mediates homeostatic and Toll-like receptor (TLR)-induced maturation. Importantly, we identified the receptor tyrosine kinase AXL as a regulator of the NPC1-dependent construction of lipid nanodomains. Deleting AXL from cDCs enhances their maturation, thus improving anti-tumor immunity. Altogether, our study presents new insights into cholesterol mobilization as a fundamental basis for cDC maturation and highlights AXL as a therapeutic target for modulating cDCs.

传统树突细胞（cDC）的成熟过程对于维持自身免疫耐受屏障和促进对病原体/肿瘤的免疫应答至关重要，但其亚细胞成熟机制尚不明确。本研究发现，cDC通过利用胆固醇内源储备（来源于胞外细胞碎片及细胞内新生合成）在细胞表面组装脂质纳米结构域，从而增强成熟标志物表达并稳定免疫受体信号传导。该过程依赖于尼曼-匹克病C1型（NPC1）介导的胆固醇转运，可调控稳态及Toll样受体（TLR）诱导的cDC成熟。值得注意的是，研究鉴定出受体酪氨酸激酶AXL是NPC1依赖性脂质纳米域构建的关键调控因子。cDC中AXL的缺失可促进其成熟，进而增强抗肿瘤免疫。本研究揭示了胆固醇动态转运作为cDC成熟的基础机制，并确立了AXL作为调控cDC功能的治疗靶点。

3.IRE1α–XBP1 safeguards hematopoietic stem and progenitor cells by restricting pro-leukemogenic gene programs

IRE1α–XBP1信号轴通过抑制促白血病基因程序保护造血干祖细胞

浙江大学生命科学研究院细胞信号转导网络创新中心

美国俄亥俄州克利夫兰凯斯西储大学医学院病理学系

四川农业大学动物科技学院

Hematopoietic stem cells must mitigate myriad stressors throughout their lifetime to ensure normal blood cell generation. Here, we uncover unfolded protein response stress sensor inositol-requiring enzyme-1α (IRE1α) signaling in hematopoietic stem and progenitor cells (HSPCs) as a safeguard against myeloid leukemogenesis. Activated in part by an NADPH oxidase-2 mechanism, IRE1α-induced X-box binding protein-1 (XBP1) mediated repression of pro-leukemogenic programs exemplified by the Wnt–β-catenin pathway. Transcriptome analysis and genome-wide mapping of XBP1 targets in HSPCs identified an ‘18-gene signature’ of XBP1-repressed β-catenin targets that were highly expressed in acute myeloid leukemia (AML) cases with worse prognosis. Accordingly, IRE1α deficiency cooperated with a myeloproliferative oncogene in HSPCs to cause a lethal AML in mice, while genetic induction of XBP1 suppressed the leukemia stem cell program and activity of patient-derived AML cells. Thus, IRE1α–XBP1 signaling safeguards the integrity of the blood system by restricting pro-leukemogenic programs in HSPCs.

造血干细胞必须在其生命周期中应对多种应激源，以确保正常血细胞的生成。本研究揭示了造血干祖细胞（HSPCs）中未折叠蛋白反应应激传感器——肌醇需求酶1α（IRE1α）信号通路是抵御髓系白血病发生的重要保护机制。该通路部分通过NADPH氧化酶2机制激活，其中IRE1α诱导的X盒结合蛋白1（XBP1）可抑制以Wnt–β-catenin通路为代表的促白血病基因程序。通过对HSPCs进行转录组分析和XBP1靶点的全基因组定位，文中鉴定出由18个XBP1抑制的β-catenin靶基因组成的特征集，这些基因在预后较差的急性髓系白血病（AML）病例中高表达。相应地，HSPCs中IRE1α缺失会协同骨髓增殖性致癌基因诱发小鼠致死性AML，而XBP1的遗传诱导则可抑制白血病干细胞程序及患者来源AML细胞的活性。因此，IRE1α–XBP1信号通路通过限制HSPCs中的促白血病程序，维护血液系统的完整性。

4.Temporal profiling of human lymphoid tissues reveals coordinated defense against viral challenge

人类淋巴组织时程分析揭示协同抗病毒防御机制

英国剑桥大学医学系分子免疫研究中心

Adaptive immunity is generated in lymphoid organs, but how these structures defend themselves during infection in humans is unknown. The nasal epithelium is a major site of viral entry, with adenoid nasal-associated lymphoid tissue (NALT) generating early adaptive responses. In the present study, using a nasopharyngeal biopsy technique, we investigated longitudinal immune responses in NALT after a viral challenge, using severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection as a natural experimental model. In acute infection, infiltrating monocytes formed a subepithelial and perifollicular shield, recruiting neutrophil extracellular trap-forming neutrophils, whereas tissue macrophages expressed pro-repair molecules during convalescence to promote the restoration of tissue integrity. Germinal center B cells expressed antiviral transcripts that inversely correlated with fate-defining transcription factors. Among T cells, tissue-resident memory CD8 T cells alone showed clonal expansion and maintained cytotoxic transcriptional programs into convalescence. Together, our study provides unique insights into how human nasal adaptive immune responses are generated and sustained in the face of viral challenge.

适应性免疫应答虽生成于淋巴器官，但这些结构在人类感染过程中如何自我防御尚属未知。鼻咽上皮作为病毒入侵的主要门户，其腺样体在鼻相关淋巴组织（NALT）负责产生早期适应性免疫应答。本研究采用鼻咽活检技术，以严重急性呼吸综合征冠状病毒2（SARS-CoV-2）感染为自然实验模型，系统研究了病毒挑战后NALT的纵向免疫应答动态。研究发现，在急性感染期，浸润单核细胞形成上皮下层和滤泡周围的防御屏障，并招募形成中性粒细胞胞外陷阱的中性粒细胞；而恢复期组织中，巨噬细胞表达促修复分子以促进组织完整性重建。生发中心B细胞表达的抗病毒转录本与命运决定转录因子呈负相关。在T细胞中，唯组织驻留记忆CD8 T细胞表现出克隆扩增，并将细胞毒性转录程序维持至恢复期。该研究为理解人类鼻咽适应性免疫应答在病毒挑战下的生成与维持机制提供了独特见解。

5.Differential roles of human CD4+ and CD8+ regulatory T cells in controlling self-reactive immune responses

CD4+与CD8+调节性T细胞在控制自身反应性免疫应答中的差异化作用

美国加利福尼亚州斯坦福大学免疫、移植和感染研究所

   Here we analyzed the relative contributions of CD4+ regulatory T cells expressing Forkhead box protein P3 (FOXP3) and CD8+ regulatory T cells expressing killer cell immunoglobulin-like receptors to the control of autoreactive T and B lymphocytes in human tonsil-derived immune organoids. FOXP3 and GZMB respectively encode proteins FOXP3 and granzyme B, which are critical to the suppressive functions of CD4+ and CD8+ regulatory T cells. Using CRISPR–Cas9 gene editing, we were able to achieve a reduction of ~90–95% in the expression of these genes. FOXP3 knockout in tonsil T cells led to production of antibodies against a variety of autoantigens and increased the affinity of influenza-specific antibodies. By contrast, GZMB knockout resulted in an increase in follicular helper T cells, consistent with the ablation of CD8+ regulatory T cells observed in mouse models, and a marked expansion of autoreactive CD8+ and CD4+ T cells. These findings highlight the distinct yet complementary roles of CD8+ and CD4+ regulatory T cells in regulating cellular and humoral responses to prevent autoimmunity.

