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Synchronized development of thymic eosinophils and thymocytes. 胸腺嗜酸性粒细胞和胸腺细胞的同步发育
IF 4.8 4区 医学 Q2 Medicine Pub Date : 2024-06-25 DOI: 10.1093/intimm/dxae037
Ayami Ota, Takahiro Iguchi, Sachiko Nitta, Ryunosuke Muro, Nanami Mino, Masayuki Tsukasaki, Josef M Penninger, Takeshi Nitta, Hiroshi Takayanagi

The thymus is an organ required for T cell development and is also an eosinophil-rich organ; however, the nature and function of thymic eosinophils remain unclear. Here, we characterized the gene expression and differentiation mechanism of thymic eosinophils in mice. Thymic eosinophils showed a distinct gene expression profile compared with other organ-resident eosinophils. The number of thymic eosinophils was controlled by medullary thymic epithelial cells. In Rag-deficient mice, the unique gene expression signature of thymic eosinophils was lost but restored by pre-T cell receptor signaling, which induces CD4+ CD8+ thymocyte differentiation, indicating that T cell differentiation beyond the CD4- CD8- stage is necessary and sufficient for the induction of thymic eosinophils. These results demonstrate that thymic eosinophils are quantitatively and qualitatively regulated by medullary thymic epithelial cells and developing thymocytes, respectively, suggesting that thymic eosinophils are a distinct, thymus-specific cell subset, induced by interactions with thymic cells.

胸腺是 T 细胞发育所需的器官,也是嗜酸性粒细胞丰富的器官;然而,胸腺嗜酸性粒细胞的性质和功能仍不清楚。在这里,我们研究了小鼠胸腺嗜酸性粒细胞的基因表达和分化机制。与其他器官驻留的嗜酸性粒细胞相比,胸腺嗜酸性粒细胞显示出独特的基因表达谱。胸腺嗜酸性粒细胞的数量由胸腺髓质上皮细胞控制。在 Rag 缺失的小鼠中,胸腺嗜酸性粒细胞的独特基因表达特征消失了,但通过诱导 CD4+ CD8+ 胸腺细胞分化的前 T 细胞受体信号恢复了这一特征。这些结果表明,胸腺嗜酸性粒细胞在数量和质量上分别受到髓质胸腺上皮细胞和发育中胸腺细胞的调控,这表明胸腺嗜酸性粒细胞是一种独特的胸腺特异性细胞亚群,是通过与胸腺细胞相互作用诱导的。
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引用次数: 0
Supersulfides suppress type-Ⅰ and type-Ⅱ interferon responses by blocking JAK/STAT signaling in macrophages. 超硫化物通过阻断巨噬细胞中的 JAK/STAT 信号传导抑制Ⅰ型和Ⅱ型干扰素反应
IF 4.4 4区 医学 Q2 Medicine Pub Date : 2024-06-20 DOI: 10.1093/intimm/dxae040
Xiaoyan Li, Touya Toyomoto, Tianli Zhang, Chunyu Guo, Stephen Lindahl, Hiroyasu Tsutsuki, Ming Xian, Tomohiro Sawa

Interferons (IFNs) are cytokines produced and secreted by immune cells when viruses, tumor cells, and so forth, invade the body. Their biological effects are diverse, including antiviral, cell growth-inhibiting, and antitumor effects. The main subclasses of interferons include type-I (e.g., IFN-α and IFN-β) and type-II (IFN-γ), which activate intracellular signals by binding to type-I and type-II IFN receptors, respectively. We have previously shown that when macrophages are treated with supersulfide donors, which have polysulfide structures in which three or more sulfur atoms are linked within the molecules, IFN-β-induced cellular responses, including signal transducer and activator of transcription 1 (STAT1) phosphorylation and inducible nitric oxide synthase (iNOS) expression, were strongly suppressed. However, the subfamily specificity of the suppression of IFN signals by supersulfides and the mechanism of this suppression are unknown. This study demonstrated that supersulfide donor N-acetyl-L-cysteine tetrasulfide (NAC-S2) can inhibit IFN signaling in macrophages stimulated not only with IFN-α/β but also with IFN-γ. Our data suggest that NAC-S2 blocks phosphorylation of Janus kinases (JAKs), thereby contributes to the inhibition of phosphorylation of STAT1. Under the current experimental conditions, hydrogen sulfide (H2S) donor NaHS failed to inhibit IFN signaling. Similar to NAC-S2, carbohydrate-based supersulfide donor thioglucose tetrasulfide (TGS4) was capable of strongly inhibiting tumor necrosis factor-αproduction, iNOS expression, and nitric oxide production from macrophages stimulated with lipopolysaccharide. Further understanding of molecular mechanisms how supersulfide donors exhibit their inhibitory actions towards JAK/STAT signaling is necessary basis for development of supersulfide-based therapeutic strategy against autoimmune disorders with dysregulated IFN signaling.

