【Science Immunology】2023年11月-2024年1月刊论文导读

期刊介绍：

Science Immunology于2016年创刊，由American Association for the Advancement of Science出版商出版。发表报告免疫学研究所有领域的关键进展的研究文章，包括人类在内的所有模式生物的免疫学领域的原始研究结果。所涵盖的领域从先天免疫和适应性免疫生物学的基础研究(免疫细胞发育和分化、免疫基因组学、系统免疫学、结构免疫学、抗原呈递、免疫代谢和粘膜免疫学)到对健康和疾病的免疫贡献(宿主防御、炎症、癌症免疫、自身免疫、过敏、移植和免疫缺陷)。影响因子指数24.8。

本期文献导读将呈现2023年11月~2024年1月间共3个月内医学生物学相关的主要刊物内容。

单位：哈佛医学院免疫学系等

Exercise enhances physical performance and reduces the risk of many disorders such as cardiovascular disease, type 2 diabetes, dementia, and cancer. Exercise characteristically incites an inflammatory response, notably in skeletal muscles. Although some effector mechanisms have been identified, regulatory elements activated in response to exercise remain obscure. Here, we have addressed the roles of Foxp3+CD4+ regulatory T cells (Tregs) in the healthful activities of exercise via immunologic, transcriptomic, histologic, metabolic, and biochemical analyses of acute and chronic exercise models in mice. Exercise rapidly induced expansion of the muscle Treg compartment, thereby guarding against overexuberant production of interferon-γ and consequent metabolic disruptions, particularly mitochondrial aberrancies. The performance-enhancing effects of exercise training were dampened in the absence of Tregs. Thus, exercise is a natural Treg booster with therapeutic potential in disease and aging contexts.

锻炼可以增强身体机能，降低罹患心血管疾病、2型糖尿病、痴呆和癌症等多种疾病的风险。运动通常会引发炎症反应，尤其是骨骼肌。尽管一些响应机制已被发现，但为响应运动而激活的调节元件仍待探究。在这里，我们通过对小鼠急性和慢性运动模型的免疫学、转录组学、组织学、代谢和生化分析，探讨了Foxp3+CD4+调节性T细胞(Treg)在健康运动活动中的作用。运动会迅速诱导肌肉Treg区室扩张，从而防止干扰素γ过度产生以及随之而来的代谢紊乱，特别是线粒体异常。如果没有Tregs，运动训练的表现增强效果将受到削弱。因此，运动是天然的Treg增强剂，在疾病和衰老方面具有治疗潜力。

2.Transcriptomes and metabolism define mouse and human MAIT cell populations

转录组和代谢组学定义小鼠和人类MAIT细胞群

单位：拉霍亚免疫学研究所自身免疫和炎症中心；拉霍亚免疫学研究所传染病和疫苗研究中心

Abstract:

Mucosal-associated invariant T (MAIT) cells are a subset of T lymphocytes that respond to microbial metabolites. We defined MAIT cell populations in different organs and characterized the developmental pathway of mouse and human MAIT cells in the thymus using single-cell RNA sequencing and phenotypic and metabolic analyses. We showed that the predominant mouse subset, which produced IL-17 (MAIT17), and the subset that produced IFN-γ (MAIT1) had not only greatly different transcriptomes but also different metabolic states. MAIT17 cells in different organs exhibited increased lipid uptake, lipid storage, and mitochondrial potential compared with MAIT1 cells. All these properties were similar in the thymus and likely acquired there. Human MAIT cells in lung and blood were more homogeneous but still differed between tissues. Human MAIT cells had increased fatty acid uptake and lipid storage in blood and lung, similar to human CD8 T resident memory cells, but unlike mouse MAIT17 cells, they lacked increased mitochondrial potential. Although mouse and human MAIT cell transcriptomes showed similarities for immature cells in the thymus, they diverged more strikingly in the periphery. Analysis of pet store mice demonstrated decreased lung MAIT17 cells in these so-called "dirty" mice, indicative of an environmental influence on MAIT cell subsets and function.

粘膜相关恒定T (MAIT) 细胞是对微生物代谢产物做出反应的T淋巴细胞亚群。我们定义了不同器官中的MAIT细胞群，并使用单细胞RNA测序以及表型和代谢分析来表征小鼠和人类胸腺中MAIT细胞的发育途径。我们发现，产生IL-17(MAIT17) 的主要小鼠亚群和产生IFN-γ(MAIT1) 的主要小鼠亚群不仅转录组层面差异很大，而且两者代谢水平也不同。与MAIT1细胞相比，不同器官中的MAIT17细胞表现出更高的脂质摄取、脂质储存和线粒体电位，所有这些特性在胸腺中都很相似，并且可能是在那里获得的。人类肺和血液中的MAIT细胞更加同质，但组织之间仍然存在差异。人MAIT细胞在血液和肺中的脂肪酸摄取和脂质储存增加，与人CD8 T驻留记忆细胞相似，但与小鼠MAIT17细胞不同，它们缺乏线粒体潜能的增加。尽管小鼠和人类MAIT细胞转录组显示胸腺中未成熟细胞的相似性，但在外周具有显著差异。对宠物店小鼠的分析表明，这些所谓的“脏”小鼠的肺MAIT17细胞减少，表明环境对MAIT细胞亚群和功能的影响。

3.CSF1R-dependent macrophages in the salivary gland are essential for epithelial regeneration after radiation-induced injury

唾液腺中 CSF1R 依赖性巨噬细胞对于辐射损伤后上皮再生至关重要

单位：爱丁堡大学再生与修复研究所再生医学中心

Abstract:

The salivary glands often become damaged in individuals receiving radiotherapy for head and neck cancer, resulting in chronic dry mouth. This leads to detrimental effects on their health and quality of life, for which there is no regenerative therapy. Macrophages are the predominant immune cell in the salivary glands and are attractive therapeutic targets due to their unrivaled capacity to drive tissue repair. Yet, the nature and role of macrophages in salivary gland homeostasis and how they may contribute to tissue repair after injury are not well understood. Here, we show that at least two phenotypically and transcriptionally distinct CX3CR1+ macrophage populations are present in the adult salivary gland, which occupy anatomically distinct niches. CD11c+CD206-CD163- macrophages typically associate with gland epithelium, whereas CD11c-CD206+CD163+ macrophages associate with blood vessels and nerves. Using a suite of complementary fate mapping systems, we show that there are highly dynamic changes in the ontogeny and composition of salivary gland macrophages with age. Using an in vivo model of radiation-induced salivary gland injury combined with genetic or antibody-mediated depletion of macrophages, we demonstrate an essential role for macrophages in clearance of cells with DNA damage. Furthermore, we show that epithelial-associated macrophages are indispensable for effective tissue repair and gland function after radiation-induced injury, with their depletion resulting in reduced saliva production. Our data, therefore, provide a strong case for exploring the therapeutic potential of manipulating macrophages to promote tissue repair and thus minimize salivary gland dysfunction after radiotherapy.

