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Metabolic advantages of regulatory T cells dictated by cancer cells. 癌症细胞决定的调节性T细胞的代谢优势。
IF 4.4 4区 医学 Q2 IMMUNOLOGY Pub Date : 2024-02-14 DOI: 10.1093/intimm/dxad035
Masaki Kondo, Shogo Kumagai, Hiroyoshi Nishikawa

Cancer cells employ glycolysis for their survival and growth (the "Warburg effect"). Consequently, surrounding cells including immune cells in the tumor microenvironment (TME) are exposed to hypoglycemic, hypoxic, and low pH circumstances. Since effector T cells depend on the glycolysis for their survival and functions, the metabolically harsh TME established by cancer cells is unfavorable, resulting in the impairment of effective antitumor immune responses. By contrast, immunosuppressive cells such as regulatory T (Treg) cells can infiltrate, proliferate, survive, and exert immunosuppressive functions in the metabolically harsh TME, indicating the different metabolic dependance between effector T cells and Treg cells. Indeed, some metabolites that are harmful for effector T cells can be utilized by Treg cells; lactic acid, a harmful metabolite for effector T cells, is available for Treg cell proliferation and functions. Deficiency of amino acids such as tryptophan and glutamine in the TME impairs effector T cell activation but increases Treg cell populations. Furthermore, hypoxia upregulates fatty acid oxidation via hypoxia-inducible factor 1α (HIF-1α) and promotes Treg cell migration. Adenosine is induced by the ectonucleotidases CD39 and CD73, which are strongly induced by HIF-1α, and reportedly accelerates Treg cell development by upregulating Foxp3 expression in T cells via A2AR-mediated signals. Therefore, this review focuses on the current views of the unique metabolism of Treg cells dictated by cancer cells. In addition, potential cancer combination therapies with immunotherapy and metabolic molecularly targeted reagents that modulate Treg cells in the TME are discussed to develop "immune metabolism-based precision medicine".

癌症细胞利用糖酵解进行生存和生长(“Warburg效应”)。因此,包括肿瘤微环境(TME)中的免疫细胞在内的周围细胞暴露于低血糖、缺氧和低pH的环境中。由于效应T细胞的生存和功能依赖于糖酵解,癌症细胞建立的代谢苛刻的TME是不利的,导致有效的抗肿瘤免疫反应受损。相反,免疫抑制细胞如调节性T(Treg)细胞可以在代谢苛刻的TME中浸润、增殖、存活并发挥免疫抑制功能,这表明效应T细胞和Treg细胞之间的代谢依赖性不同。事实上,一些对效应T细胞有害的代谢产物可以被Treg细胞利用;乳酸是效应T细胞的有害代谢产物,可用于Treg细胞的增殖和功能。TME中色氨酸和谷氨酰胺等氨基酸的缺乏损害了效应T细胞的活化,但增加了Treg细胞群。此外,缺氧通过缺氧诱导因子1α(HIF-1α)上调脂肪酸氧化,并促进Treg细胞迁移。腺苷由HIF-1α强烈诱导的外核肽酶CD39和CD73诱导,据报道,腺苷通过A2AR介导的信号上调T细胞中Foxp3的表达,从而加速Treg细胞的发育。因此,这篇综述的重点是目前对癌症细胞所决定的Treg细胞独特代谢的看法。此外,还讨论了潜在的癌症联合疗法,包括免疫疗法和调节TME中Treg细胞的代谢分子靶向试剂,以开发“基于免疫代谢的精准医学”。
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引用次数: 0
Identification of immune-related gene signatures for chronic obstructive pulmonary disease with metabolic syndrome: evidence from integrated bulk and single-cell RNA sequencing data. 慢性阻塞性肺病代谢综合征免疫相关基因特征的鉴定:来自整合的大量和单细胞RNA测序数据的证据。
IF 4.4 4区 医学 Q2 IMMUNOLOGY Pub Date : 2024-01-29 DOI: 10.1093/intimm/dxad043
Yueren Wu, Mengyu Ma, Wenglam Choi, Weifang Xu, Jingcheng Dong

