Pub Date : 2024-02-20DOI: 10.1038/s41423-024-01135-z
Zeguang Wu, Qiezhong Lamao, Meichao Gu, Xuanxuan Jin, Ying Liu, Feng Tian, Ying Yu, Pengfei Yuan, Shuaixin Gao, Thomas S. Fulford, Adam P. Uldrich, Catherine CL Wong, Wensheng Wei
Vγ9Vδ2 T cells are specialized effector cells that have gained prominence as immunotherapy agents due to their ability to target and kill cells with altered pyrophosphate metabolites. In our effort to understand how cancer cells evade the cell-killing activity of Vγ9Vδ2 T cells, we performed a comprehensive genome-scale CRISPR screening of cancer cells. We found that four molecules belonging to the butyrophilin (BTN) family, specifically BTN2A1, BTN3A1, BTN3A2, and BTN3A3, are critically important and play unique, nonoverlapping roles in facilitating the destruction of cancer cells by primary Vγ9Vδ2 T cells. The coordinated function of these BTN molecules was driven by synchronized gene expression, which was regulated by IFN-γ signaling and the RFX complex. Additionally, an enzyme called QPCTL was shown to play a key role in modifying the N-terminal glutamine of these BTN proteins and was found to be a crucial factor in Vγ9Vδ2 T cell killing of cancer cells. Through our research, we offer a detailed overview of the functional genomic mechanisms that underlie how cancer cells escape Vγ9Vδ2 T cells. Moreover, our findings shed light on the importance of the harmonized expression and function of gene family members in modulating T-cell activity.
Vγ9Vδ2 T 细胞是一种特化的效应细胞，由于它们能够靶向杀伤焦磷酸代谢物发生改变的细胞，因此作为免疫疗法药物而备受瞩目。为了了解癌细胞如何逃避 Vγ9Vδ2 T 细胞的细胞杀伤活性，我们对癌细胞进行了全面的基因组规模 CRISPR 筛选。我们发现，属于丁嗜蛋白（BTN）家族的四个分子，特别是 BTN2A1、BTN3A1、BTN3A2 和 BTN3A3，在促进原代 Vγ9Vδ2 T 细胞消灭癌细胞的过程中至关重要，并发挥着独特而不重叠的作用。这些 BTN 分子的协调功能由同步基因表达驱动，而同步基因表达则受 IFN-γ 信号传导和 RFX 复合物的调控。此外，一种名为 QPCTL 的酶被证明在修饰这些 BTN 蛋白的 N 端谷氨酰胺方面起着关键作用，并被发现是 Vγ9Vδ2 T 细胞杀死癌细胞的关键因素。通过我们的研究，我们详细概述了癌细胞如何逃避 Vγ9Vδ2 T 细胞的功能基因组机制。此外，我们的研究结果还揭示了基因家族成员的协调表达和功能在调节 T 细胞活性方面的重要性。
{"title":"Unsynchronized butyrophilin molecules dictate cancer cell evasion of Vγ9Vδ2 T-cell killing","authors":"Zeguang Wu, Qiezhong Lamao, Meichao Gu, Xuanxuan Jin, Ying Liu, Feng Tian, Ying Yu, Pengfei Yuan, Shuaixin Gao, Thomas S. Fulford, Adam P. Uldrich, Catherine CL Wong, Wensheng Wei","doi":"10.1038/s41423-024-01135-z","DOIUrl":"10.1038/s41423-024-01135-z","url":null,"abstract":"Vγ9Vδ2 T cells are specialized effector cells that have gained prominence as immunotherapy agents due to their ability to target and kill cells with altered pyrophosphate metabolites. In our effort to understand how cancer cells evade the cell-killing activity of Vγ9Vδ2 T cells, we performed a comprehensive genome-scale CRISPR screening of cancer cells. We found that four molecules belonging to the butyrophilin (BTN) family, specifically BTN2A1, BTN3A1, BTN3A2, and BTN3A3, are critically important and play unique, nonoverlapping roles in facilitating the destruction of cancer cells by primary Vγ9Vδ2 T cells. The coordinated function of these BTN molecules was driven by synchronized gene expression, which was regulated by IFN-γ signaling and the RFX complex. Additionally, an enzyme called QPCTL was shown to play a key role in modifying the N-terminal glutamine of these BTN proteins and was found to be a crucial factor in Vγ9Vδ2 T cell killing of cancer cells. Through our research, we offer a detailed overview of the functional genomic mechanisms that underlie how cancer cells escape Vγ9Vδ2 T cells. Moreover, our findings shed light on the importance of the harmonized expression and function of gene family members in modulating T-cell activity.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":null,"pages":null},"PeriodicalIF":24.1,"publicationDate":"2024-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139905189","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 : 2024-02-05DOI: 10.1038/s41423-024-01136-y
Ye Seon Kim, Yu Sun Jeong, Geon Ho Bae, Ji Hyeon Kang, Mingyu Lee, Brian A. Zabel, Yoe-Sik Bae