本研究通过分析表达FOXP3的CD4+调节性T细胞与表达杀伤细胞免疫球蛋白样受体的CD8+调节性T细胞在人扁桃体来源免疫类器官中对自身反应性T/B淋巴细胞的调控作用，揭示了二者的相对贡献。FOXP3和GZMB基因分别编码对CD4+和CD8+调节性T细胞抑制功能至关重要的FOXP3蛋白和颗粒酶B。利用CRISPR-Cas9基因编辑技术实现了这两个基因表达量90-95%的敲减。研究发现：扁桃体T细胞中FOXP3基因敲除会导致多种自身抗体产生，并提高流感特异性抗体的亲和力；而GZMB基因敲除则引起滤泡辅助性T细胞增多（这与小鼠模型中CD8+调节性T细胞缺失的表型一致），并显著扩增自身反应性CD8+和CD4+ T细胞。这些发现凸显了CD8+与CD4+调节性T细胞在调控细胞和体液免疫应答以防止自身免疫中的独特且互补的作用。

6. Low-avidity T cells drive endogenous tumor immunity in mice and humans

低亲和力T细胞驱动小鼠与人类内源性肿瘤免疫应答

康涅狄格大学医学院免疫学系和癌症中心

T cells recognize neoepitope peptide-major histocompatibility complex class I on cancer cells. The strength (or avidity) of the T cell receptor–peptide-major histocompatibility complex class I interaction is a critical variable in immune control of cancers. Here, we analyze neoepitope-specific CD8 cells of distinct avidities and show that low-avidity T cells are the sole mediators of cancer control in mice and are solely responsive to checkpoint blockade in mice and humans. High-avidity T cells are ineffective and immune-suppressive. The mechanistic basis of these differences lies in the higher exhaustion status of high-avidity cells. High-avidity T cells have a distinct transcriptomic profile that is used here to calculate an ‘avidity score’, which we then use for in silico identification of low-avidity and high-avidity T cells in mice and humans. Surprisingly, CD8+ T cells with identical T cell receptors exhibit wide variation in avidities, suggesting an additional level of regulation of T cell activity. Aside from providing a better understanding of endogenous T cell responses to cancer, these findings might instruct future immunotherapy strategies.

T细胞通过识别癌细胞表面新抗原肽-MHC I类分子复合物发挥抗肿瘤作用，而T细胞受体（TCR）与该复合物结合的强度（即亲和力）是影响肿瘤免疫控制的关键因素。本研究通过分析不同亲和力的新抗原特异性CD8+ T细胞，首次揭示：在小鼠模型中，低亲和力T细胞是介导肿瘤控制的唯一效应群体，且在小鼠和人类中均对免疫检查点阻断治疗产生特异性响应；而高亲和力T细胞不仅无效，还具有免疫抑制作用。这种差异的机制基础在于高亲和力T细胞更易进入耗竭状态。研究者通过转录组分析发现，高亲和力T细胞具有独特的基因表达特征，据此建立了"亲和力评分"系统，可用于计算机模拟鉴定小鼠和人类中的高低亲和力T细胞。令人惊讶的是，具有相同TCR的CD8+ T细胞仍表现出广泛的亲和力差异，提示存在调控T细胞活性的新机制。这些发现不仅深化了对内源性T细胞抗肿瘤应答的理解，更为优化未来免疫治疗策略提供了重要指导。

7.The epitranscriptional factor PCIF1 orchestrates CD8+ T cell ferroptosis and activation to control antitumor immunity

表观转录调控因子PCIF1通过协调CD8+ T细胞铁死亡与活化调控抗肿瘤免疫应答

武汉大学中南医院医学研究院放射与肿瘤内科、免疫代谢前沿科学中心

T cell-based immunotherapies have revolutionized cancer treatment, yet durable responses remain elusive. Here we show that PCIF1, an RNA N6 2′-O-dimethyladenosine (m6Am) methyltransferase, negatively regulates CD8+ T cell antitumor responses. Whole-body or T cell-specific Pcif1 knockout (KO) reduced tumor growth in mice. Single-cell RNA sequencing shows an increase in the number of tumor-infiltrating cytotoxic CD8+ T cells in Pcif1-deficient mice. Mechanistically, proteomic and m6Am-sequencing analyses pinpoint that Pcif1 KO elevates m6Am-modified targets, specifically ferroptosis suppressor genes (Fth1, Slc3a2), and the T cell activation gene Cd69, imparting resistance to ferroptosis and enhancing CD8+ T cell activation. Of note, Pcif1-deficient mice had enhanced responses to anti-PD-1 immunotherapy, and Pcif1 KO chimeric antigen receptor T cells improved tumor control. Clinically, cancer patients with low PCIF1 expression in T cells have enhanced responses to immunotherapies. These findings suggest that PCIF1 suppresses CD8+ T cell activation and targeting PCIF1 is a promising strategy to boost antitumor immunity.