Chronic obstructive pulmonary disease (COPD) is closely related to innate and adaptive inflammatory immune responses. It is increasingly becoming evident that metabolic syndrome (MetS) affects a significant portion of COPD patients. Through this investigation, we identify shared immune-related candidate biological markers. The Weighted Gene Co-Expression Network Analysis (WGCNA) was utilized to reveal the co-expression modules linked to COPD and MetS. The commonly expressed genes in the COPD and MetS were utilized to conduct an enrichment analysis. We adopted machine-learning to screen and validate hub genes. We also assessed the relationship between hub genes and immune cell infiltration in COPD and MetS, respectively. Moreover, associations across hub genes and metabolic pathways were also explored. Finally, we chose a single-cell RNA sequencing (scRNA-seq) dataset to investigate the hub genes and shared mechanisms at the level of the cells. We also applied cell trajectory analysis and cell-cell communication analysis to focus on the vital immune cell we were interested in. As a result, we selected and validated 13 shared hub genes for COPD and MetS. The enrichment analysis and immune infiltration analysis illustrated strong associations between hub genes and immunology. Additionally, we applied metabolic pathway enrichment analysis, indicating the significant role of reactive oxygen species (ROS) in COPD with MetS. Through scRNA-seq analysis, we found that ROS might accumulate the most in the alveolar macrophages. In conclusion, the 13 hub genes related to the immune response and metabolism may serve as diagnostic biomarkers and treatment targets of COPD with MetS.

慢性阻塞性肺病(COPD)与先天性和适应性炎症免疫反应密切相关。代谢综合征(MetS)对COPD患者的影响越来越明显。通过这项研究,我们确定了共享的免疫相关候选生物标志物。加权基因共表达网络分析(WGCNA)用于揭示与COPD和MetS相关的共表达模块。利用COPD和MetS中常见表达的基因进行富集分析。我们采用机器学习来筛选和验证中枢基因。我们还分别评估了中枢基因与COPD和MetS免疫细胞浸润之间的关系。此外,还探讨了中枢基因和代谢途径之间的关联。最后,我们选择了一个单细胞RNA测序(scRNA-seq)数据集来研究细胞水平上的枢纽基因和共享机制。我们还应用细胞轨迹分析和细胞间通讯分析来关注我们感兴趣的重要免疫细胞。因此,我们选择并验证了13个COPD和MetS的共享枢纽基因。富集分析和免疫浸润分析表明中枢基因与免疫学之间有很强的相关性;此外,我们应用了代谢途径富集分析,表明活性氧(ROS)在患有代谢综合征的COPD中的重要作用。通过scRNA-seq分析,我们发现ROS可能在肺泡巨噬细胞中积累最多。总之,与免疫反应和代谢相关的13个枢纽基因可以作为COPD合并代谢综合征的诊断生物标志物和治疗靶点。
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引用次数: 0
Alcaligenes lipid A functions as a superior mucosal adjuvant to monophosphoryl lipid A via the recruitment and activation of CD11b+ dendritic cells in nasal tissue. 碱性脂质A通过募集和激活鼻组织中CD11b+树突状细胞作为单磷酰脂质A的优越粘膜佐剂。
IF 4.8 4区 医学 Q2 IMMUNOLOGY Pub Date : 2024-01-29 DOI: 10.1093/intimm/dxad045
Xiao Sun, Koji Hosomi, Atsushi Shimoyama, Ken Yoshii, Azusa Saika, Haruki Yamaura, Takahiro Nagatake, Hiroshi Kiyono, Koichi Fukase, Jun Kunisawa

We previously demonstrated that Alcaligenes-derived lipid A (ALA), which is produced from an intestinal lymphoid tissue-resident commensal bacterium, is an effective adjuvant for inducing antigen-specific immune responses. To understand the immunologic characteristics of ALA as a vaccine adjuvant, we here compared the adjuvant activity of ALA with that of a licensed adjuvant (monophosphoryl lipid A, MPLA) in mice. Although the adjuvant activity of ALA was only slightly greater than that of MPLA for subcutaneous immunization, ALA induced significantly greater IgA antibody production than did MPLA during nasal immunization. Regarding the underlying mechanism, ALA increased and activated CD11b+ CD103- CD11c+ dendritic cells in the nasal tissue by stimulating chemokine responses. These findings revealed the superiority of ALA as a mucosal adjuvant due to the unique immunologic functions of ALA in nasal tissue.