Distinct neutrophil populations arise during certain pathological conditions. The generation of dysfunctional neutrophils during sepsis and their contribution to septicemia-related systemic immune suppression remain unclear. In this study, using an experimental sepsis model that features immunosuppression, we identified a novel population of pathogenic CD200Rhigh neutrophils that are generated during the initial stages of sepsis and contribute to systemic immune suppression by enhancing regulatory T (Treg) cells. Compared to their CD200Rlow counterparts, sepsis-generated CD200Rhigh neutrophils exhibit impaired autophagy and dysfunction, with reduced chemotactic migration, superoxide anion production, and TNF-α production. Increased soluble CD200 blocks autophagy and neutrophil maturation in the bone marrow during experimental sepsis, and recombinant CD200 treatment in vitro can induce neutrophil dysfunction similar to that observed in CD200Rhigh neutrophils. The administration of an α-CD200R antibody effectively reversed neutrophil dysfunction by enhancing autophagy and protecting against a secondary infection challenge, leading to increased survival. Transcriptome analysis revealed that CD200Rhigh neutrophils expressed high levels of Igf1, which elicits the generation of Treg cells, while the administration of an α-CD200R antibody inhibited Treg cell generation in a secondary infection model. Taken together, our findings revealed a novel CD200Rhigh neutrophil population that mediates the pathogenesis of sepsis-induced systemic immunosuppression by generating Treg cells.
{"title":"CD200Rhigh neutrophils with dysfunctional autophagy establish systemic immunosuppression by increasing regulatory T cells","authors":"Ye Seon Kim, Yu Sun Jeong, Geon Ho Bae, Ji Hyeon Kang, Mingyu Lee, Brian A. Zabel, Yoe-Sik Bae","doi":"10.1038/s41423-024-01136-y","DOIUrl":"10.1038/s41423-024-01136-y","url":null,"abstract":"Distinct neutrophil populations arise during certain pathological conditions. The generation of dysfunctional neutrophils during sepsis and their contribution to septicemia-related systemic immune suppression remain unclear. In this study, using an experimental sepsis model that features immunosuppression, we identified a novel population of pathogenic CD200Rhigh neutrophils that are generated during the initial stages of sepsis and contribute to systemic immune suppression by enhancing regulatory T (Treg) cells. Compared to their CD200Rlow counterparts, sepsis-generated CD200Rhigh neutrophils exhibit impaired autophagy and dysfunction, with reduced chemotactic migration, superoxide anion production, and TNF-α production. Increased soluble CD200 blocks autophagy and neutrophil maturation in the bone marrow during experimental sepsis, and recombinant CD200 treatment in vitro can induce neutrophil dysfunction similar to that observed in CD200Rhigh neutrophils. The administration of an α-CD200R antibody effectively reversed neutrophil dysfunction by enhancing autophagy and protecting against a secondary infection challenge, leading to increased survival. Transcriptome analysis revealed that CD200Rhigh neutrophils expressed high levels of Igf1, which elicits the generation of Treg cells, while the administration of an α-CD200R antibody inhibited Treg cell generation in a secondary infection model. Taken together, our findings revealed a novel CD200Rhigh neutrophil population that mediates the pathogenesis of sepsis-induced systemic immunosuppression by generating Treg cells.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":null,"pages":null},"PeriodicalIF":24.1,"publicationDate":"2024-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139680666","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 : 2024-01-31DOI: 10.1038/s41423-024-01130-4
Yan Xin, Sihan Xiong, Linghong Zhou, Xin Lin
Invasive fungal infections are life-threatening, and neutrophils are vital cells of the innate immune system that defend against them. The role of LTA4H-LTB4-BLT1 axis in regulation of neutrophil responses to fungal infection remains poorly understood. Here, we demonstrated that the LTA4H-LTB4-BLT1 axis protects the host against Candida albicans and Aspergillus fumigatus, but not Cryptococcus neoformans infection, by regulating the antifungal activity of neutrophils. Our results show that deleting Lta4h or Blt1 substantially impairs the fungal-specific phagocytic capacity of neutrophils. Moreover, defective activation of the spleen tyrosine kinase (Syk) and extracellular signal-related kinase (ERK1/2) pathways in neutrophils accompanies this impairment. Mechanistically, BLT1 regulates CR3-mediated, β-1,3-glucan-induced neutrophil phagocytosis, while a physical interaction with CR3 with slight influence on its dynamics is observed. Our findings thus demonstrate that the LTA4H-LTB4-BLT1 axis is essential for the phagocytic function of neutrophils in host antifungal immune response against Candida albicans and Aspergillus fumigatus.