干扰素(IFNs)是免疫细胞在病毒、肿瘤细胞等入侵人体时产生和分泌的细胞因子。其生物效应多种多样,包括抗病毒、抑制细胞生长和抗肿瘤作用。干扰素的主要亚类包括 I 型(如 IFN-α 和 IFN-β)和 II 型(IFN-γ),它们分别通过与 I 型和 II 型 IFN 受体结合来激活细胞内信号。我们以前的研究表明,当用超硫化物供体处理巨噬细胞时,IFN-β 诱导的细胞反应,包括信号转导和激活转录 1(STAT1)磷酸化和诱导型一氧化氮合酶(iNOS)的表达,都会受到强烈抑制。然而,超硫化物抑制 IFN 信号的亚家族特异性及其抑制机制尚不清楚。本研究表明,超硫化物供体 N-乙酰-L-半胱氨酸四硫化物(NAC-S2)不仅能抑制 IFN-α/β 刺激巨噬细胞中的 IFN 信号,还能抑制 IFN-γ 刺激巨噬细胞中的 IFN 信号。我们的数据表明,NAC-S2 可阻断 Janus 激酶(JAKs)的磷酸化,从而有助于抑制 STAT1 的磷酸化。在目前的实验条件下,硫化氢(H2S)供体 NaHS 未能抑制 IFN 信号转导。与 NAC-S2 类似,基于碳水化合物的硫化氢供体硫代葡萄糖四硫化物(TGS4)也能强烈抑制受脂多糖刺激的巨噬细胞产生肿瘤坏死因子-α、iNOS 表达和一氧化氮。进一步了解超硫化物供体如何对 JAK/STAT 信号转导产生抑制作用的分子机制,是开发基于超硫化物的治疗策略以防治 IFN 信号转导失调的自身免疫性疾病的必要基础。
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引用次数: 0
Regulation of memory CD4+ T cell generation by intrinsic and extrinsic IL-27 signaling during malaria infection. 在疟疾感染过程中,IL-27 的内在和外在信号调节记忆 CD4+ T 细胞的生成。
IF 4.4 4区 医学 Q2 Medicine Pub Date : 2024-06-19 DOI: 10.1093/intimm/dxae039
Sanjaadorj Tsogtsaikhan, Shin-Ichi Inoue, Ganchimeg Bayarsaikhan, Maria Lourdes Macalinao, Daisuke Kimura, Mana Miyakoda, Masahiro Yamamoto, Hiromitsu Hara, Hiroki Yoshida, Katsuyuki Yui

