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Immunogenicity and protective capacity of a CpG ODN adjuvanted alum adsorbed bivalent meningococcal outer membrane vesicle vaccine. CpG ODN 佐剂明矾吸附双价脑膜炎球菌外膜囊泡疫苗的免疫原性和保护能力
IF 4.8 4区 医学 Q2 IMMUNOLOGY Pub Date : 2024-07-13 DOI: 10.1093/intimm/dxae016
Tugce Canavar Yildirim, Yasemin Ozsurekci, Muzaffer Yildirim, Irem Evcili, Volkan Yazar, Kubra Aykac, Ulku Guler, Bekir Salih, Mayda Gursel, Ihsan Gursel

Invasive meningococcal disease (IMD) is caused by Neisseria meningitidis, with the main serogroups responsible for the disease being A, B, C, W, X, and Y. To date, several vaccines targeting N. meningitidis have been developed albeit with a short-lived protection. Given that MenW and MenB are the most common causes of IMD in Europe, Turkey, and the Middle East, we aimed to develop an outer membrane vesicle (OMV) based bivalent vaccine as the heterologous antigen source. Herein, we compared the immunogenicity, and breadth of serum bactericidal activity (SBA) assay-based protective coverage of OMV vaccine to the X serotype with existing commercial meningococcal conjugate and polysaccharide (PS) vaccines in a murine model. BALB/c mice were immunized with preclinical batches of the W + B OMV vaccine, either adjuvanted with Alum, CpG ODN, or their combinations, and compared with a MenACYW conjugate vaccine (NimenrixTM, Pfizer), and a MenB OMV-based vaccine (Bexsero®, GSK), The immune responses were assessed through enzyme-linked immunosorbent assay (ELISA) and SBA assay. Antibody responses and SBA titers were significantly higher in the W + B OMV vaccine when adjuvanted with Alum or CpG ODN, as compared to the control groups. Moreover, the SBA titers were not only significantly higher than those achieved with available conjugated ACYW vaccines but also on par with the 4CMenB vaccines. In conclusion, the W + B OMV vaccine demonstrated the capacity to elicit robust antibody responses, surpassing or matching the levels induced by licensed meningococcal vaccines. Consequently, the W + B OMV vaccine could potentially serve as a viable alternative or supplement to existing meningococcal vaccines.

侵袭性脑膜炎球菌病(IMD)由奈瑟氏脑膜炎球菌(Neisseria meningitidis)引起,主要致病血清群为 A、B、C、W、X 和 Y。鉴于 MenW 和 MenB 是欧洲、土耳其和中东地区最常见的 IMD 病因,我们的目标是开发一种基于外膜囊(OMV)的二价疫苗作为异源抗原。在此,我们在小鼠模型中比较了 OMV 疫苗与现有商业脑膜炎球菌结合疫苗和多糖疫苗对 X 血清型的免疫原性和基于血清杀菌测定(SBA)的保护范围。用临床前批次的 W+B OMV 疫苗对 BALB/c 小鼠进行免疫接种,疫苗可添加明矾、CpG ODN 或其组合佐剂,并与 MenACYW 结合疫苗(NimenrixTM,辉瑞公司)和基于 OMV 的 MenB 疫苗(Bexsero®,葛兰素史克公司)进行比较。与对照组相比,添加明矾或 CpG ODN 佐剂的 W+B OMV 疫苗的抗体反应和 SBA 滴度明显更高。此外,SBA 滴度不仅明显高于现有的共轭 ACYW 疫苗,而且与 4CMenB 疫苗相当。总之,W+B OMV 疫苗表现出了诱导强大抗体反应的能力,其水平超过或达到了已获许可的脑膜炎球菌疫苗所诱导的水平。因此,W+B OMV 疫苗有可能成为现有脑膜炎球菌疫苗的可行替代品或补充品。
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引用次数: 0
Recent advances regarding the potential roles of invariant natural killer T cells in cardiovascular diseases with immunological and inflammatory backgrounds. 关于不变自然杀伤 T 细胞在具有免疫和炎症背景的心血管疾病中的潜在作用的最新进展。
IF 4.8 4区 医学 Q2 IMMUNOLOGY Pub Date : 2024-07-13 DOI: 10.1093/intimm/dxae019
Kazuya Iwabuchi, Masashi Satoh, Kazuhisa Yoshino, Naoki Ishimori

