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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 4.8 4区 医学 Q2 IMMUNOLOGY Pub Date : 2024-11-14 DOI: 10.1093/intimm/dxae034
Shizue Tani-Ichi, Koichi Ikuta

An age-dependent increase in interferon (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 signalling 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
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 IMMUNOLOGY Pub Date : 2024-11-14 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 (mTECs). In Rag-deficient mice, the unique gene expression signature of thymic eosinophils was lost but restored by pre-T cell receptor signalling, 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 mTECs 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
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 4.8 4区 医学 Q2 IMMUNOLOGY Pub Date : 2024-11-14 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 T-cell antigen receptor (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 role of dendritic cells in the instruction of helper T cells in the allergic march. 树突状细胞在过敏前行过程中对辅助性 T 细胞的指导作用。
IF 4.8 4区 医学 Q2 IMMUNOLOGY Pub Date : 2024-10-26 DOI: 10.1093/intimm/dxae050
Masato Kubo, Yasuyo Harada, Takanori Sasaki

Allergy is a complex array of diseases influenced by innate and adaptive immunity, genetic polymorphisms, and environmental triggers. Atopic dermatitis is a chronic inflammatory skin disease characterized by barrier defects and immune dysregulation, sometimes leading to asthma and food allergies because of the atopic march. During atopic skin inflammation, Langerhans cells and dendritic cells (DCs) in the skin capture and deliver allergen information to local lymph nodes. DCs are essential immune sensors coordinating immune reactions by capturing and presenting antigens to T cells. In the context of allergic responses, DCs play a crucial role in instructing two types of helper T cells-type 2 helper T (Th2) cells and follicular helper T (TFH) cells-in allergic responses and IgE antibody responses. In skin sensitization, the differentiation and function of Th2 cells and TFH cells are influenced by skin-derived factors, including epithelial cytokines, chemokines, and signalling pathways to modify the function of migratory DCs and conventional DCs. In this review, we aim to understand the specific mechanisms involving DCs in allergic responses to provide insights into the pathogenesis of allergic diseases and potential therapeutic strategies.

过敏是受先天性免疫和适应性免疫、基因多态性和环境诱因影响的一系列复杂疾病。特应性皮炎(AD)是一种慢性炎症性皮肤病,其特点是屏障缺陷和免疫调节失调,有时会因特应性进展而导致哮喘和食物过敏。在特应性皮肤炎症期间,皮肤中的朗格汉斯细胞和树突状细胞(DC)会捕捉过敏原信息并将其传递到局部淋巴结。DC 是重要的免疫传感器,通过捕捉抗原并将其呈现给 T 细胞来协调免疫反应。在过敏反应中,DC 在指导两种辅助性 T 细胞(2 型辅助性 T 细胞(Th2)和滤泡辅助性 T 细胞(TFH))的过敏反应和 IgE 抗体反应中发挥着至关重要的作用。在皮肤过敏中,Th2 细胞和 TFH 细胞的分化和功能受皮肤衍生因子的影响,包括上皮细胞因子、趋化因子和信号通路,从而改变迁移性 DC 和传统 DC 的功能。在这篇综述中,我们旨在了解 DCs 参与过敏反应的具体机制,以便深入了解过敏性疾病的发病机制和潜在的治疗策略。
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引用次数: 0
The skin barrier and microbiome in infantile atopic dermatitis development: can skincare prevent onset? 婴儿特应性皮炎发育过程中的皮肤屏障和微生物群:皮肤护理能预防发病吗?
IF 4.8 4区 医学 Q2 IMMUNOLOGY Pub Date : 2024-10-26 DOI: 10.1093/intimm/dxae038
Tomoka Ito, Yuumi Nakamura

