Pub Date : 2024-10-17DOI: 10.1038/s41423-024-01219-w
Yan Wang, Ursula Rambold, Petra Fiedler, Tea Babushku, Claas L. Tapken, Kai P. Hoefig, Thomas P. Hofer, Heiko Adler, Ali Önder Yildirim, Lothar J. Strobl, Ursula Zimber-Strobl
Initially, identified as a Hodgkin lymphoma marker, CD30 was subsequently detected on a subset of human B cells within and around germinal centers (GCs). While CD30 expression is typically restricted to a few B cells, expansion of CD30-expressing B cells occurs in certain immune disorders and during viral infections. The role of CD30 in B cells remains largely unclear. To address this gap in knowledge, we established a conditional CD30-knockin mouse strain. In these mice, B-cell-specific CD30 expression led to a normal B-cell phenotype in young mice, but most aged mice exhibited significant expansion of B cells, T cells and myeloid cells and increased percentages of GC B cells and IgG1-switched cells. This may be driven by the expansion of CD4+ senescence-associated T cells and T follicular helper cells, which partially express CD30-L (CD153) and may stimulate CD30-expressing B cells. Inducing CD30 expression in antigen-activated B cells accelerates the GC reaction and augments plasma cell differentiation, possibly through the posttranscriptional upregulation of CXCR4. Furthermore, CD30 expression in GC B cells promoted the expansion of IgG1-switched cells, which displayed either a GC or memory-like B-cell phenotype, with abnormally high IgG1 levels compared with those in controls. These findings shed light on the role of CD30 signaling in GC B cells and suggest that elevated CD30+ B-cell numbers lead to pathological lymphocyte activation and proliferation.
CD30 最初被认为是霍奇金淋巴瘤的标志物，后来在生殖中心（GC）内部和周围的人类 B 细胞亚群中被检测到。虽然 CD30 的表达通常仅限于少数 B 细胞，但在某些免疫紊乱和病毒感染时，会出现表达 CD30 的 B 细胞扩增。CD30 在 B 细胞中的作用在很大程度上仍不清楚。为了填补这一知识空白，我们建立了一个条件性 CD30 基因敲除小鼠品系。在这些小鼠中，B 细胞特异性 CD30 表达导致年轻小鼠的 B 细胞表型正常，但大多数老年小鼠的 B 细胞、T 细胞和髓系细胞显著扩增，GC B 细胞和 IgG1 切换细胞的百分比增加。这可能是由 CD4+ 衰老相关 T 细胞和 T 滤泡辅助细胞的扩增驱动的，这些细胞部分表达 CD30-L（CD153），并可能刺激表达 CD30 的 B 细胞。诱导抗原激活的 B 细胞表达 CD30 可加速 GC 反应并促进浆细胞分化，这可能是通过转录后上调 CXCR4 实现的。此外，GC B 细胞中 CD30 的表达促进了 IgG1 切换细胞的扩增，这些细胞显示出 GC 或记忆样 B 细胞表型，与对照组相比，其 IgG1 水平异常高。这些发现揭示了 CD30 信号在 GC B 细胞中的作用，并表明 CD30+ B 细胞数量升高会导致病理性淋巴细胞活化和增殖。
{"title":"CD30 influences germinal center B-cell dynamics and the expansion of IgG1-switched B cells","authors":"Yan Wang, Ursula Rambold, Petra Fiedler, Tea Babushku, Claas L. Tapken, Kai P. Hoefig, Thomas P. Hofer, Heiko Adler, Ali Önder Yildirim, Lothar J. Strobl, Ursula Zimber-Strobl","doi":"10.1038/s41423-024-01219-w","DOIUrl":"10.1038/s41423-024-01219-w","url":null,"abstract":"Initially, identified as a Hodgkin lymphoma marker, CD30 was subsequently detected on a subset of human B cells within and around germinal centers (GCs). While CD30 expression is typically restricted to a few B cells, expansion of CD30-expressing B cells occurs in certain immune disorders and during viral infections. The role of CD30 in B cells remains largely unclear. To address this gap in knowledge, we established a conditional CD30-knockin mouse strain. In these mice, B-cell-specific CD30 expression led to a normal B-cell phenotype in young mice, but most aged mice exhibited significant expansion of B cells, T cells and myeloid cells and increased percentages of GC B cells and IgG1-switched cells. This may be driven by the expansion of CD4+ senescence-associated T cells and T follicular helper cells, which partially express CD30-L (CD153) and may stimulate CD30-expressing B cells. Inducing CD30 expression in antigen-activated B cells accelerates the GC reaction and augments plasma cell differentiation, possibly through the posttranscriptional upregulation of CXCR4. Furthermore, CD30 expression in GC B cells promoted the expansion of IgG1-switched cells, which displayed either a GC or memory-like B-cell phenotype, with abnormally high IgG1 levels compared with those in controls. These findings shed light on the role of CD30 signaling in GC B cells and suggest that elevated CD30+ B-cell numbers lead to pathological lymphocyte activation and proliferation.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 12","pages":"1410-1425"},"PeriodicalIF":21.8,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41423-024-01219-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-15DOI: 10.1038/s41423-024-01226-x