The generation and maintenance of memory T cells are regulated by various factors, including cytokines. Previous studies have shown that IL-27 is produced during the early acute phase of Plasmodium chabaudi chabaudi AS (Pcc) infection and inhibits the development of Th1-type memory CD4+ T cells. However, whether IL-27 acts directly on its receptor on Plasmodium-specific CD4+ T cells or indirectly via its receptor on other immune cells remains unclear. We aimed to determine the role of IL-27 receptor signaling in different immune cell types in regulating the generation and phenotype of memory CD4+ T cells during Plasmodium infection. We utilized Plasmodium-specific TCR transgenic mice, PbT-II, and Il27rα-/- mice to assess the direct and indirect effects of IL-27 signaling on memory CD4+ T-cell generation. Mice were transferred with PbT-II or Il27rα-/- PbT-II cells and infected with Pcc. Conditional knockout mice lacking the IL-27 receptor in T cells or dendritic cells were employed to discern the specific immune cell types involved in IL-27 receptor signaling. High levels of memory in PbT-II cells with Th1-shift occurred only when both PbT-II and host cells lacked the IL-27 receptor, suggesting the predominant inhibitory role of IL-27 signaling in both cell types. Furthermore, IL-27 receptor signaling in T cells limited the number of memory CD4+ T cells, while signaling in both T and dendritic cells contributed to the Th1 dominance of memory CD4+ T cells. These findings underscore the complex cytokine signaling network regulating memory CD4+ T cells during Plasmodium infection.

记忆 T 细胞的生成和维持受多种因素(包括细胞因子)的调控。先前的研究表明,IL-27 在沙鲍迪疟原虫(Pcc)感染的早期急性期产生,并抑制 Th1 型记忆 CD4+ T 细胞的发育。然而,IL-27是直接作用于其在疟原虫特异性CD4+ T细胞上的受体,还是间接通过其在其他免疫细胞上的受体发挥作用,目前仍不清楚。我们的目的是确定在疟原虫感染期间,IL-27 受体信号在不同免疫细胞类型中调节记忆 CD4+ T 细胞的生成和表型的作用。我们利用疟原虫特异性 TCR 转基因小鼠 PbT-II 和 Il27rα-/- 小鼠来评估 IL-27 信号传导对记忆 CD4+ T 细胞生成的直接和间接影响。用 PbT-II 或 Il27rα-/- PbT-II 细胞转移小鼠并用 Pcc 感染。利用T细胞或树突状细胞中缺乏IL-27受体的条件性基因敲除小鼠来确定参与IL-27受体信号转导的特定免疫细胞类型。只有当 PbT-II 细胞和宿主细胞都缺乏 IL-27 受体时,PbT-II 细胞才会出现高水平的 Th1 转移记忆,这表明 IL-27 信号在两种细胞类型中都起着主要的抑制作用。此外,T细胞中的IL-27受体信号限制了记忆CD4+ T细胞的数量,而T细胞和树突状细胞中的信号则导致记忆CD4+ T细胞的Th1优势。这些发现强调了在疟原虫感染期间调节记忆CD4+ T细胞的复杂细胞因子信号网络。
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引用次数: 0
The tryptophan metabolic pathway of the microbiome and host cells in health and disease. 微生物组和宿主细胞在健康和疾病中的色氨酸代谢途径。
IF 4.4 4区 医学 Q2 Medicine Pub Date : 2024-06-13 DOI: 10.1093/intimm/dxae035
Kentaro Miyamoto, Tomohisa Sujino, Takanori Kanai

The intricate and dynamic tryptophan (Trp) metabolic pathway in both the microbiome and host cells highlights its profound implications for health and disease. This pathway involves complex interactions between host cellular and bacteria processes, producing bioactive compounds such as 5-Hydroxytryptamine (5-HT) and kynurenine (Kyn) derivatives. Immune responses to Trp metabolites through specific receptors have been explored, highlighting the role of the aryl hydrocarbon receptor (AHR) in inflammation modulation. Dysregulation of this pathway is implicated in various diseases, such as Alzheimer's and Parkinson's diseases, mood disorders, neuronal diseases, autoimmune diseases such as multiple sclerosis (MS), and cancer. In this article, we describe the impact of the 5-HT, Trp, indole, and Trp metabolites on health and disease. Further, we review the impact of microbiome-derived Trp metabolites that affect immune responses and contribute to maintaining homeostasis, especially in an experimental autoimmune encephalitis (EAE) model of MS.