基于T细胞的免疫疗法虽已革新癌症治疗，但持久应答仍难实现。本研究发现RNA N6,2'-O-二甲基腺苷（m6Am）甲基转移酶PCIF1可负调控CD8+ T细胞抗肿瘤应答。全身性或T细胞特异性Pcif1基因敲除（KO）可抑制小鼠肿瘤生长。单细胞RNA测序显示，Pcif1缺陷小鼠肿瘤浸润性细胞毒性CD8+ T细胞数量增加。机制研究表明：通过蛋白质组学和m6Am测序分析发现，Pcif1 KO可上调m6Am修饰靶标——特别是铁死亡抑制基因（Fth1、Slc3a2）和T细胞活化基因Cd69，从而赋予CD8+ T细胞铁死亡抗性并增强其活化状态。值得注意的是，Pcif1缺陷小鼠对抗PD-1免疫治疗应答增强，且Pcif1 KO的嵌合抗原受体T细胞（CAR-T）表现出更强的肿瘤控制能力。临床数据分析显示，T细胞中PCIF1低表达的癌症患者对免疫治疗应答更佳。这些发现表明PCIF1抑制CD8+ T细胞活化，靶向PCIF1是增强抗肿瘤免疫的潜在策略。

8.T cell immune evasion by SARS-CoV-2 JN.1 escapees targeting two cytotoxic T cell epitope hotspots

SARS-CoV-2 JN.1变异株通过靶向两个细胞毒性T细胞表位热点实现免疫逃逸

中国疾病预防控制中心病毒病预防控制所

Although antibody escape is observed in emerging severe acute respiratory syndrome coronavirus 2 variants, T cell escape, especially after the global circulation of BA.2.86/JN.1, is unexplored. Here we demonstrate that T cell evasion exists in epitope hotspots spanning BA.2.86/JN.1 mutations. The newly emerging Q229K at this conserved nucleocapsid protein site impairs HLA-A2 epitope hotspot recognition. The association between HLA-A24 convalescents and T cell immune escape points to the spike (S) protein epitope S448–456NYNYLYRLF, with multiple mutations from Delta to JN.1, including L452Q, L452R, F456L, N450D and L452W, and N450D, L452W and L455S. A cliff drop of immune responses was observed for S448–456NYNYRYRLF (Delta/BA.5.2) and S448–456NYDYWYRSF (JN.1), but with immune preservation of S448–456NYDYWYRLF (BA.2.86). Structural analyses showed that hydrophobicity exposure determines the pronounced escape of L452R and L455S mutants, which was further confirmed by T cell receptor binding. This study highlights the characteristics and molecular mechanisms of the T cell immune escape for JN.1 and provides new insights into understanding the dominant circulation of variants, from the viewpoint of cytotoxic T cell evasion.

尽管新出现的严重急性呼吸综合征冠状病毒2（SARS-CoV-2）变异株已表现出抗体逃逸能力，但T细胞逃逸现象——尤其是在BA.2.86/JN.1变异株全球传播后——仍未被充分探索。本研究发现，BA.2.86/JN.1突变热点区域存在T细胞表位逃逸现象。其中，高度保守的核衣壳蛋白位点新出现的Q229K突变会损害HLA-A2限制性表位热点的识别。对HLA-A24康复患者的分析揭示，刺突蛋白（S蛋白）表位S448–456NYNYLYRLF（从Delta到JN.1变异株累积了包括L452Q、L452R、F456L、N450D、L452W及L455S在内的多重突变）与T细胞免疫逃逸密切相关。研究发现，针对Delta/BA.5.2变异株的S448–456NYNYRYRLF表位和JN.1变异株的S448–456NYDYWYRSF表位的T细胞应答出现断崖式下降，但对BA.2.86变异株的S448–456NYDYWYRLF表位仍保持免疫识别。结构分析表明，疏水性暴露程度决定了L452R和L455S突变体的显著逃逸能力，这一发现通过T细胞受体结合实验得到进一步验证。该研究不仅阐明了JN.1变异株T细胞免疫逃逸的特征与分子机制，更为从细胞毒性T细胞逃逸视角理解变异株优势传播的免疫学基础提供了新见解。

9.A multi-kinase inhibitor screen identifies inhibitors preserving stem-cell-like chimeric antigen receptor T cells

多激酶抑制剂筛选鉴定出可维持干细胞样嵌合抗原受体T细胞的抑制剂

美国北卡罗来纳州教堂山市北卡罗来纳大学教堂山分校药理学系

Chimeric antigen receptor T cells (CAR T cells) with T stem (TSCM) cell-like phenotypic characteristics promote sustained antitumor effects. We performed an unbiased and automated high-throughput screen of a kinase-focused compound set to identify kinase inhibitors (KIs) that preserve human TSCM cell-like CAR T cells. We identified three KIs, UNC10225387B, UNC10225263A and UNC10112761A, that combined in vitro increased the frequency of CD45RA+CCR7+TCF1hi TSCM cell-like CAR T cells from both healthy donors and patients with cancer. KI-treated CAR T cells showed enhanced antitumor effects both in vitro and in vivo in mouse tumor models. The KI cocktail maintains TSCM cell-like phenotype preferentially in CAR T cells originating from naive T cells and causes transcriptomic changes without arresting T cell activation or modulating the chromatin organization. Specific kinases, ITK, ADCK3, MAP3K4 and CDK13, targeted by the KI cocktail in a dose-dependent manner are directly associated with the preservation of TSCM cell-like CAR T cells. Knockdown of these kinases individually or in combination enriches for TSCM cell-like CAR T cells, but only CAR T cells generated in the presence of the KI cocktail show robust expansion and differentiation on stimulation with tumor cells. Overall, transient pharmacological inhibition of strategically targeted kinases maintains stem-like features in CAR T cells and improves their antitumor activity.

具有T干细胞样（TSCM）表型特征的嵌合抗原受体T细胞（CAR-T细胞）可产生持续抗肿瘤效应。本研究通过无偏倚、自动化的高通量筛选，从激酶靶向化合物库中鉴定出能维持人TSCM样CAR-T细胞的激酶抑制剂（KIs）。研究发现了三种激酶抑制剂（UNC10225387B、UNC10225263A和UNC10112761A），其组合在体外实验中能显著增加健康供体和癌症患者来源的CAR-T细胞中CD45RA+CCR7+TCF1hi TSCM样细胞的比例。经KI处理的CAR-T细胞在小鼠肿瘤模型中展现出增强的体外和体内抗肿瘤效果。该KI组合可优先维持源自初始T细胞的CAR-T细胞的TSCM样表型，并在不阻滞T细胞活化或改变染色质结构的情况下，引起转录组变化。进一步研究发现，KI组合以剂量依赖性方式靶向的特定激酶（ITK、ADCK3、MAP3K4和CDK13）与TSCM样CAR-T细胞的维持直接相关。单独或联合敲低这些激酶虽能富集TSCM样CAR-T细胞，但只有在KI组合存在下生成的CAR-T细胞才能在肿瘤细胞刺激下表现出强劲的扩增和分化能力。这项研究表明，通过瞬时药理学抑制策略性靶向激酶，可维持CAR-T细胞的干细胞样特性并提升其抗肿瘤活性。

Volume 26, Issue 3

本期共发表论著9篇。

1.Transcriptional activation of regenerative hematopoiesis via microenvironmental sensing

微环境感知驱动的再生造血转录激活机制

康奈尔医学院医学系器官再生研究所

Transition between activation and quiescence states in hematopoietic stem and progenitor cells (HSPCs) is tightly governed by cell-intrinsic means and microenvironmental co-adaptation. Although this balance is fundamental for lifelong hematopoiesis and immunity, the underlying molecular mechanisms remain poorly defined. Multimodal analysis divulging differential transcriptional activity between distinct HSPC states indicates the presence of Fli-1 transcription factor binding motif in activated hematopoietic stem cells. We reveal that Fli-1 activity is essential during regenerative hematopoiesis in mice. Fli-1 directs activation programs while priming cellular sensory and output machineries, enabling HSPCs co-adoptability with a stimulated vascular niche through propagation of niche-derived angiocrine Notch1 signaling. Constitutively induced Notch1 signaling is sufficient to recuperate functional hematopoietic stem cells impairments in the absence of Fli-1, without leukemic transformation. Applying FLI-1 transient modified-mRNA transduction into latent adult human mobilized HSPCs, enables their niche-mediated expansion and superior engraftment capacities. Thus, decryption of stem cell activation programs offers valuable insights for immunological regenerative medicine.