Invariant natural killer T (iNKT) cells, which bear αβ-type T-cell antigen-receptors (TCRs), recognize glycolipid antigens in a cluster of differentiation 1d (CD1d)-restricted manner. Regarding these cells, the unique modes of thymic selection and maturation elucidate innateness, irrespective of them also being members of the adaptive immune system as a T-cell. iNKT cells develop and differentiate into NKT1 [interferon γ (IFN-γ)-producing], NKT2 [interleukin 4 (IL-4)/IL-13-producing], or NKT17 (IL-17-producing) subsets in the thymus. After egress, NKT10 (IL-10-producing), follicular helper NKT (NKTfh; IL-21-producing), and regulatory NKT (NKTreg) subsets emerge following stimulation in the periphery. Moreover, iNKT cells have been shown to possess several physiological or pathological roles. iNKT cells exhibit dual alleviating or aggravating roles in experimentally induced immune and/or inflammatory diseases in mice. These findings indicate that the modulation of iNKT cells can be employed for therapeutic use or prevention of human diseases. In this review, we discuss the potential roles of iNKT cells in the development of immune/inflammatory diseases of the cardiovascular system, with emphasis on atherosclerosis, aortic aneurysms, and cardiac remodeling.

不变自然杀伤 T 细胞(iNKT)带有 αβ 型 T 细胞抗原受体,能以分化 1d 簇(CD1d)限制的方式识别糖脂抗原。iNKT细胞在胸腺中发育并分化成NKT1[产生干扰素γ(IFN-γγ)]、NKT2[产生白细胞介素4(IL-4)/IL-13]或NKT17(产生IL-17)亚群。出境后,NKT10(产生 IL-10)、滤泡辅助 NKT(NKTfh;产生 IL-21)和调节性 NKT(NKTreg)亚群在外周受到刺激后出现。iNKT 细胞在小鼠实验性免疫和/或炎症性疾病中表现出双重缓解或加重作用。这些发现表明,调节 iNKT 细胞可用于治疗或预防人类疾病。在这篇综述中,我们将讨论 iNKT 细胞在心血管系统免疫/炎症性疾病发展过程中的潜在作用,重点是动脉粥样硬化、主动脉瘤和心脏重塑。
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引用次数: 0
Correction to: Computer model of IL-6-dependent rheumatoid arthritis in F759 mice. 更正:F759 小鼠 IL-6 依赖性类风湿性关节炎的计算机模型。
IF 4.8 4区 医学 Q2 IMMUNOLOGY Pub Date : 2024-07-13 DOI: 10.1093/intimm/dxae030
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引用次数: 0
The canonical Hippo pathway components modulate the differentiation of lamina propria regulatory T cells and T helper 17-like regulatory T cells in mouse colitis. 在小鼠结肠炎中,典型 Hippo 通路成分可调节固有膜调节性 T 细胞和 T 辅助 17 样调节性 T 细胞的分化。
IF 4.8 4区 医学 Q2 IMMUNOLOGY Pub Date : 2024-07-03 DOI: 10.1093/intimm/dxae043
Liuqing Ge, Min Xu, Meifang Huang, Shaoping Liu, Zhidai Zhou, Ziqin Xia, Shouquan Dong, Qiu Zhao, Ruiping Zhu, Feng Zhou

Regulatory T cells (Tregs) ameliorate inflammatory bowel diseases. However, their plasticity is not completely understood. In this study using a mouse colitis model, Tregs and T helper 17 (Th17)-like Tregs were detected and sorted using flow cytometry, followed by transcriptome sequencing, real-time RT-PCR, and flow cytometry to analyze the mRNA profiles of these cells. Treg plasticity was evaluated by in vitro differentiation assays. The immunosuppressive activities of Tregs and Th17-like Tregs were assessed in an adoptive transfer assay. We found Tregs-derived Th17-like Tregs in inflamed colonic lamina propria (LP). LP Th17-like Tregs expressed higher Th17-related cytokines and lower immunosuppressive cytokines compared with LP Tregs. Notably, Tregs expressed higher Yes-associated protein 1 (YAP1) but lower transcriptional coactivator with PDZ‑binding motif (TAZ) than Th17-like Tregs. Verteporfin-mediated inhibition of YAP1 activity enhanced Th17-like Treg generation, whereas IBS008739-induced TAZ activation did not affect Th17-like Treg generation. Besides, verteporfin enhanced while IBS008739 suppressed the differentiation of Th17-like Tregs into Th17 cells. Furthermore, YAP1 activated STAT5 signaling in Tregs, whereas YAP1 and TAZ activated STAT3 and STAT5 signaling in Th17-like Tregs. Compared with Tregs, Th17-like Tregs were less efficacious in ameliorating colitis. Therefore, YAP1 suppressed Treg differentiation into Th17-like Tregs. Both YAP1 and TAZ inhibited the differentiation of Th17-like Tregs into Th17 cells. Therefore, YAP1 and TAZ probably maintain the immunosuppressive activities of Tregs and Th17-like Tregs in colitis.