微生物组和宿主细胞中错综复杂而又充满活力的色氨酸(Trp)代谢途径凸显了其对健康和疾病的深远影响。这一途径涉及宿主细胞和细菌过程之间复杂的相互作用,产生生物活性化合物,如 5-羟色胺(5-HT)和犬尿氨酸(Kyn)衍生物。通过特定受体对 Trp 代谢物的免疫反应已得到探讨,其中突出了芳基烃受体(AHR)在炎症调节中的作用。这一途径的失调与多种疾病有关,如阿尔茨海默氏症和帕金森氏症、情绪障碍、神经元疾病、自身免疫性疾病(如多发性硬化症)和癌症。本文介绍了 5-羟色胺、Trp、吲哚和 Trp 代谢物对健康和疾病的影响。此外,我们还回顾了微生物衍生的 Trp 代谢物对免疫反应的影响以及对维持体内平衡的作用,尤其是在多发性硬化症的实验性自身免疫性脑炎 (EAE) 模型中的作用。
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引用次数: 0
An inhibitory immunoreceptor Allergin-1 regulates the intestinal dysbiosis and barrier function in mice. 抑制性免疫受体 Allergin-1 调节小鼠肠道菌群失调和屏障功能。
IF 4.4 4区 医学 Q2 Medicine Pub Date : 2024-06-08 DOI: 10.1093/intimm/dxae010
Yu-Hsien Lin, Satoko Tahara-Hanaoka, Nozomu Obana, Shinji Fukuda, Akira Shibuya

The intestinal barrier consists of mucosal, epithelial, and immunological barriers and serves as a dynamic interface between the host and its environment. Disruption of the intestinal barrier integrity is a leading cause of various gastrointestinal diseases, such as inflammatory bowel disease. The homeostasis of the intestinal barrier is tightly regulated by crosstalk between gut microbes and the immune system; however, the implication of the immune system on the imbalance of gut microbes that disrupts barrier integrity remains to be fully elucidated. An inhibitory immunoglobulin-like receptor, Allergin-1, is expressed on mast cells and dendritic cells and inhibits Toll-like receptor (TLR)-2 and TLR-4 signaling in these cells. Since TLRs are major sensors of microbiota and are involved in local epithelial homeostasis, we investigated the role of Allergin-1 in maintaining intestinal homeostasis. Allergin-1-deficient (Milr1-/-) mice exhibited more severe dextran sulfate sodium (DSS)-induced colitis than did wild-type (WT) mice. Milr1-/- mice showed an enhanced intestinal permeability compared with WT mice even before DSS administration. Treatment of Milr1-/- mice with neomycin, but not ampicillin, restored intestinal barrier integrity. The 16S rRNA gene sequencing analysis demonstrated that Bifidobacterium pseudolongum was the dominant bacterium in Milr1-/- mice after treatment with ampicillin. Although the transfer of B. pseudolongum to germ-free WT mice had no effect on intestinal permeability, its transfer into ampicillin-treated WT mice enhanced intestinal permeability. These results demonstrated that Allergin-1 deficiency enhanced intestinal dysbiosis with expanded B. pseudolongum, which contributes to intestinal barrier dysfunction in collaboration with neomycin-sensitive and ampicillin-resistant microbiota.

肠道屏障由粘膜、上皮和免疫屏障组成,是宿主与其环境之间的动态界面。肠屏障完整性的破坏是导致炎症性肠病等各种胃肠道疾病的主要原因。肠道屏障的平衡受到肠道微生物和免疫系统之间相互影响的密切调节;然而,免疫系统对肠道微生物失衡破坏屏障完整性的影响仍有待全面阐明。一种抑制性免疫球蛋白样受体 Allergin-1 在肥大细胞和树突状细胞上表达,可抑制这些细胞中的 Toll 样受体(TLR)-2 和 TLR-4 信号传导。由于 TLR 是微生物群的主要传感器并参与局部上皮细胞的平衡,我们研究了 Allergin-1 在维持肠道平衡中的作用。与野生型(WT)小鼠相比,Allergin-1缺陷型(Milr1-/-)小鼠表现出更严重的葡聚糖硫酸钠(DSS)诱导的结肠炎。即使在服用右旋糖酐硫酸钠之前,Milr1-/-小鼠的肠道通透性也比 WT 小鼠强。用新霉素(而非氨苄青霉素)治疗 Milr1-/- 小鼠可恢复肠道屏障的完整性。16S rRNA 基因测序分析表明,在使用氨苄青霉素治疗后,假长双歧杆菌是 Milr1-/- 小鼠体内的优势细菌。虽然将假龙双歧杆菌转入无菌的 WT 小鼠体内对肠道通透性没有影响,但将其转入氨苄青霉素处理过的 WT 小鼠体内会增强肠道通透性。这些结果表明,Allergin-1 缺乏会增强肠道菌群失调,假龙胆(B. pseudolongum)扩大,与新霉素敏感和氨苄西林耐药微生物群共同导致肠道屏障功能障碍。
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引用次数: 0
Metabolic reprogramming and macrophage polarization in granuloma formation. 肉芽肿形成过程中的代谢重编程和巨噬细胞极化
IF 4.4 4区 医学 Q2 Medicine Pub Date : 2024-06-08 DOI: 10.1093/intimm/dxae013
Satoshi Nakamizo, Kenji Kabashima