Atopic dermatitis (AD), a prevalent Th2-dominant skin disease, involves complex genetic and environmental factors, including mutations in the Filaggrin gene and dysbiosis of skin microbiota characterized by an increased abundance of Staphylococcus aureus. Our recent findings emphasize the pivotal role of the skin barrier's integrity and microbial composition in infantile AD and allergic diseases. Early skin dysbiosis predisposes infants to AD, suggesting targeted skincare practices as a preventive strategy. The effects of skincare interventions, particularly the application of moisturizers with the appropriate molar concentration of ceramides, cholesterol, and fatty acids, play a crucial role in restoring the skin barrier. Notably, our study revealed that appropriate skincare can reduce Streptococcus abundance while supporting Cutibacterium acnes presence, thus directly linking skincare practices to microbial modulation in neonatal skin. Despite the mixed outcomes of previous Randomized Controlled Trials on the efficacy of moisturizers in AD prevention, our research points to the potential of skincare intervention as a primary preventive method against AD by minimizing the impact of genetic and environmental factors. Furthermore, our research supports the notion that early aggressive management of eczema may reduce the incidence of food allergies, highlighting the necessity for multifaceted prevention strategies that address both the skin barrier and immune sensitization. By focusing on repairing the skin barrier and adjusting the skin's microbiome from birth, we propose a novel perspective on preventing infantile AD and allergic diseases, opening new avenues for future studies, and practices in allergy prevention.

特应性皮炎(AD)是一种流行的 Th2 主导型皮肤病,涉及复杂的遗传和环境因素,包括 Filaggrin 基因突变和以金黄色葡萄球菌增多为特征的皮肤微生物群失调。我们最近的研究结果强调了皮肤屏障的完整性和微生物组成在婴儿 AD 和过敏性疾病中的关键作用。早期皮肤菌群失调容易导致婴儿过敏性鼻炎,这表明有针对性的护肤方法是一种预防策略。护肤干预的效果,尤其是使用含有适当摩尔浓度神经酰胺、胆固醇和脂肪酸的保湿剂,对恢复皮肤屏障起着至关重要的作用。值得注意的是,我们的研究表明,适当的护肤品可以减少链球菌的数量,同时支持痤疮棒状杆菌的存在,从而将护肤方法与新生儿皮肤的微生物调节直接联系起来。尽管之前的随机对照试验对保湿剂在预防AD方面的功效结果不一,但我们的研究表明,护肤干预可最大限度地减少遗传和环境因素的影响,从而有可能成为预防AD的主要方法。此外,我们的研究还支持这样一种观点,即早期积极治疗湿疹可降低食物过敏的发病率,这突出说明了同时解决皮肤屏障和免疫致敏问题的多方面预防策略的必要性。通过关注从出生开始修复皮肤屏障和调整皮肤的微生物群,我们提出了预防婴幼儿AD和过敏性疾病的新观点,为过敏预防的未来研究和实践开辟了新途径。
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引用次数: 0
Dysfunction of type 1 and type 2 immune cells: a lesson from exhausted-like ILC2s and their activation-induced cell death. 1 型和 2 型免疫细胞的功能失调:从枯竭样 ILC2 及其活化诱导的细胞死亡中汲取教训。
IF 4.8 4区 医学 Q2 IMMUNOLOGY Pub Date : 2024-10-26 DOI: 10.1093/intimm/dxae032
Takashi Ebihara, Toshiki Yamada, Akane Fuchimukai, Shunsuke Takasuga, Tentaro Endo, Takechiyo Yamada, Megumi Tatematsu

The concept of immune cell exhaustion/dysfunction has developed mainly to understand impaired type 1 immune responses, especially by CD8 T-cells against tumors or virus-infected cells, and has been applied to other lymphocytes. Natural killer (NK) cells and CD4 T cells support the efficient activation of CD8 T cells but exhibit dysfunctional phenotypes in tumor microenvironments and in chronic viral infections. In contrast, the concept of type 2 immune cell exhaustion/dysfunction is poorly established. Group 2 innate lymphoid cells (ILC2s) and T-helper 2 (Th2) cells are the major lymphocyte subsets that initiate and expand type 2 immune responses for antiparasitic immunity or allergy. In mouse models of chronic parasitic worm infections, Th2 cells display impaired type 2 immune responses. Chronic airway allergy induces exhausted-like ILC2s that quickly fall into activation-induced cell death to suppress exaggerated inflammation. Thus, the modes of exhaustion/dysfunction are quite diverse and rely on the types of inflammation and the cells. In this review, we summarize current knowledge of lymphocyte exhaustion/dysfunction in the context of type 1 and type 2 immune responses and discuss ILC2-specific regulatory mechanisms during chronic allergy.

