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.
{"title":"Immunogenicity and protective capacity of a CpG ODN adjuvanted alum adsorbed bivalent meningococcal outer membrane vesicle vaccine.","authors":"Tugce Canavar Yildirim, Yasemin Ozsurekci, Muzaffer Yildirim, Irem Evcili, Volkan Yazar, Kubra Aykac, Ulku Guler, Bekir Salih, Mayda Gursel, Ihsan Gursel","doi":"10.1093/intimm/dxae016","DOIUrl":"10.1093/intimm/dxae016","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":" ","pages":"393-404"},"PeriodicalIF":4.8,"publicationDate":"2024-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140305534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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。
{"title":"Recent advances regarding the potential roles of invariant natural killer T cells in cardiovascular diseases with immunological and inflammatory backgrounds.","authors":"Kazuya Iwabuchi, Masashi Satoh, Kazuhisa Yoshino, Naoki Ishimori","doi":"10.1093/intimm/dxae019","DOIUrl":"10.1093/intimm/dxae019","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":" ","pages":"377-392"},"PeriodicalIF":4.8,"publicationDate":"2024-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140335485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Correction to: Computer model of IL-6-dependent rheumatoid arthritis in F759 mice.","authors":"","doi":"10.1093/intimm/dxae030","DOIUrl":"10.1093/intimm/dxae030","url":null,"abstract":"","PeriodicalId":13743,"journal":{"name":"International immunology","volume":" ","pages":"425"},"PeriodicalIF":4.8,"publicationDate":"2024-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141093238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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.
{"title":"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.","authors":"Liuqing Ge, Min Xu, Meifang Huang, Shaoping Liu, Zhidai Zhou, Ziqin Xia, Shouquan Dong, Qiu Zhao, Ruiping Zhu, Feng Zhou","doi":"10.1093/intimm/dxae043","DOIUrl":"https://doi.org/10.1093/intimm/dxae043","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141491814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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。
{"title":"Diverse roles of dendritic cell and regulatory T cell crosstalk in controlling health and disease.","authors":"Sayuri Yamazaki","doi":"10.1093/intimm/dxae042","DOIUrl":"https://doi.org/10.1093/intimm/dxae042","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141491813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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.
{"title":"New approaches to the control of chronic inflammatory diseases with a focus on the endolysosomal system of immune cells.","authors":"Noriko Toyama-Sorimachi","doi":"10.1093/intimm/dxae041","DOIUrl":"https://doi.org/10.1093/intimm/dxae041","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141467800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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.
{"title":"An inhibitory immunoreceptor Allergin-1 regulates the intestinal dysbiosis and barrier function in mice.","authors":"Yu-Hsien Lin, Satoko Tahara-Hanaoka, Nozomu Obana, Shinji Fukuda, Akira Shibuya","doi":"10.1093/intimm/dxae010","DOIUrl":"10.1093/intimm/dxae010","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":" ","pages":"365-371"},"PeriodicalIF":4.4,"publicationDate":"2024-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140039262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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.
{"title":"Metabolic reprogramming and macrophage polarization in granuloma formation.","authors":"Satoshi Nakamizo, Kenji Kabashima","doi":"10.1093/intimm/dxae013","DOIUrl":"10.1093/intimm/dxae013","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":" ","pages":"329-338"},"PeriodicalIF":4.4,"publicationDate":"2024-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140027948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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。
{"title":"High CD62L expression predicts the generation of chimeric antigen receptor T cells with potent effector functions.","authors":"Hitomi Kasuya, Haosong Zhang, Yusuke Ito, Toshiaki Yoshikawa, Takahiro Nakashima, Yang Li, Tetsuya Matsukawa, Satoshi Inoue, Yuki Kagoya","doi":"10.1093/intimm/dxae015","DOIUrl":"10.1093/intimm/dxae015","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":" ","pages":"353-364"},"PeriodicalIF":4.4,"publicationDate":"2024-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140184369","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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。
{"title":"Acute malaria suppresses the B lymphocytic niche in the bone marrow through the alteration of CXCL12-abundant reticular cells.","authors":"Michelle Sue Jann Lee, Julia Matsuo-Dapaah, Camila Del Rosario Zorrilla, Yoshiki Omatsu, Takashi Nagasawa, Shun Uemura, Atsushi Iwama, Ken J Ishii, Cevayir Coban","doi":"10.1093/intimm/dxae012","DOIUrl":"10.1093/intimm/dxae012","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":" ","pages":"339-352"},"PeriodicalIF":4.4,"publicationDate":"2024-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11161414/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140021661","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}