This review article delves into the complexities of granuloma formation, focusing on the metabolic reprogramming within these immune structures, especially in tuberculosis and sarcoidosis. It underscores the role of the monocyte-macrophage lineage in granuloma formation and maintenance, emphasizing the adaptability of these cells to environmental cues and inflammatory stimuli. Key to the discussion is the macrophage polarization influenced by various cytokines, with a detailed exploration of the metabolic shifts towards glycolysis under hypoxic conditions and the utilization of the pentose phosphate pathway (PPP) for crucial biosynthetic processes. Significant attention is given to the metabolism of L-arginine in macrophages and its impact on immune response and granuloma function. The review also highlights the role of mechanistic target of rapamycin (mTOR) signaling in macrophage differentiation and its implications in granulomatous diseases. Discoveries such as elevated PPP activity in granuloma-associated macrophages and the protective role of NADPH against oxidative stress offer novel insights into granuloma biology. The review concludes by suggesting potential therapeutic targets within these metabolic pathways to modulate granuloma formation and function, proposing new treatment avenues for conditions characterized by chronic inflammation and granuloma formation. This work contributes significantly to the understanding of immune regulation and chronic inflammation, presenting avenues for future research and therapy in granulomatous diseases.

这篇综述文章深入探讨了肉芽肿形成的复杂性,重点是这些免疫结构内部的新陈代谢重编程,尤其是在结核病和肉样瘤病中。文章强调了单核-巨噬细胞系在肉芽肿形成和维持中的作用,强调了这些细胞对环境线索和炎症刺激的适应性。讨论的关键是受各种细胞因子影响的巨噬细胞极化,详细探讨了在缺氧条件下向糖酵解的代谢转变,以及利用磷酸戊糖途径(PPP)进行关键的生物合成过程。其中特别关注巨噬细胞中 L-精氨酸的代谢及其对免疫反应和肉芽肿功能的影响。综述还强调了雷帕霉素机械靶标(mTOR)信号在巨噬细胞分化中的作用及其对肉芽肿疾病的影响。肉芽肿相关巨噬细胞中 PPP 活性的升高以及 NADPH 对氧化应激的保护作用等发现为肉芽肿生物学提供了新的见解。综述最后提出了在这些代谢途径中调节肉芽肿形成和功能的潜在治疗靶点,为以慢性炎症和肉芽肿形成为特征的疾病提出了新的治疗途径。这项工作极大地促进了人们对免疫调节和慢性炎症的理解,为肉芽肿疾病的未来研究和治疗提供了途径。
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引用次数: 0
High CD62L expression predicts the generation of chimeric antigen receptor T cells with potent effector functions. CD62L 的高表达预示着具有强大效应功能的嵌合抗原受体 T 细胞的产生。
IF 4.4 4区 医学 Q2 Medicine Pub Date : 2024-06-08 DOI: 10.1093/intimm/dxae015
Hitomi Kasuya, Haosong Zhang, Yusuke Ito, Toshiaki Yoshikawa, Takahiro Nakashima, Yang Li, Tetsuya Matsukawa, Satoshi Inoue, Yuki Kagoya