免疫细胞衰竭/功能障碍的概念主要是为了理解受损的第一类免疫反应,尤其是 CD8 T 细胞对肿瘤或病毒感染细胞的反应,这一概念也被应用于其他淋巴细胞。自然杀伤(NK)细胞和 CD4 T 细胞支持 CD8 T 细胞的有效激活,但在肿瘤微环境和慢性病毒感染中表现出功能失调的表型。相比之下,第 2 类免疫细胞衰竭/功能失调的概念尚未确立。第 2 组先天性淋巴细胞(ILC2s)和 T 辅助细胞 2(Th2)是启动和扩大 2 型免疫反应的主要淋巴细胞亚群,可用于抗寄生虫免疫或过敏。在慢性寄生蠕虫感染的小鼠模型中,Th2 细胞显示出受损的 2 型免疫反应。慢性气道过敏会诱导类似衰竭的 ILC2,这些 ILC2 会迅速陷入活化诱导的细胞死亡,以抑制夸张的炎症反应。因此,衰竭/功能障碍的模式多种多样,取决于炎症类型和细胞。在这篇综述中,我们总结了目前在 1 型和 2 型免疫反应背景下有关淋巴细胞衰竭/功能障碍的知识,并讨论了慢性过敏过程中 ILC2 的特异性调节机制。
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引用次数: 0
The role of the skin in the atopic march. 皮肤在特应性进展中的作用。
IF 4.4 4区 医学 Q2 IMMUNOLOGY Pub Date : 2024-09-13 DOI: 10.1093/intimm/dxae053
Xin Tang,Mei Li
Atopic diseases, including atopic dermatitis (AD), food allergy (FA), asthma, and allergic rhinitis (AR) are closely related to inflammatory diseases involving different body sites (i.e. the skin, airway, and digestive tract) with characteristic features including specific IgE to allergens (so-called 'atopy') and Th2 cell-mediated inflammation. It has been recognized that AD often precedes the development of other atopic diseases. The progression from AD during infancy to FA or asthma/AR in later childhood is referred as the 'atopic march' (AM). Clinical, genetic and experimental studies have provided evidence that allergen sensitization occurring through AD skin could be the origin of the AM. Here, we provide an updated review focusing on the role of the skin in the AM, from genetic mutations and environmental factors associated with epidermal barrier dysfunction in AD and the AM, to immunological mechanisms for skin sensitization, particularly recent progress on the function of key cytokines produced by epidermal keratinocytes or by immune cells infiltrating the skin during AD. We also highlight the importance of developing strategies that target AD skin to prevent and attenuate the AM.
特应性疾病,包括特应性皮炎(AD)、食物过敏(FA)、哮喘和过敏性鼻炎(AR)与涉及不同身体部位(即皮肤、气道和消化道)的炎症性疾病密切相关,其特征包括对过敏原的特异性 IgE(所谓的 "特应性")和 Th2 细胞介导的炎症。人们已经认识到,渐冻人症往往先于其他特应性疾病的发生。从婴儿期的过敏性鼻炎发展到儿童后期的过敏性鼻炎或哮喘/过敏性鼻炎被称为 "特应性进展"(AM)。临床、遗传和实验研究已经提供了证据,证明通过 AD 皮肤发生的过敏原致敏可能是特应性哮喘的起源。在此,我们对皮肤在特应性哮喘中的作用进行了最新综述,从与 AD 和特应性哮喘中表皮屏障功能障碍相关的基因突变和环境因素,到皮肤过敏的免疫学机制,特别是最近在研究 AD 期间表皮角质形成细胞或浸润皮肤的免疫细胞产生的关键细胞因子的功能方面取得的进展。我们还强调了制定针对 AD 皮肤的策略以预防和减轻 AM 的重要性。
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引用次数: 0
Regnase-1 D141N mutation induces CD4+ T cell-mediated lung granuloma formation via upregulation of Pim2. Regnase-1 D141N突变通过上调Pim2诱导CD4+ T细胞介导的肺肉芽肿形成。
IF 4.8 4区 医学 Q2 IMMUNOLOGY Pub Date : 2024-09-10 DOI: 10.1093/intimm/dxae026
Thin Sandi Htun, Hiroki Tanaka, Shailendra Kumar Singh, Diego Diez, Shizuo Akira