我们之前已经证明,Alcaligenes-derived脂质A (ALA)是一种有效的佐剂,可以诱导抗原特异性免疫反应,这种脂质A是由肠道淋巴组织中的共生细菌产生的。为了了解ALA作为疫苗佐剂的免疫学特性,我们在这里比较了ALA与一种许可佐剂(单磷酰脂质a, MPLA)在小鼠中的佐剂活性。虽然ALA在皮下免疫时的佐剂活性仅略高于MPLA,但在鼻腔免疫时,ALA诱导的IgA抗体产生明显高于MPLA。至于其潜在机制,ALA通过刺激趋化因子反应增加和激活鼻腔组织中的CD11b+ CD103- CD11c+树突状细胞。由于ALA在鼻组织中具有独特的免疫功能,这些发现揭示了ALA作为粘膜佐剂的优越性。
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引用次数: 0
Peripheral helper T cells, mavericks of peripheral immune responses. 外周辅助性T细胞,外周免疫反应的特立独行者。
IF 4.8 4区 医学 Q2 IMMUNOLOGY Pub Date : 2024-01-29 DOI: 10.1093/intimm/dxad041
Hiroyuki Yoshitomi

Peripheral helper T (Tph) cells have been established, through intensive efforts to elucidate local immune responses in human rheumatoid arthritis (RA), as a CD4 subset intimately involved in acquired immunity in peripheral tissues. Initially, Tph cells were noted as a CD4 population that produces high levels of CXCL13 in RA synovial tissues, followed by a demonstration of their ability to help B cells. In contrast to follicular helper T (Tfh) cells, Tph cells do not express the transcription factor BCL6 but express molecules such as CXCL13, interleukin (IL)-21, and inducible T-cell costimulator (ICOS) to help B cells in peripheral tissues. Subsequent studies showed that Tph cells are associated with various diseases, including autoimmune diseases, infections, and malignancies, and with the development of early life immunity. This review summarizes the phenotype and function of Tph cells in RA and discusses their differentiation and diversity in various conditions.

通过深入研究人类类风湿性关节炎(RA)的局部免疫反应,已经建立了外周辅助T细胞(Tph),作为与外周组织获得性免疫密切相关的CD4亚群。最初,Tph细胞被认为是在RA滑膜组织中产生高水平CXCL13的CD4群体,随后证明了它们帮助B细胞的能力。与滤泡辅助性T(Tfh)细胞相比,Tph细胞不表达转录因子BCL6,但表达CXCL13、IL-21和ICOS等分子,以帮助外周组织中的B细胞。随后的研究表明,Tph细胞与各种疾病有关,包括自身免疫性疾病、感染和恶性肿瘤,并与早期生命免疫的发展有关。本文综述了RA中Tph细胞的表型和功能,并讨论了它们在各种条件下的分化和多样性。
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引用次数: 0
Highlights from International Immunology in 2023 2023 年国际免疫学要点
IF 4.4 4区 医学 Q2 IMMUNOLOGY Pub Date : 2024-01-10 DOI: 10.1093/intimm/dxad044
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引用次数: 0
Systemic immunometabolism and responses to vaccines: insights from T and B cell perspectives. 全身免疫代谢和对疫苗的反应:从 T 细胞和 B 细胞的角度看问题。
IF 4.4 4区 医学 Q2 IMMUNOLOGY Pub Date : 2023-12-23 DOI: 10.1093/intimm/dxad021
Sam Nettelfield, Di Yu, Pablo F Cañete

Vaccination stands as the cornerstone in the battle against infectious diseases, and its efficacy hinges on several host-related factors like genetics, age, and metabolic status. Vulnerable populations, such as malnourished individuals, the obese, and the elderly, commonly exhibit diminished vaccine responses and efficacy. While the specific factors contributing to this impairment may vary, these individuals typically display a degree of metabolic dysregulation, thereby underscoring its potential significance as a fundamental determinant of suboptimal vaccine responses. The emerging field of immunometabolism aims to unravel the intricate interplay between immune regulation and metabolic pathways, and recent research has revealed diverse metabolic signatures linked to various vaccine responses and outcomes. In this review, we summarize the major metabolic pathways utilized by B and T cells during vaccine responses, their complex and varied metabolic requirements, and the impact of micronutrients and metabolic hormones on vaccine outcomes. Furthermore, we examine how systemic metabolism influences vaccine responses and the evidence suggesting that metabolic dysregulation in vulnerable populations can lead to impaired vaccine responses. Lastly, we reflect on the challenge of proving causality with respect to the contribution of metabolic dysregulation to poor vaccine outcomes, and highlight the need for a systems biology approach that combines multimodal profiling and mathematical modelling to reveal the underlying mechanisms of such complex interactions.