{"title":"Activation of leukotriene B4 receptor 1 is a prerequisite for complement receptor 3-mediated antifungal responses of neutrophils","authors":"Yan Xin, Sihan Xiong, Linghong Zhou, Xin Lin","doi":"10.1038/s41423-024-01130-4","DOIUrl":"10.1038/s41423-024-01130-4","url":null,"abstract":"Invasive fungal infections are life-threatening, and neutrophils are vital cells of the innate immune system that defend against them. The role of LTA4H-LTB4-BLT1 axis in regulation of neutrophil responses to fungal infection remains poorly understood. Here, we demonstrated that the LTA4H-LTB4-BLT1 axis protects the host against Candida albicans and Aspergillus fumigatus, but not Cryptococcus neoformans infection, by regulating the antifungal activity of neutrophils. Our results show that deleting Lta4h or Blt1 substantially impairs the fungal-specific phagocytic capacity of neutrophils. Moreover, defective activation of the spleen tyrosine kinase (Syk) and extracellular signal-related kinase (ERK1/2) pathways in neutrophils accompanies this impairment. Mechanistically, BLT1 regulates CR3-mediated, β-1,3-glucan-induced neutrophil phagocytosis, while a physical interaction with CR3 with slight influence on its dynamics is observed. Our findings thus demonstrate that the LTA4H-LTB4-BLT1 axis is essential for the phagocytic function of neutrophils in host antifungal immune response against Candida albicans and Aspergillus fumigatus.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":null,"pages":null},"PeriodicalIF":24.1,"publicationDate":"2024-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139646191","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 : 2024-01-29DOI: 10.1038/s41423-023-01118-6
Yiming Li, Mingwei Han, Haolin Wei, Wan Huang, Zhinan Chen, Tianjiao Zhang, Meirui Qian, Lin Jing, Gang Nan, Xiuxuan Sun, Shuhui Dai, Kun Wang, Jianli Jiang, Ping Zhu, Liang Chen
CD8+ T-cell exhaustion is a state of dysfunction that promotes tumor progression and is marked by the generation of Slamf6+ progenitor exhausted (Texprog) and Tim-3+ terminally exhausted (Texterm) subpopulations. Inhibitor of DNA binding protein 2 (Id2) has been shown to play important roles in T-cell development and CD8+ T-cell immunity. However, the role of Id2 in CD8+ T-cell exhaustion is unclear. Here, we found that Id2 transcriptionally and epigenetically regulates the generation of Texprog cells and their conversion to Texterm cells. Genetic deletion of Id2 dampens CD8+ T-cell-mediated immune responses and the maintenance of stem-like CD8+ T-cell subpopulations, suppresses PD-1 blockade and increases tumor susceptibility. Mechanistically, through its HLH domain, Id2 binds and disrupts the assembly of the Tcf3-Tal1 transcriptional regulatory complex, and thus modulates chromatin accessibility at the Slamf6 promoter by preventing the interaction of Tcf3 with the histone lysine demethylase LSD1. Therefore, Id2 increases the abundance of the permissive H3K4me2 mark on the Tcf3-occupied E-boxes in the Slamf6 promoter, modulates chromatin accessibility at the Slamf6 promoter and epigenetically regulates the generation of Slamf6+ Texprog cells. An LSD1 inhibitor GSK2879552 can rescue the Id2 knockout phenotype in tumor-bearing mice. Inhibition of LSD1 increases the abundance of Slamf6+Tim-3− Texprog cells in tumors and the expression level of Tcf1 in Id2-deleted CD8+ T cells. This study demonstrates that Id2-mediated transcriptional and epigenetic modification drives hierarchical CD8+ T-cell exhaustion, and the mechanistic insights gained may have implications for therapeutic intervention with tumor immune evasion.