造血干祖细胞（HSPCs）在活化与静息状态间的转换受到细胞内在机制与微环境协同适应的精密调控。尽管这种平衡对维持终生造血和免疫功能至关重要，其分子机制却尚未阐明。通过多模态分析揭示不同HSPC状态间的转录活性差异，研究发现活化态造血干细胞中存在Fli-1转录因子结合基序。研究表明，Fli-1在小鼠造血再生过程中不可或缺——它既能主导活化程序，又可启动细胞感知与输出机制，通过传递血管微环境来源的血管分泌型Notch1信号，使HSPCs与受刺激的血管生态位形成协同适应。值得注意的是，持续激活Notch1信号足以在Fli-1缺失时恢复功能性造血干细胞活性，且不会诱发白血病转化。应用FLI-1修饰mRNA瞬时转导技术处理成人潜伏期动员HSPCs，可显著增强其生态位介导的扩增能力和移植效能。这项研究揭示的干细胞活化程序解码策略，为免疫再生医学提供了重要启示。

2.The lactate receptor HCAR1 drives the recruitment of immunosuppressive PMN-MDSCs in colorectal cancer

乳酸受体HCAR1驱动免疫抑制性PMN-MDSCs在结直肠癌中的募集

华东师范大学生物医学研究所、生命科学学院

Most patients with colorectal cancer do not achieve durable clinical benefits from immunotherapy, underscoring the existence of alternative immunosuppressive mechanisms. Here we found that activation of the lactate receptor HCAR1 signaling pathway induced the expression of chemokines CCL2 and CCL7 in colorectal tumor cells, leading to the recruitment of immunosuppressive CCR2+ polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) to the tumor microenvironment. Ablation of Hcar1 in mice with colorectal tumors significantly decreased the abundance of tumor-infiltrating CCR2+ PMN-MDSCs, enhanced the activation of CD8+ T cells and, consequently, reduced tumor burden. We detected immunosuppressive CCR2+ PMN-MDSCs in tumor specimens from individuals with colorectal and other cancers. The US Food and Drug Administration-approved drug reserpine suppressed lactate-mediated HCAR1 activation, impaired the recruitment of CCR2+ PMN-MDSCs, boosted CD8+ T cell-dependent antitumor immunity and sensitized immunotherapy-resistant tumors to programmed cell death protein 1 antibody therapy in mice with colorectal tumors. Altogether, we described HCAR1-driven recruitment of CCR2+ PMN-MDSCs as a mechanism of immunosuppression.

大多数结直肠癌患者无法从免疫治疗中获得持久疗效，这一现象提示存在其他免疫抑制机制。本研究发现，乳酸受体HCAR1信号通路的激活可诱导结直肠肿瘤细胞表达趋化因子CCL2和CCL7，进而招募具有免疫抑制功能的CCR2+多形核髓系来源抑制细胞（PMN-MDSCs）至肿瘤微环境。在结直肠癌模型小鼠中，敲除Hcar1基因可显著减少肿瘤浸润性CCR2+ PMN-MDSCs的数量，增强CD8+ T细胞活化，从而降低肿瘤负荷。作者在结直肠癌及其他癌症患者的肿瘤样本中也检测到了这类免疫抑制性CCR2+ PMN-MDSCs。美国FDA批准药物利血平可抑制乳酸介导的HCAR1活化，阻断CCR2+ PMN-MDSCs的招募，增强CD8+ T细胞依赖性抗肿瘤免疫，并使免疫治疗耐药的结直肠癌模型小鼠对PD-1抗体治疗重新敏感。该研究揭示了HCAR1驱动CCR2+ PMN-MDSCs募集的免疫抑制新机制。

3.Enteric GABAergic neuron-derived γ-aminobutyric acid initiates expression of Igfbp7 to sustain ILC3 homeostasis

肠道GABA能神经元来源的γ-氨基丁酸通过启动Igfbp7表达维持3型固有淋巴细胞稳态

中国科学院生物物理研究所、RNA科学与工程重点实验室、表观遗传调控与干预重点实验室

Neuronal signals have emerged as critical factors that regulate group 3 innate lymphoid cell (ILC3) response and tissue homeostasis, but the molecular mechanisms underlying this regulation remain largely elusive. Here, we identified that the enteric GABAergic neuron-derived neurotransmitter γ-aminobutyric acid (GABA) inhibited proliferation and IL-17A production in ILC3s in a manner dependent on the GABA receptors Gabbr1 and Gabbr2. Conditional deletion of Gabbr1 or ablation of GABAergic neurons caused increased IL-17A production and aggravated colitis. Mechanistically, GABA suppressed the expression of the LIP isoform of the transcription factor C/EBP-β in ILC3s, which repressed the transcription of Igfbp7, which encodes the secreted factor Igfbp7. Autocrine Igfbp7 signaling through the receptor Igf1R inhibited ILC3 proliferation and IL-17A production. Suppression of signaling through the GABA-C/EBP-β-IGFBP7 pathway highly correlated with severity of intestinal inflammation in patients with inflammatory bowel disease (IBD). Collectively, our findings describe an important molecular mechanism underlying the maintenance of gut immune homeostasis.