调节性 T 细胞(Tregs)可改善炎症性肠病。然而,人们对它们的可塑性还不完全了解。本研究使用小鼠结肠炎模型,用流式细胞术检测和分选Tregs和T辅助细胞17(Th17)样Tregs,然后用转录组测序、实时RT-PCR和流式细胞术分析这些细胞的mRNA谱。体外分化试验评估了 Treg 的可塑性。在收养性转移试验中评估了Tregs和Th17样Tregs的免疫抑制活性。我们在发炎的结肠固有膜(LP)中发现了Tregs衍生的Th17样Tregs。与 LP Tregs 相比,LP Th17-like Tregs 表达较高的 Th17 相关细胞因子和较低的免疫抑制细胞因子。值得注意的是,与Th17样Tregs相比,Tregs表达较高的Yes相关蛋白1(YAP1),但表达较低的具有PDZ结合基调的转录辅激活因子(TAZ)。Verteporfin介导的YAP1活性抑制增强了Th17样Treg的生成,而IBS008739诱导的TAZ激活并不影响Th17样Treg的生成。此外,verteporfin 增强了 Th17-like Tregs 向 Th17 细胞的分化,而 IBS008739 则抑制了 Th17-like Tregs 向 Th17 细胞的分化。此外,YAP1能激活Tregs中的STAT5信号,而YAP1和TAZ能激活Th17样Tregs中的STAT3和STAT5信号。与Tregs相比,Th17样Tregs改善结肠炎的效果较差。因此,YAP1抑制了Treg向Th17样Treg的分化。YAP1和TAZ都能抑制Th17样Tregs分化为Th17细胞。因此,YAP1和TAZ可能维持了Tregs和Th17样Tregs在结肠炎中的免疫抑制活性。
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引用次数: 0
Diverse roles of dendritic cell and regulatory T cell crosstalk in controlling health and disease. 树突状细胞和调节性 T 细胞串联在控制健康和疾病方面的多种作用。
IF 4.8 4区 医学 Q2 IMMUNOLOGY Pub Date : 2024-07-02 DOI: 10.1093/intimm/dxae042
Sayuri Yamazaki

Dendritic cells (DCs) are specialized antigen-presenting cells for lymphocytes, including regulatory T (Treg) cells, a subset of CD4+ T cells expressing CD25 and Foxp3, a transcription factor. Treg cells maintain immunological self-tolerance in mice and humans, and suppress autoimmunity and other various immune responses such as tumor immunity, transplant rejection, allergy, responses to microbes, and inflammation. Treg cell proliferation is controlled by antigen-presenting DCs. On the other hand, Treg cells suppress the function of DCs by restraining DC maturation. Therefore, the interaction between DCs and Treg cells, DC-Treg crosstalk, could contribute to controlling health and disease. We recently found that unique DC-Treg crosstalk plays a role in several conditions. First, Treg cells are expanded in ultraviolet-B (UVB)-exposed skin by interacting with DCs, and the UVB-expanded Treg cells have a healing function. Second, manipulating DC-Treg crosstalk can induce effective acquired immune responses against SARS-CoV2 antigens without adjuvants. Third, Treg cells with a special feature interact with DCs in the tumor microenvironment of human head and neck squamous cell cancer, which may contribute to the prognosis. Understanding the underlying mechanisms of DC-Treg crosstalk may provide a novel strategy to control health and disease.