{"title":"Id2 epigenetically controls CD8+ T-cell exhaustion by disrupting the assembly of the Tcf3-LSD1 complex","authors":"Yiming Li, Mingwei Han, Haolin Wei, Wan Huang, Zhinan Chen, Tianjiao Zhang, Meirui Qian, Lin Jing, Gang Nan, Xiuxuan Sun, Shuhui Dai, Kun Wang, Jianli Jiang, Ping Zhu, Liang Chen","doi":"10.1038/s41423-023-01118-6","DOIUrl":"10.1038/s41423-023-01118-6","url":null,"abstract":"CD8+ T-cell exhaustion is a state of dysfunction that promotes tumor progression and is marked by the generation of Slamf6+ progenitor exhausted (Texprog) and Tim-3+ terminally exhausted (Texterm) subpopulations. Inhibitor of DNA binding protein 2 (Id2) has been shown to play important roles in T-cell development and CD8+ T-cell immunity. However, the role of Id2 in CD8+ T-cell exhaustion is unclear. Here, we found that Id2 transcriptionally and epigenetically regulates the generation of Texprog cells and their conversion to Texterm cells. Genetic deletion of Id2 dampens CD8+ T-cell-mediated immune responses and the maintenance of stem-like CD8+ T-cell subpopulations, suppresses PD-1 blockade and increases tumor susceptibility. Mechanistically, through its HLH domain, Id2 binds and disrupts the assembly of the Tcf3-Tal1 transcriptional regulatory complex, and thus modulates chromatin accessibility at the Slamf6 promoter by preventing the interaction of Tcf3 with the histone lysine demethylase LSD1. Therefore, Id2 increases the abundance of the permissive H3K4me2 mark on the Tcf3-occupied E-boxes in the Slamf6 promoter, modulates chromatin accessibility at the Slamf6 promoter and epigenetically regulates the generation of Slamf6+ Texprog cells. An LSD1 inhibitor GSK2879552 can rescue the Id2 knockout phenotype in tumor-bearing mice. Inhibition of LSD1 increases the abundance of Slamf6+Tim-3− Texprog cells in tumors and the expression level of Tcf1 in Id2-deleted CD8+ T cells. This study demonstrates that Id2-mediated transcriptional and epigenetic modification drives hierarchical CD8+ T-cell exhaustion, and the mechanistic insights gained may have implications for therapeutic intervention with tumor immune evasion.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":null,"pages":null},"PeriodicalIF":24.1,"publicationDate":"2024-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41423-023-01118-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139574348","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 : 2024-01-24DOI: 10.1038/s41423-024-01131-3
Zhi-Dong Zhang, Chang-Rui Shi, Fang-Xu Li, Hu Gan, Yanhong Wei, Qianhui Zhang, Xin Shuai, Min Chen, Yu-Lin Lin, Tian-Chen Xiong, Xiaoqi Chen, Bo Zhong, Dandan Lin
STING (also known as MITA) is an adaptor protein that mediates cytoplasmic DNA-triggered signaling, and aberrant activation of STING/MITA by cytosolic self-DNA or gain-of-function mutations causes severe inflammation. Here, we show that STING-mediated inflammation and autoimmunity are promoted by RNF115 and alleviated by the RNF115 inhibitor disulfiram (DSF). Knockout of RNF115 or treatment with DSF significantly inhibit systemic inflammation and autoimmune lethality and restore immune cell development in Trex1–/– mice and STINGN153S/WT bone marrow chimeric mice. In addition, knockdown or pharmacological inhibition of RNF115 substantially downregulate the expression of IFN-α, IFN-γ and proinflammatory cytokines in PBMCs from patients with systemic lupus erythematosus (SLE) who exhibit high concentrations of dsDNA in peripheral blood. Mechanistically, knockout or inhibition of RNF115 impair the oligomerization and Golgi localization of STING in various types of cells transfected with cGAMP and in organs and cells from Trex1–/– mice. Interestingly, knockout of RNF115 inhibits the activation and Golgi localization of STINGN153S as well as the expression of proinflammatory cytokines in myeloid cells but not in endothelial cells or fibroblasts. Taken together, these findings highlight the RNF115-mediated cell type-specific regulation of STING and STINGN153S and provide potential targeted intervention strategies for STING-related autoimmune diseases.