接受头颈癌放射治疗的人的唾液腺经常受损，导致慢性口干。这会对他们的健康和生活质量产生不利影响，而对此没有再生疗法。巨噬细胞是唾液腺中的主要免疫细胞，由于其驱动组织修复的强大能力而成为有吸引力的治疗靶点。然而，巨噬细胞在唾液腺稳态中的性质和作用以及它们如何促进损伤后的组织修复尚不清楚。在这里，我们发现成人唾液腺中至少存在两个表型和转录上不同的CX3CR1+巨噬细胞群，它们占据了解剖学上不同的生态位。CD11c+CD206-CD163-巨噬细胞通常与腺上皮相关，而CD11c-CD206+CD163+巨噬细胞与血管和神经相关。使用一套互补的命运映射系统，我们发现唾液腺巨噬细胞的个体发育和组成随着年龄的增长而发生高度动态的变化。利用辐射诱导唾液腺损伤的体内模型，结合遗传或抗体介导的巨噬细胞耗竭，我们证明了巨噬细胞在清除DNA损伤细胞中的重要作用。此外，我们发现上皮相关巨噬细胞对于辐射引起的损伤后的有效组织修复和腺体功能是不可或缺的，其消耗会导致唾液产生减少。因此，我们的数据为探索操控巨噬细胞促进组织修复的治疗潜力提供了强有力的案例，从而最大限度地减少放射治疗后的唾液腺功能障碍。

4.Myeloid OTULIN deficiency couples RIPK3-dependent cell death to Nlrp3 inflammasome activation and IL-1β secretion

髓系OTULIN缺陷将RIPK3依赖性细胞死亡与Nlrp3炎症小体激活和IL-1β分泌结合起来

单位：根特大学内科和儿科系、炎症研究中心、生物医学分子生物学系、药物生物技术实验室；安特卫普大学生物医学系蛋白质科学、蛋白质组学和表观遗传信号传导实验室

Abstract:

Loss-of-function mutations in the deubiquitinase OTULIN result in an inflammatory pathology termed "OTULIN-related autoinflammatory syndrome" (ORAS). Genetic mouse models revealed essential roles for OTULIN in inflammatory and cell death signaling, but the mechanisms by which OTULIN deficiency connects cell death to inflammation remain unclear. Here, we identify OTULIN deficiency as a cellular condition that licenses RIPK3-mediated cell death in murine macrophages, leading to Nlrp3 inflammasome activation and subsequent IL-1β secretion. OTULIN deficiency uncoupled Nlrp3 inflammasome activation from gasdermin D-mediated pyroptosis, instead allowing RIPK3-dependent cell death to act as an Nlrp3 inflammasome activator and mechanism for IL-1β release. Accordingly, elevated serum IL-1β levels in myeloid-specific OTULIN-deficient mice were diminished by deleting either Ripk3 or Nlrp3. These findings identify OTULIN as an inhibitor of RIPK3-mediated IL-1β release in mice.

去泛素酶OTULIN的功能丧失突变会导致“OTULIN 相关自身炎症综合征”(ORAS)。基因小鼠模型揭示了OTULIN在炎症和细胞死亡信号传导中的重要作用，但OTULIN缺陷将细胞死亡与炎症联系起来的机制仍不清楚。在这里，我们将OTULIN缺陷确定为一种细胞疾病，它准许RIPK3介导的小鼠巨噬细胞死亡，导致Nlrp3炎症小体激活和随后的IL-1β分泌。OTULIN缺陷使Nlrp3炎症小体激活与Gasdermin D介导的细胞焦亡解偶联，转而使RIPK3 依赖性细胞死亡充当Nlrp3炎症小体激活剂，进而引起IL-1β释放。因此，通过删除Ripk3或Nlrp3，可以减少髓系特异性OTULIN缺陷小鼠血清 IL-1β水平升高。这些发现确定了OTULIN是小鼠体内RIPK3介导的IL-1β释放的抑制剂。

5.Emergence and fate of stem cell–like Tcf7+ CD8+ T cells during a primary immune response to viral infection

病毒感染的初级免疫反应期间干细胞样Tcf7+ CD8+ T细胞的出现和命运

单位：洛桑大学肿瘤学系、瑞士生物信息学研究所、瑞士巴塞尔大学生物医学系实验病毒学系

Abstract:

In response to infection, naïve CD8+ T (TN) cells yield a large pool of short-lived terminal effector (TTE) cells that eliminate infected host cells. In parallel, a minor population of stem cell-like central memory (TCM) cells forms, which has the capacity to maintain immunity after pathogen clearance. It has remained uncertain whether stem-like TCM cells arise by dedifferentiation from a subset of cytolytic TTE cells or whether priming generates stem-like cells capable of seeding the TCM compartment and, if so, when cytolytic TTE cells branch off. Here, we show that CD8+ T cells with stem-like properties, which are identified by the expression of TCF1 (encoded by Tcf7), are present across the primary response to infection. Priming programs TN cells to undergo multiple cell divisions, over the course of which TCF1 expression is maintained. These TCF1+ cells further expand relatively independently of systemic inflammation, antigen dose, or affinity, and they quantitatively yield TCF1+ TCM cells after pathogen clearance. Inflammatory signals suppress TCF1 expression in early divided TCF1+ cells. TCF1 down-regulation is associated with the irreversible loss of self-renewal capacity and the silencing of stem/memory genes, which precedes the stable acquisition of a TTE state. TCF1 expression restrains cell cycling, explaining in part the limited expansion of TCF1+ relative to TCF1- cells during the primary response. Thus, our data are consistent with terminal differentiation of effector cells being a step-wise process that is initiated by inflammation in primed stem-like cells, which would otherwise become central memory cells by default.

为了应对感染，初始CD8+ T (TN)细胞会产生大量短寿命的终末效应(TTE)细胞，从而消除受感染的宿主细胞。与此同时，一小部分类似干细胞的中央记忆(TCM)细胞形成，它们有能力在病原体清除后维持免疫力。目前仍不确定干细胞样TCM细胞是否由溶细胞TTE细胞亚群去分化产生，或者启动是否产生能够接种TCM区室的干细胞样细胞，如果是这样，溶细胞TTE细胞何时分支。在这里，我们发现具有干细胞样特性的CD8+ T细胞存在于对感染的初级反应中，这些细胞通过TCF1(由Tcf7编码)的表达来识别。启动程序使TN细胞经历多次细胞分裂，在此过程中TCF1表达得以维持。这些TCF1+细胞相对独立于全身炎症、抗原剂量或亲和力进一步扩增，并且在病原体清除后定量产生TCF1+ TCM细胞。炎症信号抑制早期分裂的TCF1+细胞中的TCF1表达。TCF1下调与自我更新能力的不可逆丧失和干/记忆基因的沉默有关，这先于TTE状态的稳定获得。TCF1表达抑制细胞周期，部分解释了在初次反应期间TCF1+细胞相对于TCF1-细胞的有限扩张。因此，我们的数据与效应细胞的终末分化是一个逐步过程的结论是一致的，该过程是由引发的干细胞样细胞中的炎症启动的，否则默认情况下干细胞样细胞将成为中央记忆细胞。

6.Distinct use of super-enhancer elements controls cell type–specific CD25 transcription and function

不同的超级增强子元件控制细胞类型特异性 CD25 转录和功能

单位：美国国立卫生研究院国家心肺血液研究所免疫学中心分子免疫学

Abstract:

The IL-2 receptor α chain (IL-2Rα/CD25) is constitutively expressed on double-negative (DN2/DN3 thymocytes and regulatory T cells (Tregs) but induced by IL-2 on T and natural killer (NK) cells, with Il2ra expression regulated by a STAT5-dependent super-enhancer. We investigated CD25 regulation and function using a series of mice with deletions spanning STAT5-binding elements. Deleting the upstream super-enhancer region mainly affected constitutive CD25 expression on DN2/DN3 thymocytes and Tregs, with these mice developing autoimmune alopecia, whereas deleting an intronic region decreased IL-2-induced CD25 on peripheral T and NK cells. Thus, distinct super-enhancer elements preferentially control constitutive versus inducible expression in a cell type-specific manner. The mediator-1 coactivator colocalized with specific STAT5-binding sites. Moreover, both upstream and intronic regions had extensive chromatin interactions, and deletion of either region altered the super-enhancer structure in mature T cells. These results demonstrate differential functions for distinct super-enhancer elements, thereby indicating previously unknown ways to manipulate CD25 expression in a cell type-specific fashion.