The efficient generation of chimeric antigen receptor (CAR) T cells is highly influenced by the quality of apheresed T cells. Healthy donor-derived T cells usually proliferate better than patients-derived T cells and are precious resources to generate off-the-shelf CAR-T cells. However, relatively little is known about the determinants that affect the efficient generation of CAR-T cells from healthy donor-derived peripheral blood mononuclear cells (PBMCs) compared with those from the patients' own PBMCs. We here examined the efficiency of CAR-T cell generation from multiple healthy donor samples and analyzed its association with the phenotypic features of the starting peripheral blood T cells. We found that CD62L expression levels within CD8+ T cells were significantly correlated with CAR-T cell expansion. Moreover, high CD62L expression within naïve T cells was associated with the efficient expansion of T cells with a stem cell-like memory phenotype, an indicator of high-quality infusion products. Intriguingly, genetic disruption of CD62L significantly impaired CAR-T cell proliferation and cytokine production upon antigen stimulation. Conversely, ectopic expression of a shedding-resistant CD62L mutant augmented CAR-T cell effector functions compared to unmodified CAR-T cells, resulting in improved antitumor activity in vivo. Collectively, we identified the surface expression of CD62L as a concise indicator of potent T-cell proliferation. CD62L expression is also associated with the functional properties of CAR-T cells. These findings are potentially applicable to selecting optimal donors to massively generate CAR-T cell products.

嵌合抗原受体(CAR)T 细胞的高效生成在很大程度上受到无细胞捐献 T 细胞质量的影响。健康供体来源的T细胞通常比患者来源的T细胞增殖能力更强,是生成现成CAR-T细胞的宝贵资源。然而,与患者自身的外周血单核细胞(PBMC)相比,人们对影响从健康供体来源的外周血单核细胞(PBMC)高效生成 CAR-T 细胞的决定因素知之甚少。我们在此研究了从多个健康供体样本中生成 CAR-T 细胞的效率,并分析了其与起始外周血 T 细胞表型特征的关联。我们发现,CD8+ T 细胞中 CD62L 的表达水平与 CAR-T 细胞的扩增显著相关。此外,CD62L在幼稚T细胞中的高表达与具有干细胞记忆表型的T细胞的高效扩增有关,而干细胞记忆表型是高质量输注产品的指标。耐人寻味的是,CD62L的基因干扰会显著影响CAR-T细胞的增殖和抗原刺激时细胞因子的产生。相反,与未修饰的 CAR-T 细胞相比,异位表达抗脱落的 CD62L 突变体能增强 CAR-T 细胞的效应功能,从而提高体内的抗肿瘤活性。总之,我们发现 CD62L 的表面表达是 T 细胞有效增殖的简明指标。CD62L 的表达还与 CAR-T 细胞的功能特性有关。这些发现可能适用于选择最佳供体以大规模生成 CAR-T 细胞产品。
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引用次数: 0
Acute malaria suppresses the B lymphocytic niche in the bone marrow through the alteration of CXCL12-abundant reticular cells. 急性疟疾通过改变CXCL12丰富的网状细胞来抑制骨髓中的B淋巴细胞龛。
IF 4.4 4区 医学 Q2 Medicine Pub Date : 2024-06-08 DOI: 10.1093/intimm/dxae012
Michelle Sue Jann Lee, Julia Matsuo-Dapaah, Camila Del Rosario Zorrilla, Yoshiki Omatsu, Takashi Nagasawa, Shun Uemura, Atsushi Iwama, Ken J Ishii, Cevayir Coban