{"title":"Disulfiram ameliorates STING/MITA-dependent inflammation and autoimmunity by targeting RNF115","authors":"Zhi-Dong Zhang, Chang-Rui Shi, Fang-Xu Li, Hu Gan, Yanhong Wei, Qianhui Zhang, Xin Shuai, Min Chen, Yu-Lin Lin, Tian-Chen Xiong, Xiaoqi Chen, Bo Zhong, Dandan Lin","doi":"10.1038/s41423-024-01131-3","DOIUrl":"10.1038/s41423-024-01131-3","url":null,"abstract":"STING (also known as MITA) is an adaptor protein that mediates cytoplasmic DNA-triggered signaling, and aberrant activation of STING/MITA by cytosolic self-DNA or gain-of-function mutations causes severe inflammation. Here, we show that STING-mediated inflammation and autoimmunity are promoted by RNF115 and alleviated by the RNF115 inhibitor disulfiram (DSF). Knockout of RNF115 or treatment with DSF significantly inhibit systemic inflammation and autoimmune lethality and restore immune cell development in Trex1–/– mice and STINGN153S/WT bone marrow chimeric mice. In addition, knockdown or pharmacological inhibition of RNF115 substantially downregulate the expression of IFN-α, IFN-γ and proinflammatory cytokines in PBMCs from patients with systemic lupus erythematosus (SLE) who exhibit high concentrations of dsDNA in peripheral blood. Mechanistically, knockout or inhibition of RNF115 impair the oligomerization and Golgi localization of STING in various types of cells transfected with cGAMP and in organs and cells from Trex1–/– mice. Interestingly, knockout of RNF115 inhibits the activation and Golgi localization of STINGN153S as well as the expression of proinflammatory cytokines in myeloid cells but not in endothelial cells or fibroblasts. Taken together, these findings highlight the RNF115-mediated cell type-specific regulation of STING and STINGN153S and provide potential targeted intervention strategies for STING-related autoimmune diseases.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":null,"pages":null},"PeriodicalIF":24.1,"publicationDate":"2024-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139545825","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}
The COVID-19 pandemic, which was caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a worldwide health crisis due to its transmissibility. SARS-CoV-2 infection results in severe respiratory illness and can lead to significant complications in affected individuals. These complications encompass symptoms such as coughing, respiratory distress, fever, infectious shock, acute respiratory distress syndrome (ARDS), and even multiple-organ failure. Animal models serve as crucial tools for investigating pathogenic mechanisms, immune responses, immune escape mechanisms, antiviral drug development, and vaccines against SARS-CoV-2. Currently, various animal models for SARS-CoV-2 infection, such as nonhuman primates (NHPs), ferrets, hamsters, and many different mouse models, have been developed. Each model possesses distinctive features and applications. In this review, we elucidate the immune response elicited by SARS-CoV-2 infection in patients and provide an overview of the characteristics of various animal models mainly used for SARS-CoV-2 infection, as well as the corresponding immune responses and applications of these models. A comparative analysis of transcriptomic alterations in the lungs from different animal models revealed that the K18-hACE2 and mouse-adapted virus mouse models exhibited the highest similarity with the deceased COVID-19 patients. Finally, we highlighted the current gaps in related research between animal model studies and clinical investigations, underscoring lingering scientific questions that demand further clarification.