IL-2受体α链(IL-2Rα/CD25)在双阴性(DN2/DN3)胸腺细胞和调节性T细胞 (Treg)上组成性表达，但在T细胞和自然杀伤(NK)细胞上受IL-2诱导，Il2ra表达受STAT5依赖性超级增强子调节。我们使用一系列STAT5结合元件缺失的小鼠研究了CD25调节和功能。删除上游超级增强子区域主要影响DN2/DN3胸腺细胞和Tregs上的组成型CD25表达，这些小鼠出现自身免疫性脱发，而删除内含子区域会降低外周T和NK细胞上IL-2诱导的CD25。因此，不同的超级增强子元件优先以细胞类型特异性方式控制组成型表达而不是诱导型表达。介质-1共激活因子与特定的STAT5结合位点共定位。此外，上游和内含子区域都具有广泛的染色质相互作用，并且任一区域的缺失都会改变成熟T细胞中的超级增强子结构。这些结果证明了不同的超级增强子元件的不同功能，从而阐明以前未知的以细胞类型特异性方式操纵CD25表达的方法。

7.Zfp281 and Zfp148 control CD4+ T cell thymic development and TH2 functions

Zfp281和Zfp148控制CD4+ T细胞胸腺发育和TH2功能

单位：美国国立卫生研究院国家癌症研究所癌症研究中心免疫细胞生物学实验室

Abstract:

How CD4+ lineage gene expression is initiated in differentiating thymocytes remains poorly understood. Here, we show that the paralog transcription factors Zfp281 and Zfp148 control both this process and cytokine expression by T helper cell type 2 (TH2) effector cells. Genetic, single-cell, and spatial transcriptomic analyses showed that these factors promote the intrathymic CD4+ T cell differentiation of class II major histocompatibility complex (MHC II)-restricted thymocytes, including expression of the CD4+ lineage-committing factor Thpok. In peripheral T cells, Zfp281 and Zfp148 promoted chromatin opening at and expression of TH2 cytokine genes but not of the TH2 lineage-determining transcription factor Gata3. We found that Zfp281 interacts with Gata3 and is recruited to Gata3 genomic binding sites at loci encoding Thpok and TH2 cytokines. Thus, Zfp148 and Zfp281 collaborate with Gata3 to promote CD4+ T cell development and TH2 cell responses.

CD4+谱系基因表达在分化胸腺细胞中如何启动仍知之甚少。在这里，我们证明了旁系同源转录因子Zfp281和Zfp148控制这一过程以及2型T辅助细胞(TH2)效应细胞的细胞因子表达。基因组、单细胞和空间转录组分析结果表明，这些因子促进II类主要组织相容性复合体(MHC II) 限制性胸腺细胞的胸腺内CD4+ T细胞分化，包括CD4+谱系决定因子Thpok的表达。在外周T细胞中，Zfp281和Zfp148促进TH2细胞因子基因的染色质开放和表达，但不促进TH2谱系决定转录因子Gata3的表达。我们发现Zfp281与Gata3相互作用，并被招募到编码Thpok和TH2细胞因子位点上的Gata3基因组结合位点。因此，Zfp148和Zfp281与Gata3协同促进CD4+ T细胞发育和TH2细胞反应。

8.Cancer immunotherapy via synergistic coactivation of myeloid receptors CD40 and Dectin-1

通过协同激活髓系受体CD40和Dectin-1进行癌症免疫治疗

单位：美国宾夕法尼亚州费城宾夕法尼亚大学佩雷尔曼医学院医学系血液学和肿瘤学系、艾布拉姆森癌症中心

Abstract:

Myeloid cells facilitate T cell immune evasion in cancer yet are pliable and have antitumor potential. Here, by cotargeting myeloid activation molecules, we leveraged the myeloid compartment as a therapeutic vulnerability in mouse models of pancreatic cancer. Myeloid cells in solid tumors expressed activation receptors including the pattern recognition receptor Dectin-1 and the TNF receptor superfamily member CD40. In mouse models of checkpoint inhibitor-resistant pancreatic cancer, coactivation of Dectin-1, via systemic β-glucan therapy, and CD40, with agonist antibody treatment, eradicated established tumors and induced immunological memory. Antitumor activity was dependent on cDC1s and T cells but did not require classical T cell-mediated cytotoxicity or blockade of checkpoint molecules. Rather, targeting CD40 drove T cell-mediated IFN-γ signaling, which converged with Dectin-1 activation to program distinct macrophage subsets to facilitate tumor responses. Thus, productive cancer immune surveillance in pancreatic tumors resistant to checkpoint inhibition can be invoked by coactivation of complementary myeloid signaling pathways.

髓系细胞有助于癌症中T细胞的免疫逃避，但具有可塑性且具有抗肿瘤潜力。在这里，通过共靶向髓系激活分子，我们利用髓系区室作为胰腺癌小鼠模型的治疗薄弱环节。实体瘤中的髓系细胞表达激活受体，包括模式识别受体Dectin-1和TNF受体超家族成员CD40。在检查点抑制剂耐药性胰腺癌小鼠模型中，通过全身β-葡聚糖治疗和CD40与激动剂抗体治疗共同激活Dectin-1，根除已形成的肿瘤并诱导免疫记忆。抗肿瘤活性依赖于cDC1和T细胞，但不需要经典的T细胞介导的细胞毒性或阻断免疫检查点。相反，靶向CD40驱动了T细胞介导的IFN-γ信号传导，该信号传导与Dectin-1激活相结合，对不同的巨噬细胞子集进行编程，以促进肿瘤反应。因此，对免疫检查点抑制具有抵抗力的胰腺肿瘤来说，其有效的癌症免疫监视可以通过互补髓系信号通路的共激活来启动。

9.Resident regulatory T cells reflect the immune history of individual lymph nodes

常驻调节性T细胞反映个体淋巴结的免疫历史

单位：亚琛工业大学分子医学研究所、计算基因组学研究所；维尔茨堡系统免疫学研究所

Abstract:

Regulatory T cells (Tregs) are present in lymphoid and nonlymphoid tissues where they restrict immune activation, prevent autoimmunity, and regulate inflammation. Tregs in nonlymphoid tissues are typically resident, whereas those in lymph nodes (LNs) are considered to recirculate. However, Tregs in LNs are not a homogenous population, and circulation kinetics of different Treg subsets are poorly characterized. Furthermore, whether Tregs can acquire memory T cell properties and persist for extended periods after their activation in LNs is unclear. Here, we used in situ labeling with a stabilized photoconvertible protein to uncover turnover rates of Tregs in LNs in vivo. We found that, whereas most Tregs in LNs recirculate, 10 to 20% are memory-like resident cells that remain in their respective LNs for weeks to months. Single-cell RNA sequencing revealed that LN-resident cells are a functionally and ontogenetically heterogeneous population and share the same core residency gene signature with conventional CD4+ and CD8+ T cells. Resident cells in LNs did not actively proliferate and did not require continuous T cell receptor (TCR) signaling for their residency. However, resident and circulating Tregs had distinct TCR repertoires, and each LN contained exclusive clonal subpopulations of resident Tregs. Our results demonstrate that, similar to conventional T cells, Tregs can form resident memory-like populations in LNs after adaptive immune responses. Specific and local suppression of immune responses by resident Tregs in draining LNs might provide previously unidentified therapeutic opportunities for the treatment of local chronic inflammatory conditions.

调节性T细胞(Treg)存在于淋巴和非淋巴组织中，它们限制免疫激活、预防自身免疫并调节炎症。非淋巴组织中的Treg通常是常驻的，而淋巴结(LN)中的 Treg被认为是再循环的。然而，LN中的Tregs并不是同质群体，并且不同Treg亚群的循环动力学特征很少。此外，Tregs在LN中激活后是否可以获得记忆T细胞特性并持续较长时间尚不清楚。在这里，我们使用稳定的光转换蛋白进行原位标记，以揭示体内LN中Tregs的周转率。我们发现，虽然LN中的大多数Tregs会再循环，但有10%到20%是类似记忆的常驻细胞，它们会在各自的LN中保留数周至数月。单细胞RNA测序表明，LN驻留细胞是功能和个体发育异质群体，与传统CD4+和CD8+ T细胞具有相同的核心驻留基因特征。LN中的驻留细胞不会活跃增殖，并且不需要持续的T细胞受体(TCR)信号传导来驻留。然而，驻留和循环的Tregs具有不同的TCR库，并且每个LN都包含驻留Tregs的专有克隆亚群。我们的结果表明，与传统T细胞类似，Treg细胞在适应性免疫反应后可以在LN中形成常驻记忆样群体。引流淋巴结中常驻Treg细胞对免疫反应的特异性和局部抑制可能为局部慢性炎症的治疗提供先前未知的治疗机会。

单位：宾夕法尼亚大学兽医学院病理生物学系

Abstract:

Germinal centers (GCs) or analogous secondary lymphoid microstructures (SLMs) are thought to have evolved in endothermic species. However, living representatives of their ectothermic ancestors can mount potent secondary antibody responses upon infection or immunization, despite the apparent lack of SLMs in these cold-blooded vertebrates. How and where adaptive immune responses are induced in ectothermic species in the absence of GCs or analogous SLMs remain poorly understood. Here, we infected a teleost fish (trout) with the parasite Ichthyophthirius multifiliis (Ich) and identified the formation of large aggregates of highly proliferating IgM+ B cells and CD4+ T cells, contiguous to splenic melanomacrophage centers (MMCs). Most of these MMC-associated lymphoid aggregates (M-LAs) contained numerous antigen (Ag)-specific B cells. Analysis of the IgM heavy chain CDR3 repertoire of microdissected splenic M-LAs and non-M-LA areas revealed that the most frequent B cell clones induced after Ich infection were highly shared only within the M-LAs of infected animals. These M-LAs represented highly polyclonal SLMs in which Ag-specific B cell clonal expansion occurred. M-LA-associated B cells expressed high levels of activation-induced cytidine deaminase and underwent significant apoptosis, and somatic hypermutation of Igμ genes occurred prevalently in these cells. Our findings demonstrate that ectotherms evolved organized SLMs with GC-like roles. Moreover, our results also point to primordially conserved mechanisms by which M-LAs and mammalian polyclonal GCs develop and function.

生发中心(GC)或类似的次级淋巴微结构(SLM)被认为是在恒温物种中进化而来的。然而，尽管这些冷血脊椎动物明显缺乏SLM，但它们的变温祖先的现存代表可以在感染或免疫后产生有效的再次免疫应答。在缺乏GC或类似SLM的情况下，变温物种如何以及在何处诱导适应性免疫反应仍知之甚少。在这里，我们用寄生虫Ich感染硬骨鱼(鳟鱼)，并鉴定出高度增殖的IgM+ B细胞和CD4+ T细胞的大聚集体的形成，这些聚集体邻近脾黑素巨噬细胞中心 (MMC)。大多数MMC相关淋巴聚集体(M-LA)含有大量抗原(Ag)特异性B细胞。对显微切割的脾M-LA和非M-LA区域的IgM重链CDR3库的分析表明，Ich感染后诱导的最常见的B细胞克隆仅在受感染动物的M-LA内高度共享。这些M-LA代表高度多克隆的SLM，其中发生Ag特异性B细胞克隆扩增。M-LA相关B细胞表达高水平的激活诱导的胞苷脱氨酶并经历显着的凋亡，并且这些细胞中普遍发生Igμ基因的体细胞超突变。我们的研究结果表明，变温动物进化出了具有类似GC作用的有组织的SLM。此外，我们的结果还指出了M-LA和哺乳动物多克隆GC发育和发挥功能的原始保守机制。

2.Acquisition of suppressive function by conventional T cells limits antitumor immunity upon Treg depletion

常规T细胞获得抑制功能限制了Treg耗竭后的抗肿瘤免疫

单位：剑桥大学病理学系

Abstract:

Regulatory T (Treg) cells contribute to immune homeostasis but suppress immune responses to cancer. Strategies to disrupt Treg cell-mediated cancer immunosuppression have been met with limited clinical success, but the underlying mechanisms for treatment failure are poorly understood. By modeling Treg cell-targeted immunotherapy in mice, we find that CD4+ Foxp3- conventional T (Tconv) cells acquire suppressive function upon depletion of Foxp3+ Treg cells, limiting therapeutic efficacy. Foxp3- Tconv cells within tumors adopt a Treg cell-like transcriptional profile upon ablation of Treg cells and acquire the ability to suppress T cell activation and proliferation ex vivo. Suppressive activity is enriched among CD4+ Tconv cells marked by expression of C-C motif receptor 8 (CCR8), which are found in mouse and human tumors. Upon Treg cell depletion, CCR8+ Tconv cells undergo systemic and intratumoral activation and expansion, and mediate IL-10-dependent suppression of antitumor immunity. Consequently, conditional deletion of Il10 within T cells augments antitumor immunity upon Treg cell depletion in mice, and antibody blockade of IL-10 signaling synergizes with Treg cell depletion to overcome treatment resistance. These findings reveal a secondary layer of immunosuppression by Tconv cells released upon therapeutic Treg cell depletion and suggest that broader consideration of suppressive function within the T cell lineage is required for development of effective Treg cell-targeted therapies.

调节性T (Treg) 细胞有助于维持免疫稳态，但会抑制对癌症的免疫反应。破坏Treg细胞介导的癌症免疫抑制的策略在临床上疗效有限，但对于治疗失败的潜在机制却知之甚少。通过对小鼠Treg细胞靶向免疫疗法进行建模，我们发现 CD4+ Foxp3- 常规T (Tconv)细胞在Foxp3+ Treg细胞耗尽后获得抑制功能，从而限制了治疗效果。肿瘤内的Foxp3- Tconv细胞在Treg细胞消融后采用Treg细胞样转录谱，并获得离体抑制T细胞活化和增殖的能力。抑制活性在以C-C基序受体8 (CCR8)表达为标志的CD4+ Tconv细胞中极为丰富，这些细胞存在于小鼠和人类肿瘤中。Treg细胞耗竭后，CCR8+ Tconv细胞会经历全身和瘤内激活和扩增，并介导IL-10依赖性抗肿瘤免疫抑制。因此，T细胞内IL-10的条件性缺失可增强小鼠Treg细胞耗竭后的抗肿瘤免疫力，并且IL-10信号传导的抗体阻断与Treg细胞耗竭协同作用以克服治疗耐药性。这些发现揭示了治疗性Treg细胞耗竭后释放的Tconv细胞的第二层免疫抑制，并表明需要更广泛地考虑T细胞谱系内的抑制功能，以开发有效的Treg细胞靶向疗法。

3.Exocrine gland–resident memory CD8+ T cells use mechanosensing for tissue surveillance

外分泌腺驻留记忆CD8+ T细胞利用机械传感进行组织监测

单位：弗里堡大学肿瘤学、微生物学和免疫学系

Abstract:

Tissue-resident CD8+ T cells (TRM) continuously scan peptide-MHC (pMHC) complexes in their organ of residence to intercept microbial invaders. Recent data showed that TRM lodged in exocrine glands scan tissue in the absence of any chemoattractant or adhesion receptor signaling, thus bypassing the requirement for canonical migration-promoting factors. The signals eliciting this noncanonical motility and its relevance for organ surveillance have remained unknown. Using mouse models of viral infections, we report that exocrine gland TRM autonomously generated front-to-back F-actin flow for locomotion, accompanied by high cortical actomyosin contractility, and leading-edge bleb formation. The distinctive mode of exocrine gland TRM locomotion was triggered by sensing physical confinement and was closely correlated with nuclear deformation, which acts as a mechanosensor via an arachidonic acid and Ca2+ signaling pathway. By contrast, naïve CD8+ T cells or TRM surveilling microbe-exposed epithelial barriers did not show mechanosensing capacity. Inhibition of nuclear mechanosensing disrupted exocrine gland TRM scanning and impaired their ability to intercept target cells. These findings indicate that confinement is sufficient to elicit autonomous T cell surveillance in glands with restricted chemokine expression and constitutes a scanning strategy that complements chemosensing-dependent migration.