Yang Liu, Fei Zhou, Heba Ali, Justin D. Lathia, Peiwen Chen
Glioblastoma (GBM) is an aggressive and lethal type of brain tumor in human adults. The standard of care offers minimal clinical benefit, and most GBM patients experience tumor recurrence after treatment. In recent years, significant advancements have been made in the development of novel immunotherapies or other therapeutic strategies that can overcome immunotherapy resistance in many advanced cancers. However, the benefit of immune-based treatments in GBM is limited because of the unique brain immune profiles, GBM cell heterogeneity, and immunosuppressive tumor microenvironment. In this review, we present a detailed overview of current immunotherapeutic strategies and discuss the challenges and potential molecular mechanisms underlying immunotherapy resistance in GBM. Furthermore, we provide an in-depth discussion regarding the strategies that can overcome immunotherapy resistance in GBM, which will likely require combination therapies.
{"title":"Immunotherapy for glioblastoma: current state, challenges, and future perspectives","authors":"Yang Liu, Fei Zhou, Heba Ali, Justin D. Lathia, Peiwen Chen","doi":"10.1038/s41423-024-01226-x","DOIUrl":"10.1038/s41423-024-01226-x","url":null,"abstract":"Glioblastoma (GBM) is an aggressive and lethal type of brain tumor in human adults. The standard of care offers minimal clinical benefit, and most GBM patients experience tumor recurrence after treatment. In recent years, significant advancements have been made in the development of novel immunotherapies or other therapeutic strategies that can overcome immunotherapy resistance in many advanced cancers. However, the benefit of immune-based treatments in GBM is limited because of the unique brain immune profiles, GBM cell heterogeneity, and immunosuppressive tumor microenvironment. In this review, we present a detailed overview of current immunotherapeutic strategies and discuss the challenges and potential molecular mechanisms underlying immunotherapy resistance in GBM. Furthermore, we provide an in-depth discussion regarding the strategies that can overcome immunotherapy resistance in GBM, which will likely require combination therapies.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 12","pages":"1354-1375"},"PeriodicalIF":21.8,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41423-024-01226-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-14DOI: 10.1038/s41423-024-01216-z
Alberto Mantovani, Federica Marchesi, Diletta Di Mitri, Cecilia Garlanda
Invasion and metastasis are hallmarks of cancer. In addition to the well-recognized hematogenous and lymphatic pathways of metastasis, cancer cell dissemination can occur via the transcoelomic and perineural routes, which are typical of ovarian and pancreatic cancer, respectively. Macrophages are a universal major component of the tumor microenvironment and, in established tumors, promote growth and dissemination to secondary sites. Here, we review the role of tumor-associated macrophages (TAMs) in cancer cell dissemination and metastasis, emphasizing the diversity of myeloid cells in different tissue contexts (lungs, liver, brain, bone, peritoneal cavity, nerves). The generally used models of lung metastasis fail to capture the diversity of pathways and tissue microenvironments. A better understanding of TAM diversity in different tissue contexts may pave the way for tailored diagnostic and therapeutic approaches.