Regnase-1 is an RNase that plays a critical role in negatively regulating immune responses by destabilizing inflammatory messenger RNAs (mRNAs). Dysfunction of Regnase-1 can be a major cause of various inflammatory diseases with tissue injury and immune cell infiltration into organs. This study focuses on the role of the RNase activity of Regnase-1 in developing inflammatory diseases. We have constructed mice with a single point mutation at the catalytic center of the Regnase-1 RNase domain, which lacks endonuclease activity. D141N mutant mice demonstrated systemic inflammation, immune cell infiltration into various organs, and progressive development of lung granuloma. CD4+ T cells, mainly affected by this mutation, upregulated the mTORC1 pathway and facilitated the autoimmune trait in the D141N mutation. Moreover, serine/threonine kinase Pim2 contributed to lung inflammation in this mutation. Inhibition of Pim2 kinase activity ameliorated granulomatous inflammation, immune cell infiltration, and proliferation in the lungs. Additionally, Pim2 inhibition reduced the expression of adhesion molecules on CD4+ T cells, suggesting a role for Pim2 in facilitating leukocyte adhesion and migration to inflamed tissues. Our findings provide new insights into the role of Regnase-1 RNase activity in controlling immune functions and underscore the therapeutic relevance of targeting Pim2 to modulate abnormal immune responses.

Regnase-1 是一种 RNase,它通过破坏炎症 mRNA 的稳定性,在负向调节免疫反应方面发挥着关键作用。Regnase-1 的功能障碍可能是导致组织损伤和免疫细胞浸润器官的各种炎症性疾病的主要原因。本研究主要探讨 Regnase-1 的 RNase 活性在炎症性疾病发生中的作用。我们构建了Regnase-1 RNase结构域催化中心单点突变的小鼠,该突变缺乏内切酶活性。D141N突变小鼠表现出全身性炎症、免疫细胞浸润各器官以及肺肉芽肿的进行性发展。主要受该突变影响的 CD4+ T 细胞上调了 mTORC1 通路,促进了 D141N 突变小鼠的自身免疫特征。此外,丝氨酸/苏氨酸激酶Pim2也导致了这种突变的肺部炎症。抑制 Pim2 激酶的活性可改善肺部肉芽肿性炎症、免疫细胞浸润和增殖。此外,抑制 Pim2 还能减少 CD4+ T 细胞上粘附分子的表达,这表明 Pim2 在促进白细胞粘附和向炎症组织迁移方面发挥了作用。我们的研究结果为了解 Regnase-1 RNase 活性在控制免疫功能中的作用提供了新的视角,并强调了靶向 Pim2 以调节异常免疫反应的治疗意义。
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引用次数: 0
Humoral responses are enhanced by facilitating B cell viability by Fcrl5 overexpression in B cells. B 细胞中 Fcrl5 的过表达可促进 B 细胞的活力,从而增强体液反应。
IF 4.8 4区 医学 Q2 IMMUNOLOGY Pub Date : 2024-09-10 DOI: 10.1093/intimm/dxae028
Chisato Ono, Yuta Kochi, Yoshihiro Baba, Shinya Tanaka

B cell initial activity is regulated through a balance of activation and suppression mediated by regulatory molecules expressed in B cells; however, the molecular mechanisms underlying this process remain incompletely understood. In this study, we investigated the function of the Fc receptor-like (Fcrl) family molecule Fcrl5, which is constitutively expressed in naive B cells, in humoral immune responses. Our study demonstrated that B cell-specific overexpression of Fcrl5 enhanced antibody (Ab) production in both T cell-independent type 1 (TI1) and T cell-dependent (TD) responses. Additionally, it promoted effector B cell formation under competitive conditions in TD responses. Mechanistically, in vitro ligation of Fcrl5 by agonistic Abs reduced cell death and enhanced proliferation in lipopolysaccharide-stimulated B cells. In the presence of anti-CD40 Abs and IL-5, the Fcrl5 ligation not only suppressed cell death but also enhanced differentiation into plasma cells. These findings reveal a novel role of Fcrl5 in promoting humoral immune responses by enhancing B cell viability and plasma cell differentiation.