组织驻留CD8+ T细胞(TRM)持续扫描其驻留器官中的肽-MHC (pMHC)复合物，以拦截微生物入侵者。最近的数据表明，TRM在没有任何化学引诱剂或粘附受体信号传导的情况下驻留在外分泌腺扫描组织中，从而绕过了对典型迁移促进因子的要求。引起这种非典型运动的信号及其与器官监测的相关性仍然未知。使用病毒感染的小鼠模型，我们发现外分泌腺TRM自主产生用于运动的从前到后的F-肌动蛋白流，伴随着高皮质肌动球蛋白收缩性和前缘泡形成。外分泌腺TRM运动的独特模式是由感知物理限制触发的，并且与核变形密切相关，核变形通过花生四烯酸和Ca2+信号通路充当机械传感器。相比之下，监测暴露于微生物的上皮屏障的初始CD8+ T细胞或TRM并未表现出机械传感能力。核机械传感的抑制会破坏外分泌腺TRM扫描并削弱其拦截靶细胞的能力。这些发现表明，限制足以在趋化因子表达受限的腺体中引发自主T细胞监视，并构成补充化学传感依赖性迁移的扫描策略。

4.KCNN4 links PIEZO-dependent mechanotransduction to NLRP3 inflammasome activation

KCNN4将PIEZO依赖性机械转导与NLRP3炎症小体激活联系起来

单位：法国斯特拉斯堡大学遗传学、分子和细胞生物学研究所

Abstract:

Immune cells sense the microenvironment to fine-tune their inflammatory responses. Patients with cryopyrin-associated periodic syndrome (CAPS), caused by mutations in the NLRP3 gene, develop autoinflammation triggered by nonantigenic cues such as from the environment. However, the underlying mechanisms are poorly understood. Here, we uncover that KCNN4, a calcium-activated potassium channel, links PIEZO-mediated mechanotransduction to NLRP3 inflammasome activation. Yoda1, a PIEZO1 agonist, lowered the threshold for NLRP3 inflammasome activation. PIEZO-mediated sensing of stiffness and shear stress increased NLRP3-dependent inflammation. Myeloid-specific deletion of PIEZO1/2 protected mice from gouty arthritis. Mechanistically, activation of PIEZO1 triggers calcium influx, which activates KCNN4 to evoke potassium efflux and promotes NLRP3 inflammasome activation. Activation of PIEZO signaling was sufficient to activate the inflammasome in cells expressing CAPS-causing NLRP3 mutants via KCNN4. Last, pharmacological inhibition of KCNN4 alleviated autoinflammation in cells of patients with CAPS and in mice bearing a CAPS mutation. Thus, PIEZO-dependent mechanical inputs boost inflammation in NLRP3-dependent diseases, including CAPS.

免疫细胞感知微环境以微调其炎症反应。由NLRP3基因突变引起的冷热蛋白相关周期性综合征(CAPS)患者会因环境等非抗原性信号而引发自身炎症。然而，人们对其潜在机制知之甚少。在这里，我们发现KCNN4(一种钙激活钾通道)将PIEZO介导的机械转导与NLRP3炎性体激活联系起来。Yoda1是一种PIEZO1激动剂，可降低NLRP3炎性体激活的阈值。PIEZO介导的刚度和剪切应力感知增加了NLRP3依赖性炎症。髓系特异性PIEZO1/2的删除可保护小鼠免受痛风性关节炎的影响。从机制上讲，PIEZO1的激活会触发钙内流，从而激活KCNN4引起钾流出并促进NLRP3炎症小体激活。PIEZO信号传导的激活足以通过KCNN4激活表达CAPS引起的NLRP3突变体的细胞中的炎症小体。最后，KCNN4的药理抑制减轻了CAPS患者和携带CAPS突变的小鼠细胞的自身炎症。因此，PIEZO依赖性机械输入会促进NLRP3依赖性疾病(包括CAPS)的炎症。

5.Noncanonical MAVS signaling restrains dendritic cell–driven antitumor immunity by inhibiting IL-12

非经典MAVS信号通过抑制IL-12抑制树突状细胞驱动的抗肿瘤免疫

单位：上海交通大学医学院上海免疫研究所， 免疫与微生物学教研室， 细胞分化与凋亡教育部重点实验室；上海交通大学药学院， 上海前沿药物靶点识别与递送科学中心， 创新免疫治疗国家重点实验室

Abstract:

Mitochondrial antiviral signaling protein (MAVS)-mediated cytosolic RNA sensing plays a central role in tumor immunogenicity. However, the effects of host MAVS signaling on antitumor immunity remain unclear. Here, we demonstrate that the host MAVS pathway supports tumor growth and impairs antitumor immunity, whereas MAVS deficiency in dendritic cells (DCs) promotes tumor-reactive CD8+ T cell responses. Specifically, CD8+ T cell priming capacity was enhanced by MAVS ablation in a type I interferon-independent, but IL-12-dependent, manner. Mechanistically, loss of the RIG-I/MAVS cascade activated the noncanonical NF-κB pathway and in turn induced IL-12 production by DCs. MAVS-restrained IL-12 promoted cross-talk between CD8+ T cells and DCs, which was licensed by IFN-γ. Moreover, ablation of host MAVS sensitized tumors to immunotherapy and attenuated radiation resistance, thereby facilitating the maintenance of effector CD8+ T cells. These findings demonstrate that the host MAVS pathway acts as an immune regulator of DC-driven antitumor immunity and support the development of immunotherapies that antagonize MAVS signaling in DCs.

线粒体抗病毒信号蛋白 (MAVS) 介导的胞质RNA传感在肿瘤免疫原性中发挥着核心作用。然而，宿主MAVS信号传导对抗肿瘤免疫的影响仍不清楚。在这里，我们证明宿主MAVS通路支持肿瘤生长并损害抗肿瘤免疫，而树突状细胞(DC)中的MAVS缺陷会促进肿瘤反应性CD8+ T细胞反应。具体来说，MAVS 消融以独立于I型干扰素但依赖IL-12的方式增强了CD8+ T细胞的启动能力。从机制上讲，RIG-I/MAVS级联的缺失激活了非经典NF-κB通路，进而诱导DC产生IL-12。MAVS抑制的IL-12促进CD8+ T细胞和DC之间的串扰，这是由IFN-γ授权的。此外，宿主MAVS的消融使肿瘤对免疫治疗敏感并减弱了放射抵抗力，从而促进效应CD8+ T细胞的维持。这些发现表明，宿主MAVS通路充当DC驱动的抗肿瘤免疫的免疫调节剂，并支持拮抗DC中MAVS信号传导的免疫疗法的发展。

6、Early human lung immune cell development and its role in epithelial cell fate

单位：伦敦大学学院呼吸系

Abstract:

Studies of human lung development have focused on epithelial and mesenchymal cell types and function, but much less is known about the developing lung immune cells, even though the airways are a major site of mucosal immunity after birth. An unanswered question is whether tissue-resident immune cells play a role in shaping the tissue as it develops in utero. Here, we profiled human embryonic and fetal lung immune cells using scRNA-seq, smFISH, and immunohistochemistry. At the embryonic stage, we observed an early wave of innate immune cells, including innate lymphoid cells, natural killer cells, myeloid cells, and lineage progenitors. By the canalicular stage, we detected naive T lymphocytes expressing high levels of cytotoxicity genes and the presence of mature B lymphocytes, including B-1 cells. Our analysis suggests that fetal lungs provide a niche for full B cell maturation. Given the presence and diversity of immune cells during development, we also investigated their possible effect on epithelial maturation. We found that IL-1β drives epithelial progenitor exit from self-renewal and differentiation to basal cells in vitro. In vivo, IL-1β-producing myeloid cells were found throughout the lung and adjacent to epithelial tips, suggesting that immune cells may direct human lung epithelial development.