{"title":"Macrophage diversity in cancer dissemination and metastasis","authors":"Alberto Mantovani, Federica Marchesi, Diletta Di Mitri, Cecilia Garlanda","doi":"10.1038/s41423-024-01216-z","DOIUrl":"10.1038/s41423-024-01216-z","url":null,"abstract":"Invasion and metastasis are hallmarks of cancer. In addition to the well-recognized hematogenous and lymphatic pathways of metastasis, cancer cell dissemination can occur via the transcoelomic and perineural routes, which are typical of ovarian and pancreatic cancer, respectively. Macrophages are a universal major component of the tumor microenvironment and, in established tumors, promote growth and dissemination to secondary sites. Here, we review the role of tumor-associated macrophages (TAMs) in cancer cell dissemination and metastasis, emphasizing the diversity of myeloid cells in different tissue contexts (lungs, liver, brain, bone, peritoneal cavity, nerves). The generally used models of lung metastasis fail to capture the diversity of pathways and tissue microenvironments. A better understanding of TAM diversity in different tissue contexts may pave the way for tailored diagnostic and therapeutic approaches.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 11","pages":"1201-1214"},"PeriodicalIF":21.8,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41423-024-01216-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-14DOI: 10.1038/s41423-024-01224-z
Yong Tang, Ziqing Chen, Qianying Zuo, Yibin Kang
Dysregulation of lipid metabolism is a key characteristic of the tumor microenvironment, where tumor cells utilize lipids for proliferation, survival, metastasis, and evasion of immune surveillance. Lipid metabolism has become a critical regulator of CD8+ T-cell-mediated antitumor immunity, with excess lipids in the tumor microenvironment impeding CD8+ T-cell activities. Considering the limited efficacy of immunotherapy in many solid tumors, targeting lipid metabolism to enhance CD8+ T-cell effector functions could significantly improve immunotherapy outcomes. In this review, we examine recent findings on how lipid metabolic processes, including lipid uptake, synthesis, and oxidation, regulate CD8+ T cells within tumors. We also assessed the impact of different lipids on CD8+ T-cell-mediated antitumor immunity, with a particular focus on how lipid metabolism affects mitochondrial function in tumor-infiltrating CD8+ T cells. Furthermore, as cancer is a systemic disease, we examined systemic factors linking lipid metabolism to CD8+ T-cell effector function. Finally, we summarize current therapeutic approaches that target lipid metabolism to increase antitumor immunity and enhance immunotherapy. Understanding the molecular and functional interplay between lipid metabolism and CD8+ T cells offers promising therapeutic opportunities for cancer treatment.
脂质代谢失调是肿瘤微环境的一个主要特征，肿瘤细胞利用脂质进行增殖、生存、转移和逃避免疫监视。脂质代谢已成为 CD8+ T 细胞介导的抗肿瘤免疫的关键调节因子，肿瘤微环境中过量的脂质会阻碍 CD8+ T 细胞的活动。考虑到许多实体瘤的免疫疗法疗效有限，以脂质代谢为靶点增强 CD8+ T 细胞效应功能可显著改善免疫疗法的疗效。在这篇综述中，我们研究了有关脂质代谢过程（包括脂质摄取、合成和氧化）如何调控肿瘤内 CD8+ T 细胞的最新发现。我们还评估了不同脂质对 CD8+ T 细胞介导的抗肿瘤免疫的影响，尤其关注脂质代谢如何影响肿瘤浸润 CD8+ T 细胞的线粒体功能。此外，由于癌症是一种全身性疾病，我们研究了将脂质代谢与 CD8+ T 细胞效应功能联系起来的全身性因素。最后，我们总结了目前针对脂质代谢的治疗方法，以提高抗肿瘤免疫力和增强免疫疗法。了解脂质代谢与 CD8+ T 细胞之间的分子和功能相互作用为癌症治疗提供了大有希望的治疗机会。
{"title":"Regulation of CD8+ T cells by lipid metabolism in cancer progression","authors":"Yong Tang, Ziqing Chen, Qianying Zuo, Yibin Kang","doi":"10.1038/s41423-024-01224-z","DOIUrl":"10.1038/s41423-024-01224-z","url":null,"abstract":"Dysregulation of lipid metabolism is a key characteristic of the tumor microenvironment, where tumor cells utilize lipids for proliferation, survival, metastasis, and evasion of immune surveillance. Lipid metabolism has become a critical regulator of CD8+ T-cell-mediated antitumor immunity, with excess lipids in the tumor microenvironment impeding CD8+ T-cell activities. Considering the limited efficacy of immunotherapy in many solid tumors, targeting lipid metabolism to enhance CD8+ T-cell effector functions could significantly improve immunotherapy outcomes. In this review, we examine recent findings on how lipid metabolic processes, including lipid