神经元信号作为调控3型固有淋巴细胞（ILC3）应答与组织稳态的关键因子已被广泛认知，但其分子机制尚不明确。本研究发现，肠道γ-氨基丁酸（GABA）能神经元来源的神经递质GABA通过依赖GABA受体Gabbr1和Gabbr2的方式，抑制ILC3的增殖与IL-17A产生。条件性敲除Gabbr1或消融GABA能神经元会导致IL-17A分泌增加并加剧结肠炎。机制研究表明，GABA通过抑制ILC3中转录因子C/EBP-β的LIP亚型表达，进而阻遏分泌因子Igfbp7的编码基因转录。自分泌的Igfbp7通过受体Igf1R发出的信号可抑制ILC3增殖与IL-17A产生。在炎症性肠病（IBD）患者中，GABA-C/EBP-β-IGFBP7信号通路的抑制程度与肠道炎症严重程度高度相关。该研究揭示了维持肠道免疫稳态的重要分子机制。

4.Short IL-18 generated by caspase-3 cleavage mobilizes NK cells to suppress tumor growth

由caspase-3切割生成的短链IL-18可激活NK细胞以抑制肿瘤生长

中国科学院上海免疫与感染研究所

苏州大学苏州医学院生命科学学院

Interleukin (IL)-18 functions primarily through its 18-kDa mature form produced from caspase-1 cleavage. However, IL-18 can also be processed by other proteases, leading to the generation of different fragments with less recognized functions. Here, we discover that, in cancer cells, caspase-3 cleavage of IL-18 generates a 15-kDa form of IL-18, referred to as short IL-18. Unlike mature IL-18, short IL-18 is not secreted, and does not bind IL-18Rα; instead, it translocates into the nucleus, facilitating STAT1 phosphorylation at Ser727 via CDK8, and enhancing the expression and secretion of ISG15. This signaling cascade in cancer cells mobilizes natural killer cells with increased cytotoxicity to eliminate various syngeneic tumors and colitis-associated colorectal cancer in mice. Moreover, patients with colorectal cancer who have an abundance of short IL-18 in the nucleus have a better prognosis. This work highlights a distinct anti-tumor pathway driven by short IL-18.

白细胞介素18（IL-18）主要通过caspase-1切割产生的18 kDa成熟形式发挥作用。然而，IL-18也可被其他蛋白酶加工，产生功能尚不明确的不同片段。本研究发现，在癌细胞中，caspase-3切割IL-18可生成15 kDa的短IL-18（short IL-18）。与成熟IL-18不同，短IL-18不被分泌且不结合IL-18Rα，而是转位至细胞核内，通过CDK8促进STAT1 Ser727位点磷酸化，进而增强ISG15的表达与分泌。这一癌细胞中的信号级联反应可募集具有增强细胞毒性的自然杀伤细胞，从而清除小鼠体内多种同源肿瘤及结肠炎相关结直肠癌。此外，核内富含短IL-18的结直肠癌患者预后更佳。该研究揭示了一条由短IL-18驱动的独特抗肿瘤通路。

5.Autophagy repression by antigen and cytokines shapes mitochondrial, migration and effector machinery in CD8 T cells

抗原与细胞因子对自噬的抑制调控CD8 T细胞的线粒体动态、迁移能力及效应功能

英国邓迪大学生命科学学院细胞信号传导和免疫学系

Autophagy shapes CD8 T cell fate; yet the timing, triggers and targets of this process are poorly defined. Herein, we show that naive CD8 T cells have high autophagic flux, and we identify an autophagy checkpoint whereby antigen receptor engagement and inflammatory cytokines acutely repress autophagy by regulating amino acid transporter expression and intracellular amino acid delivery. Activated T cells with high levels of amino acid transporters have low autophagic flux in amino-acid-replete conditions but rapidly reinduce autophagy when amino acids are restricted. A census of proteins degraded and fueled by autophagy shows how autophagy shapes CD8 T cell proteomes. In cytotoxic T cells, dominant autophagy substrates include cytolytic effector molecules, and amino acid and glucose transporters. In naive T cells, mitophagy dominates and selective mitochondrial pruning supports the expression of molecules that coordinate T cell migration and survival. Autophagy thus differentially prunes naive and effector T cell proteomes and is dynamically repressed by antigen receptors and inflammatory cytokines to shape T cell differentiation.

自噬作用调控CD8 T细胞的命运，但这一过程的时机、触发因素和作用靶点尚不明确。本研究发现，初始CD8 T细胞具有较高的自噬通量，并揭示了一个关键检查点：抗原受体激活和炎症细胞因子可通过调节氨基酸转运体表达及细胞内氨基酸递送急剧抑制自噬过程。高表达氨基酸转运体的活化T细胞在氨基酸充足时自噬通量较低，但在氨基酸受限时会快速重启自噬。通过对自噬降解和供能蛋白质的系统分析，揭示了自噬如何塑造CD8 T细胞蛋白质组：在细胞毒性T细胞中，自噬的主要底物包括细胞溶解效应分子、氨基酸及葡萄糖转运体；而在初始T细胞中，线粒体自噬占主导地位，选择性线粒体修剪有助于协调T细胞迁移和存活相关分子的表达。研究表明，自噬通过差异修剪初始T细胞与效应T细胞的蛋白质组，并受抗原受体和炎症细胞因子的动态抑制，从而调控T细胞的分化进程。

6.Terminal differentiation and persistence of effector regulatory T cells essential for preventing intestinal inflammation

终末分化并长期存活的效应调节性T细胞是预防肠道炎症的关键

美国加利福尼亚州拉霍亚斯克里普斯研究中心免疫学和微生物学系

Regulatory T (Treg) cells are a specialized CD4+ T cell lineage with essential anti-inflammatory functions. Analysis of Treg cell adaptations to non-lymphoid tissues that enable their specialized immunosuppressive and tissue-supportive functions raises questions about the underlying mechanisms of these adaptations and whether they represent stable differentiation or reversible activation states. Here, we characterize distinct colonic effector Treg cell transcriptional programs. Attenuated T cell receptor (TCR) signaling and acquisition of substantial TCR-independent functionality seems to facilitate the terminal differentiation of a population of colonic effector Treg cells that are distinguished by stable expression of the immunomodulatory cytokine IL-10. Functional studies show that this subset of effector Treg cells, but not their expression of IL-10, is indispensable for colonic health. These findings identify core features of the terminal differentiation of effector Treg cells in non-lymphoid tissues and their function.