对人类肺部发育的研究主要集中在上皮细胞和间质细胞的类型和功能上，但对发育中的肺部免疫细胞知之甚少，尽管气道是出生后粘膜免疫的主要部位。一个悬而未决的问题是，组织驻留免疫细胞是否在子宫内发育的组织形成过程中发挥作用。在这里，我们使用scRNA-seq、smFISH和免疫组化对人类胚胎和胎儿肺免疫细胞进行了分析。在胚胎阶段，我们观察到了早期的先天免疫细胞浪潮，包括先天淋巴细胞、自然杀伤细胞、髓系细胞和谱系祖细胞。在小管期，我们检测到表达高水平细胞毒性基因的初始T淋巴细胞和成熟B淋巴细胞(包括B-1细胞)的存在。我们的分析表明胎儿肺为B细胞的完全成熟提供了场所。鉴于发育过程中免疫细胞的存在和多样性，我们还研究了它们对上皮成熟的可能影响。我们发现IL-1β在体外驱动上皮祖细胞自我更新并分化为基底细胞。在体内，在整个肺和上皮尖端附近发现了产生IL-1β的髓系细胞，这表明免疫细胞可能指导人肺上皮的发育。

7.Antigen-specific memory NK cell responses against HIV and influenza use the NKG2/HLA-E axis

针对HIV和流感的抗原特异性记忆NK细胞反应使用NKG2/HLA-E轴

单位：哈佛医学院贝丝以色列女执事医疗中心病毒学和疫苗研究中心；杜克大学医学院外科人类系统免疫学中心先天和比较免疫学部

Abstract:

Multiple studies have broadened the roles of natural killer (NK) cells functioning as purely innate lymphocytes by demonstrating that they are capable of putative antigen-specific immunological memory against multiple infectious agents including HIV-1 and influenza. However, the mechanisms underlying antigen specificity remain unknown. Here, we demonstrate that antigen-specific human NK cell memory develops upon exposure to both HIV and influenza, unified by a conserved and epitope-specific targetable mechanism largely dependent on the activating CD94/NKG2C receptor and its ligand HLA-E. We validated the permanent acquisition of antigen specificity by individual memory NK cells by single-cell cloning. We identified elevated expression of KLRG1, α4β7, and NKG2C as biomarkers of antigen-specific NK cell memory through complex immunophenotyping. Last, we uncovered individual HLA-E-restricted peptides that may constitute the dominant NK cell response in HIV-1- and influenza-infected persons in vivo. Our findings clarify the mechanisms contributing to antigen-specific memory NK cell responses and suggest that they could be potentially targeted therapeutically for vaccines or other therapeutic interventions.

多项研究拓展了自然杀伤 (NK) 细胞作为纯粹先天淋巴细胞的作用，证明它们能够针对包括HIV-1和流感在内的多种感染因子产生假定的抗原特异性免疫记忆。然而，抗原特异性的机制仍然未知。在这里，我们证明抗原特异性人类NK细胞记忆在暴露于HIV和流感时形成，由保守且表位特异性的靶向机制统一，很大程度上依赖于激活CD94/NKG2C受体及其配体HLA-E。我们通过单细胞克隆验证了个体记忆NK细胞永久获得抗原特异性。我们通过复杂的免疫表型分析，将KLRG1、α4β7和NKG2C的表达升高确定为抗原特异性NK细胞记忆的生物标志物。最后，我们发现了个体HLA-E限制性肽，它们可能构成HIV-1和流感感染者体内的主要NK细胞反应。我们的研究结果阐明了抗原特异性记忆NK细胞反应的机制，并表明它们可能成为疫苗或其他治疗干预措施的潜在治疗目标。

8.Structural principles of peptide-centric chimeric antigen receptor recognition guide therapeutic expansion

以肽为中心的嵌合抗原受体识别的结构原理指导治疗扩展

单位：美国宾夕法尼亚州费城费城儿童医院计算与基因组医学中心及病理学与检验医学系；美国宾夕法尼亚州费城宾夕法尼亚大学佩雷尔曼医学院生物化学与生物物理系

Abstract:

Peptide-centric chimeric antigen receptors (PC-CARs) recognize oncoprotein epitopes displayed by cell-surface human leukocyte antigens (HLAs) and offer a promising strategy for targeted cancer therapy. We have previously developed a PC-CAR targeting a neuroblastoma-associated PHOX2B peptide, leading to robust tumor cell lysis restricted by two common HLA allotypes. Here, we determine the 2.1-angstrom crystal structure of the PC-CAR-PHOX2B-HLA-A*24:02-β2m complex, which reveals the basis for antigen-specific recognition through interactions with CAR complementarity-determining regions (CDRs). This PC-CAR adopts a diagonal docking mode, where interactions with both conserved and polymorphic HLA framework residues permit recognition of multiple HLA allotypes from the A9 serological cross-reactive group, covering a combined global population frequency of up to 46.7%. Biochemical binding assays, molecular dynamics simulations, and structural and functional analyses demonstrate that high-affinity PC-CAR recognition of cross-reactive pHLAs necessitates the presentation of a specific peptide backbone, where subtle structural adaptations of the peptide are critical for high-affinity complex formation, and CAR T cell killing. Our results provide a molecular blueprint for engineering CARs with optimal recognition of tumor-associated antigens in the context of different HLAs, while minimizing cross-reactivity with self-epitopes.

以肽为中心的嵌合抗原受体(PC-CAR)可识别细胞表面人类白细胞抗原(HLA)显示的癌蛋白表位，并为靶向癌症治疗提供有前景的策略。我们之前开发了一种针对神经母细胞瘤相关PHOX2B肽的PC-CAR，可导致受两种常见同种异型HLA限制的强大肿瘤细胞裂解。在这里，我们确定了 PC-CAR-PHOX2B-HLA-A*24:02-β2m复合物的2.1埃晶体结构，该结构揭示了通过与CAR互补决定区(CDR)相互作用进行抗原特异性识别的基础。该PC-CAR采用对角对接模式，与保守且多态的HLA框架残基相互作用，允许识别来自A9血清学交叉反应组的多种HLA同种异型，覆盖全球总人群频率高达46.7%。生化结合测定、分子动力学模拟以及结构和功能分析表明，交叉反应性pHLA的高亲和力PC-CAR识别需要呈现特定的肽主链，其中肽的微妙结构适应对于高亲和力复合物的形成及CAR-T细胞杀伤至关重要。我们的结果为工程CARs提供了分子蓝图，在不同HLA的背景下优化识别肿瘤相关抗原，同时最大限度地减少与自身表位的交叉反应。

单位：美国马萨诸塞州波士顿哈佛医学院免疫学系

Abstract:

Dysbiosis in the gut microbiota affects several systemic diseases, possibly by driving the migration of perturbed intestinal immunocytes to extraintestinal tissues. Combining Kaede photoconvertible mice and single-cell genomics, we generated a detailed map of migratory trajectories from the colon, at baseline, and in several models of intestinal and extraintestinal inflammation. All lineages emigrated from the colon in an S1P-dependent manner. B lymphocytes represented the largest contingent, with the unexpected circulation of nonexperienced follicular B cells, which carried a gut-imprinted transcriptomic signature. T cell emigration included distinct groups of RORγ+ and IEL-like CD160+ subsets. Gut inflammation curtailed emigration, except for dendritic cells disseminating to lymph nodes. Colon-emigrating cells distributed differentially to distinct sites of extraintestinal models of inflammation (psoriasis-like skin, arthritic synovium, and tumors). Thus, specific cellular trails originating in the gut and influenced by microbiota may shape peripheral immunity in varied ways.

肠道微生物群的失调会影响多种全身性疾病，可能是通过驱动受干扰的肠道免疫细胞迁移到肠外组织来实现的。结合Kaede光转换小鼠和单细胞基因组学，我们在基线以及几种肠道和肠外炎症模型中生成了来源结肠的迁移轨迹的详细图谱。所有谱系均以S1P依赖性方式从结肠迁移。B淋巴细胞代表了最大的群体，其中有未经历过的滤泡B细胞的意外循环，这些细胞带有肠道印记的转录组特征。T细胞迁移包括不同的RORγ+和IEL样CD160+亚群。除了传播到淋巴结的树突状细胞外，肠道炎症减少了迁移。结肠迁移细胞差异分布到肠外炎症模型的不同部位(银屑病样皮肤、关节炎滑膜和肿瘤)。因此，源自肠道并受微生物群影响的特定细胞轨迹可能以多种方式塑造外周免疫。

2.LITAF protects against pore-forming protein-induced cell death by promoting membrane repair

LITAF通过促进细胞膜修复来防止成孔蛋白诱导的细胞死亡

单位：美国华盛顿州西雅图弗吉尼亚梅森贝纳罗亚研究所系统免疫学中心，华盛顿大学免疫学系、生物化学系蛋白质设计研究所

Abstract:

Pore-forming toxins (PFTs) are the largest class of bacterial toxins and contribute to virulence by triggering host cell death. Vertebrates also express endogenous pore-forming proteins that induce cell death as part of host defense. To mitigate damage and promote survival, cells mobilize membrane repair mechanisms to neutralize and counteract pores, but how these pathways are activated is poorly understood. Here, we use a transposon-based gene activation screen to discover pathways that counteract the cytotoxicity of the archetypal PFT Staphylococcus aureus α-toxin. We identify the endolysosomal protein LITAF as a mediator of cellular resistance to PFT-induced cell death that is active against both bacterial toxins and the endogenous pore, gasdermin D, a terminal effector of pyroptosis. Activation of the ubiquitin ligase NEDD4 by potassium efflux mobilizes LITAF to recruit the endosomal sorting complexes required for transport (ESCRT) machinery to repair damaged membrane. Cells lacking LITAF, or carrying naturally occurring disease-associated mutations of LITAF, are highly susceptible to pore-induced death. Notably, LITAF-mediated repair occurs at endosomal membranes, resulting in expulsion of damaged membranes as exosomes, rather than through direct excision of pores from the surface plasma membrane. These results identify LITAF as a key effector that links sensing of cellular damage to repair.