疫苗接种是抗击传染病的基石,其效果取决于与宿主相关的几个因素,如遗传、年龄和新陈代谢状况。营养不良者、肥胖者和老年人等易感人群对疫苗的反应和效力通常会减弱。虽然导致这种损害的具体因素可能各不相同,但这些人通常会表现出一定程度的代谢失调,从而突出了代谢失调作为次优疫苗反应基本决定因素的潜在意义。新兴的免疫代谢领域旨在揭示免疫调节与代谢途径之间错综复杂的相互作用,最近的研究揭示了与各种疫苗反应和结果相关的各种代谢特征。在这篇综述中,我们总结了 B 细胞和 T 细胞在疫苗反应过程中利用的主要代谢途径、它们复杂多样的代谢需求以及微量营养素和代谢激素对疫苗结果的影响。此外,我们还研究了全身代谢如何影响疫苗应答,以及有证据表明易感人群的代谢失调会导致疫苗应答受损。最后,我们反思了证明代谢失调对疫苗不良反应的因果关系所面临的挑战,并强调了系统生物学方法的必要性,该方法结合了多模态分析和数学建模,以揭示这种复杂相互作用的内在机制。
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引用次数: 0
Follicular regulatory T cell subsets in mice and humans: origins, antigen specificity and function. 小鼠和人类的滤泡调节性 T 细胞亚群:起源、抗原特异性和功能。
IF 4.4 4区 医学 Q2 IMMUNOLOGY Pub Date : 2023-12-23 DOI: 10.1093/intimm/dxad031
Sophia Sokolova, Irina L Grigorova

Follicular regulatory T (Tfr) cells play various roles in immune responses, contributing to both positive and negative regulation of foreign antigen-specific B cell responses, control over autoreactive antibody responses and autoimmunity, and B cell class-switching to IgE and allergy development. Studies conducted on mice uncovered various subsets of CXCR5+FoxP3+CD4+ Tfr cells that could differently contribute to immune regulation. Moreover, recent studies of human Tfr cells revealed similar complexity with various subsets of follicular T cells of different origins and immunosuppressive and/or immunostimulatory characteristics. In this review we will overview and compare Tfr subsets currently identified in mice and humans and will discuss their origins and antigen specificity, as well as potential modes of action and contribution to the control of the autoimmune and allergic reactions.

滤泡调节性 T(Tfr)细胞在免疫反应中发挥着各种作用,有助于对外来抗原特异性 B 细胞反应进行正向和负向调节、控制自身反应性抗体反应和自身免疫,以及 B 细胞类别转换为 IgE 和过敏的发生。对小鼠的研究发现,CXCR5+FoxP3+CD4+ Tfr 细胞的不同亚群可对免疫调节做出不同贡献。此外,最近对人类 Tfr 细胞的研究也揭示了类似的复杂性,即具有不同来源、免疫抑制和/或免疫刺激特性的各种滤泡 T 细胞亚群。在这篇综述中,我们将概述和比较目前在小鼠和人类中发现的 Tfr 亚群,并讨论它们的起源和抗原特异性,以及潜在的作用模式和对控制自身免疫和过敏反应的贡献。
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引用次数: 0
Memory B cell differentiation from germinal centers. 从生殖中心分化出记忆 B 细胞。
IF 4.4 4区 医学 Q2 IMMUNOLOGY Pub Date : 2023-12-23 DOI: 10.1093/intimm/dxad017
Takeshi Inoue

Establishment of humoral immune memory depends on two layers of defense: pre-existing antibodies secreted by long-lived plasma cells; and the antibodies produced by antigen-reactivated memory B cells. Memory B cells can now be considered as a second layer of defense upon re-infection by variant pathogens that have not been cleared by the long-lived plasma cell-mediated defense. Affinity-matured memory B cells are derived from the germinal center (GC) reaction, but the selection mechanism of GC B cells into the memory compartment is still incompletely understood. Recent studies have revealed the critical determinants of cellular and molecular factors for memory B cell differentiation from the GC reaction. In addition, the contribution of antibody-mediated feedback regulation to B cell selection, as exemplified by the B cell response upon COVID-19 mRNA vaccination, has now garnered considerable attention, which may provide valuable implications for future vaccine design.