调节性T细胞（Treg细胞）是一类具有重要抗炎功能的特殊CD4⁺ T细胞亚群。Treg细胞在非淋巴组织中所表现出的适应性变化，使其具备特有的免疫抑制与组织支持功能，这引发了人们对其适应机制本质的关注：这些变化究竟是稳定的分化状态，还是可逆的活化状态？本研究描述了结肠效应性Treg细胞的特异性转录程序。研究表明，减弱的T细胞受体（TCR）信号传导以及显著的TCR非依赖性功能获得，有助于一类终末分化的结肠效应性Treg细胞的形成，该细胞群以免疫调节性细胞因子IL10的稳定表达为特征。功能研究进一步发现，这一效应性Treg细胞亚群本身（而非其所表达的IL10）对于维持结肠健康至关重要。上述发现揭示了非淋巴组织中效应性Treg细胞终末分化的核心特征及其在组织稳态中的关键作用。

7.Progressively differentiated TFH13 cells are stabilized by JunB to mediate allergen germinal center responses

逐步分化的TFH13细胞通过JunB蛋白作用获得稳定性，从而介导过敏原诱导的生发中心反应

哈佛医学院，布里根和女子医院，肾脏医学部，移植研究中心

Allergic diseases are common and affect a large proportion of the population. Interleukin-13 (IL-13)-expressing follicular helper T (TFH13) cells are a newly identified population of TFH cells that have been associated with high-affinity IgE responses. However, the origins, developmental signals, transcriptional programming and precise functions of TFH13 cells are unknown. Here, we examined the developmental signals for TFH13 cells and found a direct and progressive differentiation pathway marked by the production of IL-21. These two pathways differed in kinetics and extrinsic requirements. However, both pathways converged, forming transcriptionally similar TFH13 cells that express the transcription factor JunB as a critical stabilizing factor. Using an intersectional genetics-based TFH13-diphtheria toxin receptor model to perturb these cells, we found that TFH13 cells were essential to drive broad germinal center responses and allergen-specific IgG and IgE. Moreover, we found that IL-21 is a broad positive regulator of allergen germinal center B cells and synergizes with IL-13 produced by TFH13 cells to amplify allergic responses. Thus, TFH13 cells orchestrate multiple features of allergic inflammation.

过敏性疾病十分常见，影响着广大人群。最新研究发现，分泌白细胞介素13（IL-13）的滤泡辅助性T细胞（TFH13细胞）是一类新型TFH细胞亚群，与高亲和力IgE应答密切相关。然而，TFH13细胞的起源、发育信号、转录程序及其精确功能尚不明确。本研究系统解析了TFH13细胞的发育信号，发现其通过产生IL-21标记的直接渐进式分化路径。这两种分化路径在动力学特征和外源需求方面存在差异，但最终趋同形成转录特征相似的TFH13细胞，并以转录因子JunB作为关键稳定因子。通过构建基于交叉遗传学的TFH13-白喉毒素受体模型干扰这些细胞，研究人员发现TFH13细胞对驱动广泛的生发中心应答及过敏原特异性IgG/IgE产生至关重要。更重要的是，研究揭示了IL-21是调控过敏原生发中心B细胞的广谱正向调节因子，并可与TFH13细胞分泌的IL-13协同放大过敏反应。这些发现表明，TFH13细胞可调控过敏炎症反应的多个关键环节。

8.STIM1-mediated NFAT signaling synergizes with STAT1 to control T-bet expression and TH1 differentiation

STIM1介导的NFAT信号通路与STAT1协同调控T-bet表达及TH1细胞分化

美国纽约州纽约市，纽约大学格罗斯曼医学院病理学系

Stromal interaction molecule 1 (STIM1) is critical for store-operated Ca2+ entry (SOCE) and T cell activation. T helper 1 (TH1) cells, which express T-bet (encoded by TBX21), mediate immunity to intracellular pathogens. Although SOCE is known to regulate other TH lineages, its role in Th1 differentiation remains unclear. Here, we report a patient with an intronic loss-of-function mutation in STIM1, which abolishes SOCE and causes immunodeficiency. We demonstrate that SOCE promotes nuclear factor of activated T cells (NFAT) binding to conserved noncoding sequence (CNS)-12 in the TBX21 enhancer and enables NFAT to synergize with STAT1 to mediate TBX21 expression. While SOCE-deficient CD4+ T cells have reduced expression of TBX21 in the absence of interleukin-12 (IL-12), their expression of IL-12 receptors β1 and β2 is increased, sensitizing them to IL-12 signaling and allowing IL-12 to rescue T-bet expression. Our study reveals that the STIM1-SOCE–NFAT signaling axis is essential for the differentiation of Th1 cells depending on the cytokine milieu.

基质相互作用分子1（STIM1）对钙库操纵性钙内流（SOCE）和T细胞活化至关重要。辅助性T细胞1（TH1）通过表达T-bet（由TBX21基因编码）介导对胞内病原体的免疫应答。尽管已知SOCE调控其他TH细胞亚群的分化，但其在TH1细胞分化中的作用尚不明确。本研究报道了一例STIM1基因内含子功能缺失突变患者，该突变导致SOCE功能丧失并引发免疫缺陷。研究发现，SOCE能促进活化T细胞核因子（NFAT）与TBX21增强子中的保守非编码序列CNS-12结合，并使NFAT与STAT1协同调控TBX21表达。虽然SOCE缺陷的CD4+ T细胞在缺乏白细胞介素12（IL-12）时TBX21表达降低，但其IL-12受体β1和β2的表达却显著增加，从而增强对IL-12信号通路的敏感性，使得IL-12能够恢复T-bet的表达。本研究揭示了STIM1-SOCE-NFAT信号轴在细胞因子微环境依赖的TH1细胞分化过程中发挥关键作用。

9.Robust mucosal SARS-CoV-2-specific T cells effectively combat COVID-19 and establish polyfunctional resident memory in patient lungs

黏膜驻留型SARS-CoV-2特异性T细胞高效抵御COVID-19并在患者肺部形成多功能记忆细胞群

广州医科大学第一附属医院、国家呼吸疾病临床研究中心、广州呼吸健康研究所、国家呼吸疾病重点实验室

Mucosal antigen-specific T cells are pivotal for pathogen clearance and immune modulation in respiratory infections. Dysregulated T cell responses exacerbate coronavirus disease 2019 severity, marked by cytokine storms and respiratory failure. Despite extensive description in peripheral blood, the characteristics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cells in the lungs remain elusive. Here we conducted integrated single-cell profiling of SARS-CoV-2-specific T cells in 122 bronchoalveolar lavage fluid (BALF) and 280 blood samples from 159 patients, including 27 paired BALF and blood samples from 24 patients. SARS-CoV-2-specific T cells were robustly elicited in BALF irrespective of prior vaccination, correlating with diminished viral loads, lessened systemic inflammation and improved respiratory function. SARS-CoV-2-specific T cells in BALF exhibited profound activation, along with proliferative and multi-cytokine-producing capabilities and a glycolysis-driven metabolic signature, which were distinct from those observed in peripheral blood mononuclear cells. After viral clearance, these specific T cells maintained a polyfunctional tissue-resident memory phenotype, highlighting their critical roles in infection control and long-term protection.