成孔毒素(PFT)是最大的一类细菌毒素，通过触发宿主细胞死亡来促进毒性。脊椎动物还表达内源性成孔蛋白，这些蛋白诱导细胞死亡，作为宿主防御的一部分。为了减轻损伤和促进存活，细胞动员细胞膜修复机制来中和和抵消孔隙，但这些途径是如何被激活的却知之甚少。在这里，我们使用基于转座子的基因激活筛选来发现抵消原型PFT金黄色葡萄球菌α毒素的细胞毒性的途径。我们将内溶酶体蛋白LITAF确定为细胞对PFT诱导的细胞死亡的抵抗力的介质，该介质对细菌毒素和内源性孔隙gasdermin D(焦亡的终末效应物)具有活性。钾外排激活泛素连接酶NEDD4动员LITAF募集转运所需的内体分选复合物(ESCRT)机制以修复受损的膜。缺乏LITAF或携带自然发生的疾病相关LITAF突变的细胞极易发生孔诱导的死亡。值得注意的是，LITAF介导的修复发生在内体膜上，导致受损膜作为外泌体排出，而不是通过直接从表面质膜上切除孔。这些结果将LITAF确定为将细胞损伤的感知与修复联系起来的关键效应器。

3.Tuft cells and fibroblasts promote thymus regeneration through ILC2-mediated type 2 immune response

簇细胞和成纤维细胞通过ILC2介导的2型免疫应答促进胸腺再生

单位：以色列雷霍沃特魏茨曼科学研究所免疫学和再生生物学系等

Abstract:

The thymus is a primary lymphoid organ that is essential for the establishment of adaptive immunity through generation of immunocompetent T cells. In response to various stress signals, the thymus undergoes acute but reversible involution. However, the mechanisms governing its recovery are incompletely understood. Here, we used a dexamethasone-induced acute thymic involution mouse model to investigate how thymic hematopoietic cells (excluding T cells) contribute to thymic regeneration. scRNA-seq analysis revealed marked transcriptional and cellular changes in various thymic populations and highlighted thymus-resident innate lymphoid cells type 2 (ILC2) as a key cell type involved in the response to damage. We identified that ILC2 are activated by the alarmins IL-25 and IL-33 produced in response to tissue damage by thymic tuft cells and fibroblasts, respectively. Moreover, using mouse models deficient in either tuft cells and/or IL-33, we found that these alarmins are required for effective thymus regeneration after dexamethasone-induced damage. We also demonstrate that upon their damage-dependent activation, thymic ILC2 produce several effector molecules linked to tissue regeneration, such as amphiregulin and IL-13, which in turn promote thymic epithelial cell differentiation. Collectively, our study elucidates a previously undescribed role for thymic tuft cells and fibroblasts in thymus regeneration through activation of the type 2 immune response.

胸腺是主要的淋巴器官，对于通过产生免疫活性T细胞建立适应性免疫至关重要。为了响应各种应激信号，胸腺经历急性但可逆的退化。然而，控制其恢复的机制尚不完全清楚。在这里，我们使用地塞米松诱导的急性胸腺退化小鼠模型来研究胸腺造血细胞(不包括T细胞)如何促进胸腺再生。scRNA-seq分析揭示了各种胸腺群体中明显的转录组和细胞变化，并强调了胸腺驻留的先天性淋巴细胞2型(ILC2)是参与损伤反应的关键细胞类型。我们发现ILC2分别由胸腺簇细胞和成纤维细胞的组织损伤产生的预警蛋白IL-25和IL-33激活。此外，使用缺乏簇细胞和/或IL-33的小鼠模型，我们发现这些预警蛋白是地塞米松诱导的损伤后有效胸腺再生所必需的。我们还证明，在它们的损伤依赖性激活时，胸腺ILC2会产生几种与组织再生相关的效应分子，例如双调蛋白和IL-13，这反过来又促进胸腺上皮细胞分化。总的来说，我们的研究阐明了胸腺簇细胞和成纤维细胞通过激活2型免疫反应在胸腺再生中的新作用。

4.TGFβ prevents IgE-mediated allergic disease by restraining T follicular helper 2 differentiation

TGFβ通过抑制2型滤泡辅助性T细胞分化来预防IgE介导的过敏性疾病

单位：美国国立卫生研究院国家过敏和传染病研究所过敏性疾病实验室等

Abstract:

Allergic diseases are common, affecting more than 20% of the population. Genetic variants in the TGFβ pathway are strongly associated with atopy. To interrogate the mechanisms underlying this association, we examined patients and mice with Loeys-Dietz syndrome (LDS) who harbor missense mutations in the kinase domain of TGFΒR1/2. We demonstrate that LDS mutations lead to reduced TGFβ signaling and elevated total and allergen-specific IgE, despite the presence of wild-type T regulatory cells in a chimera model. Germinal center activity was enhanced in LDS and characterized by a selective increase in type 2 follicular helper T cells (TFH2). Expression of Pik3cg was increased in LDS TFH cells and associated with reduced levels of the transcriptional repressor SnoN. PI3Kγ/mTOR signaling in LDS naïve CD4+ T cells was elevated after T cell receptor cross-linking, and pharmacologic inhibition of PI3Kγ or mTOR prevented exaggerated TFH2 and antigen-specific IgE responses after oral antigen exposure in an adoptive transfer model. Naïve CD4+ T cells from nonsyndromic allergic individuals also displayed decreased TGFβ signaling, suggesting that our mechanistic discoveries may be broadly relevant to allergic patients in general. Thus, TGFβ plays a conserved, T cell-intrinsic, and nonredundant role in restraining TFH2 development via the PI3Kγ/mTOR pathway and thereby protects against allergic disease.

过敏性疾病很常见，影响20%以上的人口。TGFβ通路中的遗传变异与特应性密切相关。为了探究这种关联背后的机制，我们检查了Loeys-Dietz综合征(LDS)患者和小鼠，这些患者和小鼠在TGFβR1/2激酶结构域中存在错义突变。我们证明，尽管嵌合体模型中存在野生型T调节细胞，但LDS突变会导致TGFβ信号传导减弱，总IgE和过敏原特异性IgE升高。LDS中生发中心活性增强，其特征是2型滤泡辅助T细胞 (TFH2) 选择性增加。Pik3cg的表达在LDS TFH细胞中增加，并与转录抑制因子SnoN水平降低相关。T细胞受体交联后，LDS 初始CD4+ T细胞中的PI3Kγ/mTOR信号传导升高，在过继转移模型中口服抗原暴露后，PI3Kγ或mTOR的药理抑制可防止过度的TFH2和抗原特异性IgE反应。来自非综合征性过敏个体的初始CD4+ T细胞也表现出TGF-β信号减弱，这表明我们的机制发现可能与一般过敏患者广泛相关。因此，TGF-β通过PI3Kγ/mTOR途径，在抑制TFH2发育中发挥保守的、T细胞固有的、非冗余的作用，从而预防过敏性疾病。

5.Regulatory T cells in skin mediate immune privilege of the hair follicle stem cell niche

皮肤中的调节性T细胞介导毛囊干细胞生态位的免疫特权

单位：加州大学旧金山分校皮肤科

Abstract:

Immune tolerance is maintained in lymphoid organs (LOs). Despite the presence of complex immune cell networks in non-LOs, it is unknown whether self-tolerance is maintained in these tissues. We developed a technique to restrict genetic recombination to regulatory T cells (Tregs) only in skin. Selective depletion of skin Tregs resulted in T cell-mediated inflammation of hair follicles (HFs). Suppression did not rely on CTLA-4, but instead on high-affinity interleukin-2 (IL-2) receptor expression by skin Tregs, functioning exclusively in a cell-extrinsic manner. In a novel model of HF stem cell (HFSC)-driven autoimmunity, we reveal that skin Tregs immunologically protect the HFSC niche. Finally, we used spatial transcriptomics to identify aberrant IL-2 signaling at stromal-HF interfaces in a rare form of human alopecia characterized by HFSC destruction and alopecia areata. Collectively, these results reveal the fundamental biology of Tregs in skin uncoupled from the systemic pool and elucidate a mechanism of self-tolerance.