B细胞的初始活性是通过B细胞中表达的调控分子介导的激活和抑制的平衡来调节的;然而,这一过程的分子机制仍不完全清楚。在这项研究中,我们研究了 Fc 受体样(Fcrl)家族分子 Fcrl5 在体液免疫反应中的功能。我们的研究表明,B细胞特异性过表达Fcrl5能增强T细胞依赖型1(TI1)和T细胞依赖型(TD)反应中抗体(Ab)的产生。此外,在 TD 反应的竞争条件下,它还能促进效应 B 细胞的形成。从机理上讲,体外激动性 Abs 与 Fcrl5 连接可减少细胞死亡,并增强脂多糖(LPS)刺激下 B 细胞的增殖。在抗CD40 Abs和IL-5存在的情况下,Fcrl5结扎不仅能抑制细胞死亡,还能促进分化成浆细胞。这些发现揭示了 Fcrl5 在通过增强 B 细胞活力和浆细胞分化促进体液免疫反应中的新作用。
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引用次数: 0
Lipid metabolism: a central modulator of RORγt-mediated Th17 cell differentiation. 脂质代谢:RORt 介导的 Th17 细胞分化的核心调节器。
IF 4.8 4区 医学 Q2 IMMUNOLOGY Pub Date : 2024-09-10 DOI: 10.1093/intimm/dxae031
Toshio Kanno, Keisuke Miyako, Yusuke Endo

Among the T helper cell subsets, Th17 cells contribute to the development of various inflammatory and autoimmune diseases, including psoriasis, rheumatoid arthritis, inflammatory bowel disease, steroid-resistant asthma, and multiple sclerosis. Retinoid-related orphan receptor gamma t (RORγt), a nuclear hormone receptor, serves as a master transcription factor for Th17 cell differentiation. Recent findings have shown that modulating the metabolic pathway is critical for Th17 cell differentiation, particularly through the engagement of de novo lipid biosynthesis. Suppression of lipid biosynthesis, either through the pharmacological inhibition or gene deletion of related enzymes in CD4+ T cells, results in significant impairment of Th17 cell differentiation. Mechanistic studies indicate that metabolic fluxes through both the fatty acid and cholesterol biosynthetic pathways have a pivotal role in the regulation of RORγt activity through the generation of endogenous RORγt lipid ligands. This review discusses recent discoveries highlighting the importance of lipid metabolism in Th17 cell differentiation and function, as well as exploring specific molecular pathways involved in RORγt activation through cellular lipid metabolism. We further elaborate on a pioneering therapeutic approach to improve inflammatory and autoimmune disorders via the inhibition of RORγt.

在 T 辅助细胞亚群中,Th17 细胞是导致牛皮癣、类风湿性关节炎、炎症性肠病、类固醇耐药哮喘和多发性硬化症等各种炎症和自身免疫性疾病的病因。视黄醇相关孤儿受体γt(RORγt)是一种核激素受体,是 Th17 细胞分化的主转录因子。最近的研究结果表明,调节新陈代谢途径对 Th17 细胞的分化至关重要,特别是通过参与脂质的从头生物合成。通过药物抑制或基因缺失 CD4+ T 细胞中的相关酶来抑制脂质生物合成,会导致 Th17 细胞分化明显受损。机理研究表明,脂肪酸和胆固醇生物合成途径的代谢通量通过生成内源性 RORγt 脂质配体在调节 RORγt 活性方面起着关键作用。这篇综述讨论了最近的发现,强调了脂质代谢在 Th17 细胞分化和功能中的重要性,并探讨了通过细胞脂质代谢激活 RORγt 所涉及的特定分子途径。我们进一步阐述了通过抑制 RORγt 改善炎症和自身免疫性疾病的开创性治疗方法。
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International immunology
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