黏膜抗原特异性T细胞在呼吸道感染的病原体清除和免疫调节中起关键作用。T细胞应答失调会加剧2019冠状病毒病（COVID-19）的严重程度，其特征是细胞因子风暴和呼吸衰竭。尽管对外周血中的T细胞已有大量研究，但严重急性呼吸综合征冠状病毒2（SARS-CoV-2）特异性T细胞在肺部的特征仍不清楚。本研究对159例患者的122份支气管肺泡灌洗液（BALF）和280份血液样本（包括24例患者的27对BALF-血液配对样本）中的SARS-CoV-2特异性T细胞进行了整合单细胞分析。结果显示，无论是否接种过疫苗，BALF中均能有效诱导SARS-CoV-2特异性T细胞，其存在与病毒载量降低、全身炎症减轻和呼吸功能改善相关。这些肺部特异性T细胞表现出显著活化状态，具有增殖和多细胞因子分泌能力，以及糖酵解驱动的代谢特征，与外周血单个核细胞中的T细胞明显不同。在病毒清除后，这些特异性T细胞仍保持多功能组织驻留记忆表型，凸显了它们在感染控制和长期保护中的关键作用。

Volume 26, Issue 4

本期共发表论著5篇

1.Tuft cell IL-17RB restrains IL-25 bioavailability and reveals context-dependent ILC2 hypoproliferation

Tuft细胞IL-17RB通过限制IL-25生物利用度调控ILC2增殖抑制的表型可塑性

苏黎世大学生理研究所

The tuft cell–group 2 innate lymphoid cell (ILC2) circuit orchestrates rapid type 2 responses upon detecting microbially derived succinate and luminal helminths. Our findings delineate key mechanistic steps involving IP3R2 engagement and Ca2+ flux, governing interleukin-25 (IL-25) production by tuft cells triggered by succinate detection. While IL-17RB has a pivotal intrinsic role in ILC2 activation, it exerts a regulatory function in tuft cells. Tuft cells exhibit constitutive Il25 expression, placing them in an anticipatory state that facilitates rapid production of IL-25 protein for ILC2 activation. Tuft cell IL-17RB is crucial for restraining IL-25 bioavailability, preventing excessive tonic ILC2 stimulation due to basal Il25 expression. Supraoptimal ILC2 stimulation by IL-25 resulting from tuft cell Il17rb deficiency or prolonged succinate exposure induces a state of hypoproliferation in ILC2s, also observed in chronic helminth infection. Our study offers critical insights into the regulatory dynamics of IL-25 in this circuit, highlighting the delicate tuning required for responses to diverse luminal states.

簇细胞-2型固有淋巴细胞（ILC2）环路通过感知微生物源性琥珀酸和管腔蠕虫，协调快速2型免疫应答。本研究揭示了琥珀酸触发簇细胞产生白细胞介素-25（IL-25）的关键机制步骤，包括IP3R2受体的激活和钙离子流调控。虽然IL-17RB在ILC2活化中具有核心内在作用，但在簇细胞中却发挥调节功能。簇细胞具有组成性Il25表达特性，使其处于"预激活"状态，可快速生成IL-25蛋白以激活ILC2。簇细胞IL-17RB对限制IL-25生物利用度至关重要，可防止基础Il25表达导致的ILC2过度刺激。当簇细胞Il17rb缺失或长期暴露于琥珀酸时，IL-25对ILC2的超阈值刺激会诱导其增殖抑制状态——这种现象在慢性蠕虫感染中同样被观察到。该研究为阐释IL-25在此环路中的调控动力学提供了关键见解，揭示了机体响应不同管腔状态所需的精细调节机制。

2. Enhancing human NK cell antitumor function by knocking out SMAD4 to counteract TGFβ and activin A suppression

通过敲除SMAD4基因拮抗TGFβ与激活素A的抑制作用增强人类NK细胞抗肿瘤功能

西班牙巴塞罗那，德尔马医院研究所

Transforming growth factor beta (TGFβ) and activin A suppress natural killer (NK) cell function and proliferation, limiting the efficacy of adoptive NK cell therapies. Inspired by the partial resistance to TGFβ of NK cells with SMAD4 haploinsufficiency, we used CRISPR–Cas9 for knockout of SMAD4 in human NK cells. Here we show that SMAD4KO NK cells were resistant to TGFβ and activin A inhibition, retaining their cytotoxicity, cytokine secretion and interleukin-2/interleukin-15-driven proliferation. They showed enhanced tumor penetration and tumor growth control, both as monotherapy and in combination with tumor-targeted therapeutic antibodies. Notably, SMAD4KO NK cells outperformed control NK cells treated with a TGFβ inhibitor, underscoring the benefit of maintaining SMAD4-independent TGFβ signaling. SMAD4KO conferred TGFβ resistance across diverse NK cell platforms, including CD19-CAR NK cells, stem cell-derived NK cells and ADAPT-NK cells. These findings position SMAD4 knockout as a versatile and compelling strategy to enhance NK cell antitumor activity, providing a new avenue for improving NK cell-based cancer immunotherapies.

转化生长因子β（TGFβ）和激活素A会抑制自然杀伤（NK）细胞的功能与增殖，从而限制过继性NK细胞疗法的疗效。受SMAD4单倍剂量不足的NK细胞对TGFβ具有部分抗性这一现象的启发，研究人员利用CRISPR-Cas9技术敲除了人类NK细胞中的SMAD4基因。研究发现，SMAD4敲除（SMAD4KO）的NK细胞能够抵抗TGFβ和激活素A的抑制作用，保持其细胞毒性、细胞因子分泌能力以及白细胞介素-2/白细胞介素-15驱动的增殖特性。无论是作为单一疗法还是与肿瘤靶向治疗抗体联用，这些NK细胞都表现出更强的肿瘤浸润能力和肿瘤生长控制效果。值得注意的是，SMAD4KO NK细胞的疗效优于经TGFβ抑制剂处理的对照NK细胞，这证实了保留SMAD4非依赖性TGFβ信号传导的益处。SMAD4敲除技术可赋予多种NK细胞平台（包括CD19-CAR NK细胞、干细胞来源的NK细胞以及ADAPT-NK细胞）对TGFβ的抗性。这些发现表明，SMAD4基因敲除是一种通用且高效的增强NK细胞抗肿瘤活性的策略，为改进基于NK细胞的癌症免疫疗法提供了新途径。

3.Distinct type 1 immune networks underlie the severity of restrictive lung disease after COVID-19

不同的1型免疫网络调控COVID-19后限制性肺疾病的严重程度

美国弗吉尼亚大学医学院内科学系

The variable origins of persistent breathlessness after coronavirus disease 2019 (COVID-19) have hindered efforts to decipher the immunopathology of lung sequelae. Here we analyzed hundreds of cellular and molecular features in the context of discrete pulmonary phenotypes to define the systemic immune landscape of post-COVID lung disease. Cluster analysis of lung physiology measures highlighted two phenotypes of restrictive lung disease that differed according to their impaired diffusion and severity of fibrosis. Machine learning revealed marked CCR5+CD95+CD8+ T cell perturbations in milder lung disease but attenuated T cell responses hallmarked by elevated CXCL13 in more severe disease. Distinct sets of cells, mediators and autoantibodies distinguished each restrictive phenotype and differed from those of patients without substantial lung involvement. These differences were reflected in divergent T cell-based type 1 networks according to the severity of lung disease. Our findings, which provide an immunological basis for active lung injury versus advanced disease after COVID-19, might offer new targets for treatment.