Bone marrow is a dynamic organ composed of stem cells that constantly receive signals from stromal cells and other hematopoietic cells in the niches of the bone marrow to maintain hematopoiesis and generate immune cells. Perturbation of the bone marrow microenvironment by infection and inflammation affects hematopoiesis and may affect immune cell development. Little is known about the effect of malaria on the bone marrow stromal cells that govern the hematopoietic stem cell (HSC) niche. In this study, we demonstrate that the mesenchymal stromal CXCL12-abundant reticular (CAR) cell population is reduced during acute malaria infection. The reduction of CXCL12 and interleukin-7 signals in the bone marrow impairs the lymphopoietic niche, leading to the depletion of common lymphoid progenitors, B cell progenitors, and mature B cells, including plasma cells in the bone marrow. We found that interferon-γ (IFNγ) is responsible for the upregulation of Sca1 on CAR cells, yet the decline in CAR cell and B cell populations in the bone marrow is IFNγ-independent. In contrast to the decline in B cell populations, HSCs and multipotent progenitors increased with the expansion of myelopoiesis and erythropoiesis, indicating a bias in the differentiation of multipotent progenitors during malaria infection. These findings suggest that malaria may affect host immunity by modulating the bone marrow niche.

骨髓是一个由干细胞组成的动态器官,干细胞不断接收来自骨髓壁龛中基质细胞和其他造血细胞的信号,以维持造血和生成免疫细胞。感染和炎症对骨髓微环境的干扰会影响造血功能,并可能影响免疫细胞的发育。人们对疟疾对管理造血干细胞(HSC)生态位的骨髓基质细胞的影响知之甚少。在这项研究中,我们证明在急性疟疾感染期间,间质基质CXCL12-丰富网状(CAR)细胞群减少。骨髓中 CXCL12 和 IL-7 信号的减少损害了淋巴造血生态位,导致骨髓中普通淋巴祖细胞、B 细胞祖细胞和成熟 B 细胞(包括浆细胞)的耗竭。我们发现,IFNγ 是导致 CAR 细胞上调 Sca1 的原因,但骨髓中 CAR 细胞和 B 细胞数量的减少与 IFNγ 无关。与 B 细胞数量下降相反,造血干细胞和多能祖细胞随着骨髓造血和红细胞生成的扩大而增加,这表明在疟疾感染期间多能祖细胞的分化出现了偏差。这些研究结果表明,疟疾可能通过调节骨髓生态位来影响宿主的免疫力。
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引用次数: 0
γδ intraepithelial lymphocytes acquire the ability to produce IFN-γ in a different time course than αβ intraepithelial lymphocytes. γδ上皮内淋巴细胞获得产生 IFN-γ 的能力的时间过程与 αβ 上皮内淋巴细胞不同。
IF 4.4 4区 医学 Q2 Medicine Pub Date : 2024-06-05 DOI: 10.1093/intimm/dxae034
Shizue Tani-Ichi, Koichi Ikuta

An age-dependent increase in IFN-γ expression by intestinal intraepithelial lymphocytes (IELs) contributes to the acquisition of resistance to infection by pathogens. However, how IELs acquire the ability to produce IFN-γ remains to be elucidated. Here, we report that IELs in the small intestine acquire the ability to rapidly produce IFN-γ at two distinct life stages. TCRαβ+ IELs (αβIELs) started producing IFN-γ at 4 weeks of age, within 1 week after weaning. In contrast, TCRγδ+ IELs (γδIELs) started producing IFN-γ at 7 weeks of age. In mice lacking Eγ4, an enhancer of the TCRγ locus (Eγ4-/- mice), Thy-1+ Vγ5+ γδIELs, a major subpopulation of γδIELs, were specifically reduced and their ability to produce IFN-γ was severely impaired, whereas Vγ2+ γδIELs normally produced IFN-γ. In Eγ4-/- mice, TCR expression levels were reduced in Vγ5+ γδIEL precursors in the thymus but unchanged in the Vγ5+ IELs. Nevertheless, TCR responsiveness in Vγ5+ γδIELs was impaired in Eγ4-/- mice, suggesting that the TCR signal received in the thymus may determine TCR responsiveness and the ability to produce IFN-γ in the gut. These results suggest that αβIELs and γδIELs start producing IFN-γ at different life stages and that the ability of Vγ5+ γδIELs to produce IFN-γ in the gut may be predetermined by TCR signaling in IEL precursors in the thymus.