uptake, synthesis, and oxidation, regulate CD8+ T cells within tumors. We also assessed the impact of different lipids on CD8+ T-cell-mediated antitumor immunity, with a particular focus on how lipid metabolism affects mitochondrial function in tumor-infiltrating CD8+ T cells. Furthermore, as cancer is a systemic disease, we examined systemic factors linking lipid metabolism to CD8+ T-cell effector function. Finally, we summarize current therapeutic approaches that target lipid metabolism to increase antitumor immunity and enhance immunotherapy. Understanding the molecular and functional interplay between lipid metabolism and CD8+ T cells offers promising therapeutic opportunities for cancer treatment.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 11","pages":"1215-1230"},"PeriodicalIF":21.8,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41423-024-01224-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-08DOI: 10.1038/s41423-024-01220-3
Han Zhang, Yi Huo, Wenjing Zheng, Peng Li, Hui Li, Lingling Zhang, Longqi Sa, Yang He, Zihao Zhao, Changhong Shi, Lequn Shan, Angang Yang, Tao Wang
The potential of macrophage-mediated phagocytosis as a cancer treatment is promising. Blocking the CD47–SIRPα interaction with a CD47-specific antibody significantly enhances macrophage phagocytosis. However, concerns regarding their toxicity to nontumor cells remain substantial. Here, we engineered chimeric antigen receptor macrophages (CAR-Ms) by fusing a humanized single-chain variable fragment with FcγRIIa and integrating short hairpin RNA to silence SIRPα, thereby disrupting the CD47–SIRPα signaling pathway. These modified CAR-shSIRPα-M cells exhibited an M1-like phenotype, superior phagocytic function, substantial cytotoxic effects on HER2-positive tumor cells, and the ability to eliminate patient-derived organoids. In vivo, CAR-M cells significantly inhibited tumor growth and prolonged survival in tumor-bearing mice. Notably, CAR-shSIRPα-M cells enhanced cytotoxic T-cell infiltration into tumors, thereby enhancing the antitumor response in both the humanized immune system mouse model and immunocompetent mice. Mechanistically, SIRPα inhibition activated inflammatory pathways and the cGAS-STING signaling cascade in CAR-M cells, leading to increased production of proinflammatory cytokines, reactive oxygen species, and nitric oxide, thereby enhancing their antitumor effects. These findings underscore the potential of SIRPα inhibition as a novel strategy to increase the antitumor efficacy of CAR-M cells in cancer immunotherapy, particularly against solid tumors.
{"title":"Silencing of SIRPα enhances the antitumor efficacy of CAR-M in solid tumors","authors":"Han Zhang, Yi Huo, Wenjing Zheng, Peng Li, Hui Li, Lingling Zhang, Longqi Sa, Yang He, Zihao Zhao, Changhong Shi, Lequn Shan, Angang Yang, Tao Wang","doi":"10.1038/s41423-024-01220-3","DOIUrl":"10.1038/s41423-024-01220-3","url":null,"abstract":"The potential of macrophage-mediated phagocytosis as a cancer treatment is promising. Blocking the CD47–SIRPα interaction with a CD47-specific antibody significantly enhances macrophage phagocytosis. However, concerns regarding their toxicity to nontumor cells remain substantial. Here, we engineered chimeric antigen receptor macrophages (CAR-Ms) by fusing a humanized single-chain variable fragment with FcγRIIa and integrating short hairpin RNA to silence SIRPα, thereby disrupting the CD47–SIRPα signaling pathway. These modified CAR-shSIRPα-M cells exhibited an M1-like phenotype, superior phagocytic function, substantial cytotoxic effects on HER2-positive tumor cells, and the ability to eliminate patient-derived organoids. In vivo, CAR-M cells significantly inhibited tumor growth and prolonged survival in tumor-bearing mice. Notably, CAR-shSIRPα-M cells enhanced cytotoxic T-cell infiltration into tumors, thereby enhancing the antitumor response in both the humanized immune system mouse model and immunocompetent mice. Mechanistically, SIRPα inhibition activated inflammatory pathways and the cGAS-STING signaling cascade in CAR-M cells, leading to increased production of proinflammatory cytokines, reactive oxygen species, and nitric oxide, thereby enhancing their antitumor effects. These findings underscore the potential of SIRPα inhibition as a novel strategy to increase the antitumor efficacy of CAR-M cells in cancer immunotherapy, particularly against solid tumors.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 11","pages":"1335-1349"},"PeriodicalIF":21.8,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41423-024-01220-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142388450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-08DOI: 10.1038/s41423-024-01221-2