2019冠状病毒病（COVID-19）后持续性呼吸困难的多源性阻碍了肺部后遗症免疫病理机制的解析。本研究通过结合离散肺部表型分析数百项细胞与分子特征，首次系统定义了COVID-19后肺疾病的全身免疫特征。肺功能指标的聚类分析揭示出两种限制性肺疾病表型，其差异主要体现在弥散功能受损程度和纤维化严重性。机器学习分析显示，较轻肺疾病患者存在显著的CCR5+CD95+CD8+ T细胞紊乱，而重症患者则表现为T细胞应答减弱并伴随CXCL13水平升高。每种限制性肺表型都具有独特的细胞、介质和自身抗体特征，这些特征与无显著肺部受累患者截然不同。基于T细胞的1型免疫网络会随肺病严重程度呈现分化态势。该研究不仅为COVID-19后活动性肺损伤与晚期疾病提供了免疫学解释，更可能为治疗提供了新靶点。

4.An SSTR2–somatostatin chemotactic axis drives T cell progenitor homing to the intestines

SSTR2-生长抑素趋化轴驱动T细胞前体向肠道定向迁移

美国加利福尼亚州帕洛阿尔托医疗系统分子生物学与医学中心

Progenitors of intraepithelial T cells (IELps) migrate from the thymus to the intestines after birth where they develop into unconventional TCRγδ and TCRαβ lymphocytes in a process of extrathymic lymphopoiesis within cryptopatches. Mechanisms of IELp migration have remained unclear. Here we show that thymic IELps express the somatostatin receptor SSTR2, which contributes to their homing to the gut. IELp homing is Sstr2 dependent and correlates with neonatal induction of Sst encoding somatostatin in neuroendocrine and lamina propria stromal cells. The SSTR2 ligands somatostatin and cortistatin attract IELps in chemotaxis assays and somatostatin triggers IELp binding to the mucosal vascular addressin MAdCAM1. T cell transduction with Sstr2 confers homing to the neonatal colon. Human fetal thymic IELp-like cells express SSTR2 and intestinal stromal cells express SST at the time of initial T cell population, suggesting conserved mechanisms of progenitor seeding of the developing intestines. These results reveal an unexpected role for the SSTR2–somatostatin axis in early immune system development and describe a new role for a small peptide hormone G-protein-coupled receptor in developmental lymphocyte trafficking.

上皮内T细胞前体（IELps）在出生后从胸腺迁移至肠道，并在肠隐窝淋巴滤泡中通过胸腺外淋巴生成过程发育为非常规TCRγδ和TCRαβ淋巴细胞。然而，IELps的迁移机制尚不明确。本研究发现，胸腺IELps表达生长抑素受体SSTR2，该受体介导其向肠道的归巢。IELps的归巢过程依赖于Sstr2基因，并与新生儿期神经内分泌细胞和固有层基质细胞中Sst基因（编码生长抑素）的诱导表达相关。趋化实验证实，SSTR2配体生长抑素和皮质抑素可吸引IELps，且生长抑素能触发IELps与黏膜血管地址素MAdCAM1的结合。通过Sstr2转导T细胞可使其获得向新生儿结肠归巢的能力。人类胎儿胸腺IELps样细胞同样表达SSTR2，且肠道基质细胞在T细胞初始定植期表达SST，提示肠道发育过程中前体细胞定植的机制具有保守性。这些结果揭示了SSTR2-生长抑素轴在免疫系统早期发育中的意外作用，并阐明了小肽激素G蛋白偶联受体在淋巴细胞发育性迁移中的新功能。

5.A critical role of N4-acetylation of cytidine in mRNA by NAT10 in T cell expansion and antiviral immunity

NAT10介导的mRNA胞苷N4-乙酰化修饰在T细胞扩增和抗病毒免疫中的关键作用

复旦大学附属中山医院 肺部炎症与损伤重点实验室

Following activation, naive T cells exit quiescence and require global translation for rapid expansion, yet the underlying mechanisms remain unclear. Here, we show that during T cell activation, cells upregulate the expression of N-acetyltransferase 10 (NAT10), an enzyme responsible for N4-acetylcytidine (ac4C) modification of mRNAs. ac4C-modified Myc mRNAs show higher translation efficiency, enabling rapid synthesis of MYC protein and supporting robust T cell expansion. Conditional deletion of Nat10 in mouse T cells causes severe cell cycle arrest and limitation of cell expansion due to MYC deficiency, ultimately exacerbating infection in an acute lymphocytic choriomeningitis virus model. Additionally, T cells from older individuals with lower NAT10 levels show proliferative defects, which may partially account for impaired antiviral responses in older individuals. This study reveals a mechanism governing T cell expansion, signal-dependent mRNA degradation induction and the potential in vivo biological significance of ac4C modification in T cell-mediated immune responses.

初始T细胞活化后会退出静息状态并需要全局翻译以支持快速扩增，然而这一过程的调控机制尚不明确。本研究发现，T细胞活化过程中会显著上调N-乙酰转移酶10（NAT10）的表达，该酶负责介导mRNA的N4-乙酰胞苷（ac4C）修饰。经ac4C修饰的Myc mRNA表现出更高的翻译效率，从而促进MYC蛋白的快速合成，支持T细胞的强效扩增。在小鼠T细胞中条件性敲除Nat10基因会导致因MYC缺乏而引起的严重的细胞周期阻滞和扩增受限，并最终加剧了急性淋巴细胞性脉络丛脑膜炎病毒感染模型的病情。此外，NAT10水平较低的老年人来源T细胞也表现出增殖缺陷，这可能是老年人抗病毒应答受损的部分原因。该研究揭示了调控T细胞扩增的新机制，即信号依赖性mRNA降解诱导途径，并阐明了ac4C修饰在T细胞介导的免疫应答中的潜在体内生物学意义。

汇报人：饶郁芳

审核：杨柠菲、蒋子涵、任建君