肠上皮内淋巴细胞(IELs)表达的 IFN-γ 随年龄增长而增加,这有助于获得抵抗病原体感染的能力。然而,IELs如何获得产生IFN-γ的能力仍有待阐明。在这里,我们报告了小肠中的 IELs 在两个不同的生命阶段获得快速产生 IFN-γ 的能力。TCRαβ+ IELs(αβIELs)在4周龄时,即断奶后1周内开始产生IFN-γ。相反,TCRγδ+ IELs(γδIELs)在 7 周龄时开始产生 IFN-γ。在缺乏 TCRγ 基因座增强子 Eγ4 的小鼠(Eγ4-/- 小鼠)中,Thy-1+ Vγ5+ γδIELs (γδIELs 的一个主要亚群)特异性减少,其产生 IFN-γ 的能力严重受损,而 Vγ2+ γδIELs 则正常产生 IFN-γ。在 Eγ4-/- 小鼠中,胸腺中 Vγ5+ γδIEL 前体的 TCR 表达水平降低,但 Vγ5+ IELs 的表达水平不变。然而,在 Eγ4-/- 小鼠中,Vγ5+ γδIEL 的 TCR 反应性受损,这表明胸腺中接收的 TCR 信号可能决定了 TCR 反应性和在肠道中产生 IFN-γ 的能力。这些结果表明,αβIELs 和 γδIELs 在不同的生命阶段开始产生 IFN-γ,Vγ5+ γδIELs 在肠道中产生 IFN-γ 的能力可能是由胸腺中 IEL 前体的 TCR 信号决定的。
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引用次数: 0
Essential role of CD155 glycosylation in functional binding to DNAM-1 on natural killer cells. CD155 糖基化在与自然杀伤细胞上的 DNAM-1 功能性结合中的重要作用。
IF 4.4 4区 医学 Q2 Medicine Pub Date : 2024-04-27 DOI: 10.1093/intimm/dxae005
Saeko Tahara, Genki Okumura, Tomohei Matsuo, Akira Shibuya, Kazuko Shibuya

The cluster of differentiation 155 (CD155) is highly expressed on tumor cells and augments or inhibits the cytotoxic activities of natural killer (NK) cells and T cells through its receptor ligands DNAX accessory molecule 1 (DNAM-1) and T-cell immunoglobulin (Ig) and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT), respectively. Although CD155 is heavily glycosylated, the role of glycosylation of CD155 in the cytotoxic activity of effector lymphocytes remains unknown. Here, we show that the N-linked glycosylation at residue 105 (N105 glycosylation) in the first Ig-like domain of CD155 is involved in the binding of CD155 to both DNAM-1 and TIGIT. The N105 glycosylation also plays an essential role to induce signaling in both DNAM-1 and TIGIT reporter cells. Moreover, we show that the N105 glycosylation of CD155 contributes preferentially to the DNAM-1-mediated activating signal over the TIGIT-mediated inhibitory signal in NK cells. Our results demonstrated the important role of the N105 glycosylation of CD155 in DNAM-1 and TIGIT functions and shed new light on the understanding of tumor immune responses.

CD155在肿瘤细胞上高度表达,并分别通过其受体配体DNAM-1和T细胞免疫球蛋白免疫受体酪氨酸抑制基团结构域(TIGIT)增强或抑制自然杀伤(NK)细胞和T细胞的细胞毒活性。虽然 CD155 被大量糖基化,但 CD155 的糖基化在效应淋巴细胞的细胞毒性活性中的作用仍然未知。在这里,我们发现 CD155 的第一个免疫球蛋白样结构域中残基 105 处的 N-连接糖基化(N105 糖基化)参与了 CD155 与 DNAM-1 和 TIGIT 的结合。N105 糖基化在 DNAM-1 和 TIGIT 报告细胞中诱导信号传导中也起着至关重要的作用。此外,我们还发现在 NK 细胞中,CD155 的 N105 糖基化对 DNAM-1 介导的激活信号的作用优于 TIGIT 介导的抑制信号。我们的研究结果证明了 CD155 的 N105 糖基化在 DNAM-1 和 TIGIT 功能中的重要作用,并为理解肿瘤免疫反应提供了新的思路。
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引用次数: 0
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International immunology
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