{"title":"SARS-CoV-2 immunity in animal models","authors":"Zhao Chen, Yaochang Yuan, Qingtao Hu, Airu Zhu, Fenghua Chen, Shu Li, Xin Guan, Chao Lv, Tian Tang, Yiyun He, Jinling Cheng, Jie Zheng, Xiaoyu Hu, Jingxian Zhao, Jincun Zhao, Jing Sun","doi":"10.1038/s41423-023-01122-w","DOIUrl":"10.1038/s41423-023-01122-w","url":null,"abstract":"The COVID-19 pandemic, which was caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a worldwide health crisis due to its transmissibility. SARS-CoV-2 infection results in severe respiratory illness and can lead to significant complications in affected individuals. These complications encompass symptoms such as coughing, respiratory distress, fever, infectious shock, acute respiratory distress syndrome (ARDS), and even multiple-organ failure. Animal models serve as crucial tools for investigating pathogenic mechanisms, immune responses, immune escape mechanisms, antiviral drug development, and vaccines against SARS-CoV-2. Currently, various animal models for SARS-CoV-2 infection, such as nonhuman primates (NHPs), ferrets, hamsters, and many different mouse models, have been developed. Each model possesses distinctive features and applications. In this review, we elucidate the immune response elicited by SARS-CoV-2 infection in patients and provide an overview of the characteristics of various animal models mainly used for SARS-CoV-2 infection, as well as the corresponding immune responses and applications of these models. A comparative analysis of transcriptomic alterations in the lungs from different animal models revealed that the K18-hACE2 and mouse-adapted virus mouse models exhibited the highest similarity with the deceased COVID-19 patients. Finally, we highlighted the current gaps in related research between animal model studies and clinical investigations, underscoring lingering scientific questions that demand further clarification.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":null,"pages":null},"PeriodicalIF":24.1,"publicationDate":"2024-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10806257/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139490019","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 : 2024-01-18DOI: 10.1038/s41423-024-01124-2
G. Aaron Holling, Colin A. Chavel, Anand P. Sharda, Mackenzie M. Lieberman, Caitlin M. James, Shivana M. Lightman, Jason H. Tong, Guanxi Qiao, Tiffany R. Emmons, Thejaswini Giridharan, Shengqi Hou, Andrew M. Intlekofer, Richard M. Higashi, Teresa W. M. Fan, Andrew N. Lane, Kevin H. Eng, Brahm H. Segal, Elizabeth A. Repasky, Kelvin P. Lee, Scott H. Olejniczak
Metabolic flexibility has emerged as a critical determinant of CD8+ T-cell antitumor activity, yet the mechanisms driving the metabolic flexibility of T cells have not been determined. In this study, we investigated the influence of the nuclear cap-binding complex (CBC) adaptor protein ARS2 on mature T cells. In doing so, we discovered a novel signaling axis that endows activated CD8+ T cells with flexibility of glucose catabolism. ARS2 upregulation driven by CD28 signaling reinforced splicing factor recruitment to pre-mRNAs and affected approximately one-third of T-cell activation-induced alternative splicing events. Among these effects, the CD28-ARS2 axis suppressed the expression of the M1 isoform of pyruvate kinase in favor of PKM2, a key determinant of CD8+ T-cell glucose utilization, interferon gamma production, and antitumor effector function. Importantly, PKM alternative splicing occurred independently of CD28-driven PI3K pathway activation, revealing a novel means by which costimulation reprograms glucose metabolism in CD8+ T cells.