树突状细胞(DC)是淋巴细胞的特化抗原递呈细胞,包括调节性 T(Treg)细胞,这是一种表达 CD25 和转录因子 Foxp3 的 CD4+ T 细胞亚群。调节性 Treg 细胞能维持小鼠和人类的免疫自身耐受性,抑制自身免疫和其他各种免疫反应,如肿瘤免疫、移植排斥、过敏、对微生物的反应和炎症。Treg 细胞的增殖受抗原递呈 DC 控制。另一方面,Treg 细胞通过抑制 DC 的成熟来抑制 DC 的功能。因此,DC 和 Treg 细胞之间的相互作用(DC-Treg crosstalk)可能有助于控制健康和疾病。我们最近发现,独特的直流-Treg串扰在多种情况下发挥作用。首先,在暴露于紫外线-B(UVB)的皮肤中,Treg细胞通过与DC相互作用而扩增,UVB扩增的Treg细胞具有治疗功能。其次,操纵 DC-Treg crosstalk 可以在不使用佐剂的情况下诱导针对 SARS-CoV2 抗原的有效获得性免疫反应。第三,在人类头颈部鳞状细胞癌的肿瘤微环境中,具有特殊功能的Treg细胞与DC相互作用,这可能有助于预后。了解DC-Treg交叉作用的内在机制可能会为控制健康和疾病提供一种新策略。
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引用次数: 0
New approaches to the control of chronic inflammatory diseases with a focus on the endolysosomal system of immune cells. 控制慢性炎症性疾病的新方法,重点关注免疫细胞的内溶酶体系统。
IF 4.8 4区 医学 Q2 IMMUNOLOGY Pub Date : 2024-07-01 DOI: 10.1093/intimm/dxae041
Noriko Toyama-Sorimachi

Chronic inflammation is implicated in many types of diseases, including cardiovascular, neurodegenerative, metabolic, and immune disorders. The search for therapeutic targets to control chronic inflammation often involves narrowing down the various molecules associated with pathology that have been discovered by various omics analyses. Herein, a different approach to identify therapeutic targets against chronic inflammation is proposed and one such target is discussed as an example. In chronically inflamed tissues, a large number of cells receive diverse proinflammatory signals, the intracellular signals are intricately integrated, and complicated intercellular interactions are orchestrated. This review focuses on effectively blocking this chaotic inflammatory signaling network via the endolysosomal system, which acts as a cellular signaling hub. In endolysosomes, the inflammatory signals mediated by pathogen sensors, such as Toll-like receptors, and the signals from nutrient and metabolic pathways are integrally regulated. Disruption of endolysosome signaling results in a strong anti-inflammatory effect by disrupting various signaling pathways, including pathogen sensor-mediated signals, in multiple immune cells. The endolysosome-resident amino acid transporter, solute carrier family 15 member 4 (SLC15A4), which plays an important role in the regulation of endolysosome-mediated signals, is a promising therapeutic target for several inflammatory diseases, including autoimmune diseases. The mechanisms by which SLC15A4 regulates inflammatory responses may provide a proof of concept for the efficacy of therapeutic strategies targeting immune cell endolysosomes.

慢性炎症与多种疾病有关,包括心血管疾病、神经退行性疾病、代谢性疾病和免疫性疾病。要寻找控制慢性炎症的治疗靶点,通常需要缩小通过各种全局分析发现的与病理有关的各种分子的范围。本文提出了一种不同的方法来确定慢性炎症的治疗靶点,并以其中一个靶点为例进行了讨论。在慢性炎症组织中,大量细胞接收各种促炎症信号,细胞内信号错综复杂,细胞间相互作用错综复杂。本综述的重点是通过作为细胞信号枢纽的内溶酶体系统有效阻断这一混乱的炎症信号网络。在内溶酶体中,由病原体传感器(如 Toll 样受体)介导的炎症信号以及来自营养和代谢途径的信号受到综合调控。干扰内溶酶体信号会导致多种免疫细胞中的各种信号通路(包括病原体传感器介导的信号)中断,从而产生强烈的抗炎效果。内溶酶体驻留氨基酸转运体--溶质运载家族 15 成员 4(SLC15A4)在调节内溶酶体介导的信号中发挥着重要作用,是包括自身免疫性疾病在内的多种炎症性疾病的有望治疗靶点。SLC15A4调控炎症反应的机制可能为针对免疫细胞内溶酶体的治疗策略的疗效提供概念证明。
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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 IMMUNOLOGY 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 IMMUNOLOGY 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 IMMUNOLOGY 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 IMMUNOLOGY 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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International immunology
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