Qiannv Liu, Weitao Li, Yan Qian, Chunlei Wang, Chun Kong, Mengqian Li, Liangliang Sun, Lang Sun, Yanli Pang, Changtao Jiang, Shuo Wang, Pengyan Xia
Inflammasomes play important roles in resisting infections caused by various pathogens. HSV-1 is a highly contagious virus among humans. The process by which HSV-1 particles bud from the nucleus is unique to herpes viruses, but the specific mechanism is still unclear. Here, we screened genes involved in HSV-1 replication. We found that TET3 plays an essential role in HSV-1 infection. TET3 recognizes the UL proteins of HSV-1 and, upon activation, can directly bind to caspase-1 to activate an ASC-independent inflammasome in the nucleus. The subsequent cleavage of GSDMD in the nucleus is crucial for the budding of HSV-1 particles from the nucleus. Inhibiting the perforation ability of GSDMD on the nuclear membrane can significantly reduce the maturation and spread of HSV-1. Our results may provide a new approach for the treatment of HSV-1 in the future.
{"title":"The TET3 inflammasome senses unique long HSV-1 proteins for virus particle budding from the nucleus","authors":"Qiannv Liu, Weitao Li, Yan Qian, Chunlei Wang, Chun Kong, Mengqian Li, Liangliang Sun, Lang Sun, Yanli Pang, Changtao Jiang, Shuo Wang, Pengyan Xia","doi":"10.1038/s41423-024-01221-2","DOIUrl":"10.1038/s41423-024-01221-2","url":null,"abstract":"Inflammasomes play important roles in resisting infections caused by various pathogens. HSV-1 is a highly contagious virus among humans. The process by which HSV-1 particles bud from the nucleus is unique to herpes viruses, but the specific mechanism is still unclear. Here, we screened genes involved in HSV-1 replication. We found that TET3 plays an essential role in HSV-1 infection. TET3 recognizes the UL proteins of HSV-1 and, upon activation, can directly bind to caspase-1 to activate an ASC-independent inflammasome in the nucleus. The subsequent cleavage of GSDMD in the nucleus is crucial for the budding of HSV-1 particles from the nucleus. Inhibiting the perforation ability of GSDMD on the nuclear membrane can significantly reduce the maturation and spread of HSV-1. Our results may provide a new approach for the treatment of HSV-1 in the future.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 11","pages":"1322-1334"},"PeriodicalIF":21.8,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142388451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-08DOI: 10.1038/s41423-024-01218-x
Daiya Ohara, Yusuke Takeuchi, Keiji Hirota
The IL-23 signaling pathway in both innate and adaptive immune cells is vital for orchestrating type 17 immunity, which is marked by the secretion of signature cytokines such as IL-17, IL-22, and GM-CSF. These proinflammatory mediators play indispensable roles in maintaining intestinal immune equilibrium and mucosal host defense; however, their involvement has also been implicated in the pathogenesis of chronic inflammatory disorders, such as inflammatory bowel diseases and autoimmunity. However, the implications of type 17 immunity across diverse inflammation models are complex. This review provides a comprehensive overview of the multifaceted roles of these cytokines in maintaining gut homeostasis and in perturbing gut barrier integrity, leading to acute and chronic inflammation in various models of gut infection and colitis. Additionally, this review focuses on type 17 immunity interconnecting multiple organs in autoimmune conditions, with a particular emphasis on the pathogenesis of autoimmune arthritis and neuroinflammation driven by T cells primed within the gut microenvironment.