淋巴器官(LO)维持免疫耐受。尽管非LO中存在复杂的免疫细胞网络，但尚不清楚这些组织中是否维持自我耐受。我们开发了一种技术，将基因重组限制在皮肤中的调节性T细胞(Treg)上。皮肤Tregs的选择性耗竭导致T细胞介导的毛囊(HF)炎症。抑制并不依赖于CTLA-4，而是依赖于皮肤Tregs的高亲和力白细胞介素2 (IL-2)受体表达，且仅以细胞外源性方式发挥作用。在HF干细胞(HFSC)驱动的自身免疫的新模型中，我们揭示了皮肤Tregs可以免疫保护HFSC生态位。最后，我们使用空间转录组学来识别以HFSC破坏和斑秃为特征的罕见人类脱发中基质-HF界面上的异常IL-2信号传导。总的来说，这些结果揭示了皮肤中与系统池分离的Tregs的基本生物学，并阐明了自我耐受的机制。

6.CD4+ T cell immunity against cutaneous melanoma encompasses multifaceted MHC II–dependent responses

针对皮肤黑色素瘤的CD4+ T细胞免疫包括多方面的MHC II依赖性反应

单位：墨尔本大学彼得·多尔蒂感染与免疫研究所微生物学和免疫学系

Abstract:

Whereas CD4+ T cells conventionally mediate antitumor immunity by providing help to CD8+ T cells, recent clinical studies have implied an important role for cytotoxic CD4+ T cells in cancer immunity. Using an orthotopic melanoma model, we provide a detailed account of antitumoral CD4+ T cell responses and their regulation by major histocompatibility complex class II (MHC II) in the skin. Intravital imaging revealed prominent interactions of CD4+ T cells with tumor debris-laden MHC II+ host antigen-presenting cells that accumulated around tumor cell nests, although direct recognition of MHC II+ melanoma cells alone could also promote CD4+ T cell control. CD4+ T cells stably suppressed or eradicated tumors even in the absence of other lymphocytes by using tumor necrosis factor-α and Fas ligand (FasL) but not perforin-mediated cytotoxicity. Interferon-γ was critical for protection, acting both directly on melanoma cells and via induction of nitric oxide synthase in myeloid cells. Our results illustrate multifaceted and context-specific aspects of MHC II-dependent CD4+ T cell immunity against cutaneous melanoma, emphasizing modulation of this axis as a potential avenue for immunotherapies.

尽管CD4+ T细胞通常通过为CD8+ T细胞提供帮助来介导抗肿瘤免疫，但最近的临床研究表明细胞毒性CD4+ T细胞在癌症免疫中发挥着重要作用。使用原位黑色素瘤模型，我们详细描述了抗肿瘤CD4+ T细胞反应及其通过皮肤中II类主要组织相容性复合物(MHC II)的调节。活体成像显示CD4+ T细胞与肿瘤细胞巢周围积累的充满肿瘤碎片的MHC II+宿主抗原呈递细胞之间存在显着的相互作用，尽管单独直接识别MHC II+黑色素瘤细胞也可以促进CD4+ T细胞控制。即使在没有其他淋巴细胞的情况下，CD4+ T细胞也能通过使用肿瘤坏死因子-α和Fas配体(FasL)稳定抑制或根除肿瘤，但不能使用穿孔素介导的细胞毒性。干扰素-γ对于保护至关重要，它既直接作用于黑色素瘤细胞，又通过诱导骨髓细胞中的一氧化氮合酶发挥作用。我们的结果说明了针对皮肤黑色素瘤的MHC II依赖性CD4+ T细胞免疫的多方面和具体情况，强调了该轴的调节作为免疫治疗的潜在途径。

7.Non-apoptotic FAS signaling controls mTOR activation and extrafollicular maturation in human B cells

非凋亡FAS信号传导控制人B细胞中mTOR激活和滤泡外成熟

单位：德国弗莱堡弗莱堡大学医学院弗莱堡大学医学中心风湿病学和临床免疫学系。

Abstract:

Defective FAS (CD95/Apo-1/TNFRSF6) signaling causes autoimmune lymphoproliferative syndrome (ALPS). Hypergammaglobulinemia is a common feature in ALPS with FAS mutations (ALPS-FAS), but paradoxically, fewer conventional memory cells differentiate from FAS-expressing germinal center (GC) B cells. Resistance to FAS-induced apoptosis does not explain this phenotype. We tested the hypothesis that defective non-apoptotic FAS signaling may contribute to impaired B cell differentiation in ALPS. We analyzed secondary lymphoid organs of patients with ALPS-FAS and found low numbers of memory B cells, fewer GC B cells, and an expanded extrafollicular (EF) B cell response. Enhanced mTOR activity has been shown to favor EF versus GC fate decision, and we found enhanced PI3K/mTOR and BCR signaling in ALPS-FAS splenic B cells. Modeling initial T-dependent B cell activation with CD40L in vitro, we showed that FAS competent cells with transient FAS ligation showed specifically decreased mTOR axis activation without apoptosis. Mechanistically, transient FAS engagement with involvement of caspase-8 induced nuclear exclusion of PTEN, leading to mTOR inhibition. In addition, FASL-dependent PTEN nuclear exclusion and mTOR modulation were defective in patients with ALPS-FAS. In the early phase of activation, FAS stimulation promoted expression of genes related to GC initiation at the expense of processes related to the EF response. Hence, our data suggest that non-apoptotic FAS signaling acts as molecular switch between EF versus GC fate decisions via regulation of the mTOR axis and transcription. The defect of this modulatory circuit may explain the observed hypergammaglobulinemia and low memory B cell numbers in ALPS.

FAS (CD95/Apo-1/TNFRSF6) 信号传导缺陷会导致自身免疫性淋巴组织增生综合征(ALPS)。高丙种球蛋白血症是具有FAS突变的ALPS (ALPS-FAS)的常见特征，但矛盾的是，从表达FAS的生发中心(GC) B细胞分化而来的传统记忆细胞较少。对FAS诱导的细胞凋亡的抵抗并不能解释这种表型。我们测试了以下假设：非凋亡FAS信号传导缺陷可能导致ALPS中B细胞分化受损。我们分析了ALPS-FAS患者的次级淋巴器官，发现记忆B细胞数量较少，GC B细胞较少，滤泡外(EF) B细胞反应扩大。增强的mTOR活性已被证明有利于EF与GC命运的决定，并且我们发现ALPS-FAS脾B细胞中PI3K/mTOR和BCR信号传导增强。在体外用CD40L模拟初始T依赖性B细胞激活，我们发现，瞬时FAS连接的FAS感受态细胞表现出特异性降低mTOR轴激活，而没有凋亡。从机制上讲，短暂的FAS参与caspase-8诱导PTEN的核排斥，导致mTOR抑制。此外，ALPS-FAS患者的FASL依赖性PTEN核排斥和mTOR调节存在缺陷。在激活的早期阶段，FAS刺激促进了与GC起始相关的基因表达，但牺牲了与EF反应相关的过程。因此，我们的数据表明，非凋亡FAS信号传导通过调节mTOR轴和转录，充当EF与GC命运决定之间的分子开关。这种调节回路的缺陷可以解释ALPS中观察到的高丙种球蛋白血症和低记忆B细胞数量。