体液免疫记忆的建立依赖于两层防御:长效浆细胞分泌的已有抗体和抗原复活记忆 B 细胞产生的抗体。现在,记忆 B 细胞可被视为第二层防御系统,当变异病原体再次感染人体时,长效浆细胞介导的防御系统无法清除这些病原体。亲和成熟的记忆 B 细胞来自生殖中心(GC)反应,但人们对 GC B 细胞进入记忆区的选择机制仍不完全清楚。最近的研究揭示了记忆 B 细胞从 GC 反应中分化出来的细胞和分子因素的关键决定因素。此外,抗体介导的反馈调节对 B 细胞选择的贡献,如 COVID-19 mRNA 疫苗接种后的 B 细胞反应,现已引起广泛关注,这可能对未来的疫苗设计提供有价值的启示。
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引用次数: 0
Introduction: Synthetic Biology for Cancer Immunology Special Issue 导言:癌症免疫学合成生物学特刊
IF 4.4 4区 医学 Q2 IMMUNOLOGY Pub Date : 2023-12-22 DOI: 10.1093/intimm/dxad052
Yuki Kagoya
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引用次数: 0
Lung group 2 innate lymphoid cells differentially depend on local IL-7 for their distribution, activation, and maintenance in innate and adaptive immunity-mediated airway inflammation. 肺2组先天性淋巴细胞在先天和适应性免疫介导的气道炎症中不同地依赖于局部IL-7的分布、激活和维持。
IF 4.4 4区 医学 Q2 IMMUNOLOGY Pub Date : 2023-11-07 DOI: 10.1093/intimm/dxad029
Daichi Takami, Shinya Abe, Akihiro Shimba, Takuma Asahi, Guangwei Cui, Shizue Tani-Ichi, Takahiro Hara, Keishi Miyata, Masashi Ikutani, Kiyoshi Takatsu, Yuichi Oike, Koichi Ikuta

Interleukin-7 (IL-7) is a cytokine critical for the development and maintenance of group 2 innate lymphoid cells (ILC2s). ILC2s are resident in peripheral tissues such as the intestine and lung. However, whether IL-7 produced in the lung plays a role in the maintenance and function of lung ILC2s during airway inflammation remains unknown. IL-7 was expressed in bronchoalveolar epithelial cells and lymphatic endothelial cells (LECs). To investigate the role of local IL-7 in lung ILC2s, we generated two types of IL-7 conditional knockout (IL-7cKO) mice: Sftpc-Cre (SPC-Cre) IL-7cKO mice specific for bronchial epithelial cells and type 2 alveolar epithelial cells and Lyve1-Cre IL-7cKO mice specific for LECs. In steady state, ILC2s were located near airway epithelia, although lung ILC2s were unchanged in the two lines of IL-7cKO mice. In papain-induced airway inflammation dependent on innate immunity, lung ILC2s localized near bronchia via CCR4 expression, and eosinophil infiltration and type 2 cytokine production were reduced in SPC-Cre IL-7cKO mice. In contrast, in house dust mite (HDM)-induced airway inflammation dependent on adaptive immunity, lung ILC2s localized near lymphatic vessels via their CCR2 expression 2 weeks after the last challenge. Furthermore, lung ILC2s were decreased in Lyve1-Cre IL-7cKO mice in the HDM-induced inflammation because of decreased cell survival and proliferation. Finally, administration of anti-IL-7 antibody attenuated papain-induced inflammation by suppressing the activation of ILC2s. Thus, this study demonstrates that IL-7 produced by bronchoalveolar epithelial cells and LECs differentially controls the activation and maintenance of lung ILC2s, where they are localized in airway inflammation.

IL-7是一种对第2组先天性淋巴细胞(ILC2)的发育和维持至关重要的细胞因子。ILC2存在于肠和肺等外周组织中。然而,在气道炎症过程中,肺中产生的IL-7是否在肺ILC2的维持和功能中发挥作用仍然未知。IL-7在支气管肺泡上皮细胞和淋巴管内皮细胞(LECs)中表达。为了研究局部IL-7在肺ILC2s中的作用,我们产生了两种类型的IL-7条件性敲除(IL-7cKO)小鼠:对支气管上皮细胞和2型肺泡上皮细胞特异性的Sftpc-Cre(SPC-Cre)IL-7cKO-小鼠和对LECs特异性的Lyve1-Cre IL-7cKO-小鼠。在稳定状态下,ILC2位于气道上皮附近,尽管肺ILC2在两个IL-7cKO小鼠系中没有变化。在木瓜蛋白酶诱导的依赖于先天免疫的气道炎症中,SPC Cre IL-7cKO小鼠的肺ILC2通过CCR4表达定位在支气管附近,嗜酸性粒细胞浸润和2型细胞因子产生减少。相反,在室内尘螨(HDM)诱导的依赖于适应性免疫的气道炎症中,肺ILC2在最后一次攻击后两周通过其CCR2表达定位在淋巴管附近。此外,在HDM诱导的炎症中,由于细胞存活和增殖降低,Lyve1-Cre IL-7cKO小鼠的肺ILC2减少。最后,给予抗IL-7抗体通过抑制ILC2的激活来减弱木瓜蛋白酶诱导的炎症。因此,这项研究表明,支气管肺泡上皮细胞和LECs产生的IL-7不同地控制着肺ILC2的激活和维持,它们在气道炎症中定位。
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引用次数: 0
期刊
International immunology
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