{"title":"Type 17 immunity: novel insights into intestinal homeostasis and autoimmune pathogenesis driven by gut-primed T cells","authors":"Daiya Ohara, Yusuke Takeuchi, Keiji Hirota","doi":"10.1038/s41423-024-01218-x","DOIUrl":"10.1038/s41423-024-01218-x","url":null,"abstract":"The IL-23 signaling pathway in both innate and adaptive immune cells is vital for orchestrating type 17 immunity, which is marked by the secretion of signature cytokines such as IL-17, IL-22, and GM-CSF. These proinflammatory mediators play indispensable roles in maintaining intestinal immune equilibrium and mucosal host defense; however, their involvement has also been implicated in the pathogenesis of chronic inflammatory disorders, such as inflammatory bowel diseases and autoimmunity. However, the implications of type 17 immunity across diverse inflammation models are complex. This review provides a comprehensive overview of the multifaceted roles of these cytokines in maintaining gut homeostasis and in perturbing gut barrier integrity, leading to acute and chronic inflammation in various models of gut infection and colitis. Additionally, this review focuses on type 17 immunity interconnecting multiple organs in autoimmune conditions, with a particular emphasis on the pathogenesis of autoimmune arthritis and neuroinflammation driven by T cells primed within the gut microenvironment.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 11","pages":"1183-1200"},"PeriodicalIF":21.8,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41423-024-01218-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142388452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-30DOI: 10.1038/s41423-024-01217-y
Xiaoxia Wu, Xiaoming Zhao, Fang Li, Yang Wang, Yangjing Ou, Haiwei Zhang, Xiaoming Li, Xuanhui Wu, Lingxia Wang, Ming Li, Yue Zhang, Jianling Liu, Mingyan Xing, Han Liu, Yongchang Tan, Yangyang Wang, Yangyang Xie, Hanwen Zhang, Yan Luo, Hong Li, Jing Wang, Liming Sun, Yu Li, Haibing Zhang
The hypersecretion of cytokines triggers life-threatening systemic inflammatory response syndrome (SIRS), leading to multiple organ dysfunction syndrome (MODS) and mortality. Although both coagulopathy and necroptosis have been identified as important factors in the pathogenesis of SIRS, the specific cell types that undergo necroptosis and the interrelationships between coagulopathy and necroptosis remain unclear. In this study, we utilized visualization analysis via intravital microscopy to demonstrate that both anticoagulant heparin and nonanticoagulant heparin (NAH) pretreatment protect mice against TNF-α-induced mortality in SIRS. Moreover, the deletion of Mlkl or Ripk3 resulted in decreased coagulation and reduced mortality in TNF-α-induced SIRS. These findings suggest that necroptosis plays a key role upstream of coagulation in SIRS-related mortality. Furthermore, using a genetic lineage tracing mouse model (Tie2-Cre;Rosa26-tdT), we tracked endothelial cells (ECs) and verified that EC necroptosis is responsible for the vascular damage observed in TNF-α-treated mice. Importantly, Mlkl deletion in vascular ECs in mice had a similar protective effect against lethal SIRS by blocking EC necroptosis to protect the integrity of the endothelium. Collectively, our findings demonstrated that RIPK3–MLKL-dependent necroptosis disrupted vascular integrity, resulting in coagulopathy and multiorgan failure, eventually leading to mortality in SIRS patients. These results highlight the importance of targeting vascular EC necroptosis for the development of effective treatments for SIRS patients.
{"title":"MLKL-mediated endothelial necroptosis drives vascular damage and mortality in systemic inflammatory response syndrome","authors":"Xiaoxia Wu, Xiaoming Zhao, Fang Li, Yang Wang, Yangjing Ou, Haiwei Zhang, Xiaoming Li, Xuanhui Wu, Lingxia Wang, Ming Li, Yue Zhang, Jianling Liu, Mingyan Xing, Han Liu, Yongchang Tan, Yangyang Wang, Yangyang Xie, Hanwen Zhang, Yan Luo, Hong Li, Jing Wang, Liming Sun, Yu Li, Haibing Zhang","doi":"10.1038/s41423-024-01217-y","DOIUrl":"10.1038/s41423-024-01217-y","url":null,"abstract":"The hypersecretion of cytokines triggers life-threatening systemic inflammatory response syndrome (SIRS), leading to multiple organ dysfunction syndrome (MODS) and mortality. Although both coagulopathy and necroptosis have been identified as important factors in the pathogenesis of SIRS, the specific cell types that undergo necroptosis and the interrelationships between coagulopathy and necroptosis remain unclear. In this study, we utilized visualization analysis via intravital microscopy to demonstrate that both anticoagulant heparin and nonanticoagulant heparin (NAH) pretreatment protect mice against TNF-α-induced mortality in SIRS. Moreover, the deletion of Mlkl or Ripk3 resulted in decreased coagulation and reduced mortality in TNF-α-induced SIRS. These findings suggest that necroptosis plays a key role upstream of coagulation in SIRS-related mortality. Furthermore, using a genetic lineage tracing mouse model (Tie2-Cre;Rosa26-tdT), we tracked endothelial cells (ECs) and verified that EC necroptosis is responsible for the vascular damage observed in TNF-α-treated mice. Importantly, Mlkl deletion in vascular ECs in mice had a similar protective effect against lethal SIRS by blocking EC necroptosis to protect the integrity of the endothelium. Collectively, our findings demonstrated that RIPK3–MLKL-dependent necroptosis disrupted vascular integrity, resulting in coagulopathy and multiorgan failure, eventually leading to mortality in SIRS patients. These results highlight the importance of targeting vascular EC necroptosis for the development of effective treatments for SIRS patients.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 11","pages":"1309-1321"},"PeriodicalIF":21.8,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-19DOI: 10.1038/s41423-024-01215-0
Shuai Wang, Lijun Meng, Nan Xu, Huan Chen, Zhaofeng Xiao, Di Lu, Xiaohui Fan, Limin Xia, Jun Chen, Shusen Zheng, Qiang Wei, Xuyong Wei, Xiao Xu
Hepatocellular carcinoma (HCC) is a highly malignant tumor with significant global health implications. The role of CD4+ T cells, particularly conventional CD4+ T cells (Tconvs), in HCC progression remains unexplored. Furthermore, epigenetic factors are crucial in immune regulation, yet their specific role in HCC-infiltrating Tconv cells remains elusive. This study elucidates the role of MATR3, an epigenetic regulator, in modulating Tconv activity and immune evasion within the HCC microenvironment. Reanalysis of the scRNA-seq data revealed that early activation of CD4+ T cells is crucial for establishing an antitumor immune response. In vivo and in vitro experiments revealed that Tconv enhances cDC1-induced CD8+ T-cell activation. Screening identified MATR3 as a critical regulator of Tconv function, which is necessary for antitumour activity but harmful when overexpressed. Excessive MATR3 expression exacerbates Tconv exhaustion and impairs function by recruiting the SWI/SNF complex to relax chromatin in the TOX promoter region, leading to aberrant transcriptional changes. In summary, MATR3 is an HCC-specific epigenetic checkpoint that bidirectionally regulates Tconv antitumour immunity, suggesting new therapeutic strategies targeting epigenetic regulators to enhance antitumour immunity in HCC.
{"title":"Hepatocellular carcinoma-specific epigenetic checkpoints bidirectionally regulate the antitumor immunity of CD4 + T cells","authors":"Shuai Wang, Lijun Meng, Nan Xu, Huan Chen, Zhaofeng Xiao, Di Lu, Xiaohui Fan, Limin Xia, Jun Chen, Shusen Zheng, Qiang Wei, Xuyong Wei, Xiao Xu","doi":"10.1038/s41423-024-01215-0","DOIUrl":"10.1038/s41423-024-01215-0","url":null,"abstract":"Hepatocellular carcinoma (HCC) is a highly malignant tumor with significant global health implications. The role of CD4+ T cells, particularly conventional CD4+ T cells (Tconvs), in HCC progression remains unexplored. Furthermore, epigenetic factors are crucial in immune regulation, yet their specific role in HCC-infiltrating Tconv cells remains elusive. This study elucidates the role of MATR3, an epigenetic regulator, in modulating Tconv activity and immune evasion within the HCC microenvironment. Reanalysis of the scRNA-seq data revealed that early activation of CD4+ T cells is crucial for establishing an antitumor immune response. In vivo and in vitro experiments revealed that Tconv enhances cDC1-induced CD8+ T-cell activation. Screening identified MATR3 as a critical regulator of Tconv function, which is necessary for antitumour activity but harmful when overexpressed. Excessive MATR3 expression exacerbates Tconv exhaustion and impairs function by recruiting the SWI/SNF complex to relax chromatin in the TOX promoter region, leading to aberrant transcriptional changes. In summary, MATR3 is an HCC-specific epigenetic checkpoint that bidirectionally regulates Tconv antitumour immunity, suggesting new therapeutic strategies targeting epigenetic regulators to enhance antitumour immunity in HCC.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 11","pages":"1296-1308"},"PeriodicalIF":21.8,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142255262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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