代谢灵活性已成为 CD8+ T 细胞抗肿瘤活性的一个关键决定因素，但驱动 T 细胞代谢灵活性的机制尚未确定。在这项研究中，我们研究了核帽结合复合体（CBC）适配蛋白 ARS2 对成熟 T 细胞的影响。在此过程中，我们发现了一个新的信号轴，它赋予活化的 CD8+ T 细胞葡萄糖分解代谢的灵活性。CD28 信号驱动的 ARS2 上调加强了剪接因子对前核糖核酸的招募，并影响了大约三分之一的 T 细胞活化诱导的替代剪接事件。在这些影响中，CD28-ARS2 轴抑制了丙酮酸激酶 M1 异构体的表达，而有利于 PKM2 的表达，PKM2 是 CD8+ T 细胞葡萄糖利用、γ 干扰素产生和抗肿瘤效应功能的关键决定因素。重要的是，PKM 替代剪接的发生与 CD28 驱动的 PI3K 通路激活无关，揭示了成本刺激重新规划 CD8+ T 细胞葡萄糖代谢的一种新方法。
{"title":"CD8+ T cell metabolic flexibility elicited by CD28-ARS2 axis-driven alternative splicing of PKM supports antitumor immunity","authors":"G. Aaron Holling, Colin A. Chavel, Anand P. Sharda, Mackenzie M. Lieberman, Caitlin M. James, Shivana M. Lightman, Jason H. Tong, Guanxi Qiao, Tiffany R. Emmons, Thejaswini Giridharan, Shengqi Hou, Andrew M. Intlekofer, Richard M. Higashi, Teresa W. M. Fan, Andrew N. Lane, Kevin H. Eng, Brahm H. Segal, Elizabeth A. Repasky, Kelvin P. Lee, Scott H. Olejniczak","doi":"10.1038/s41423-024-01124-2","DOIUrl":"10.1038/s41423-024-01124-2","url":null,"abstract":"Metabolic flexibility has emerged as a critical determinant of CD8+ T-cell antitumor activity, yet the mechanisms driving the metabolic flexibility of T cells have not been determined. In this study, we investigated the influence of the nuclear cap-binding complex (CBC) adaptor protein ARS2 on mature T cells. In doing so, we discovered a novel signaling axis that endows activated CD8+ T cells with flexibility of glucose catabolism. ARS2 upregulation driven by CD28 signaling reinforced splicing factor recruitment to pre-mRNAs and affected approximately one-third of T-cell activation-induced alternative splicing events. Among these effects, the CD28-ARS2 axis suppressed the expression of the M1 isoform of pyruvate kinase in favor of PKM2, a key determinant of CD8+ T-cell glucose utilization, interferon gamma production, and antitumor effector function. Importantly, PKM alternative splicing occurred independently of CD28-driven PI3K pathway activation, revealing a novel means by which costimulation reprograms glucose metabolism in CD8+ T cells.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":null,"pages":null},"PeriodicalIF":24.1,"publicationDate":"2024-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41423-024-01124-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139485135","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}
Remote organ injury, which is a common secondary complication of sterile tissue damage, is a major cause of poor prognosis and is difficult to manage. Here, we report the critical role of tissue-resident macrophages in lung injury after trauma or stroke through the inflammatory response. We found that depleting tissue-resident macrophages rather than disrupting the recruitment of monocyte-derived macrophages attenuated lung injury after trauma or stroke. Our findings revealed that the release of circulating alarmins from sites of distant sterile tissue damage triggered an inflammatory response in lung-resident macrophages by binding to receptor for advanced glycation end products (RAGE) on the membrane, which activated epidermal growth factor receptor (EGFR). Mechanistically, ligand-activated RAGE triggered EGFR activation through an interaction, leading to Rab5-mediated RAGE internalization and EGFR phosphorylation, which subsequently recruited and activated P38; this, in turn, promoted RAGE translation and trafficking to the plasma membrane to increase the cellular response to RAGE ligands, consequently exacerbating inflammation. Our study also showed that the loss of RAGE or EGFR expression by adoptive transfer of macrophages, blocking the function of RAGE with a neutralizing antibody, or pharmacological inhibition of EGFR activation in macrophages could protect against trauma- or stroke-induced remote lung injury. Therefore, our study revealed that targeting the RAGE-EGFR signaling pathway in tissue-resident macrophages is a potential therapeutic approach for treating secondary complications of sterile damage.
{"title":"Tissue-resident macrophages exacerbate lung injury after remote sterile damage","authors":"Hanhui Zhong, Jingjing Ji, Jinling Zhuang, Ziying Xiong, Pengyun Xie, Xiaolei Liu, Jundi Zheng, Wangli Tian, Xiaoyang Hong, Jing Tang","doi":"10.1038/s41423-024-01125-1","DOIUrl":"10.1038/s41423-024-01125-1","url":null,"abstract":"Remote organ injury, which is a common secondary complication of sterile tissue damage, is a major cause of poor prognosis and is difficult to manage. Here, we report the critical role of tissue-resident macrophages in lung injury after trauma or stroke through the inflammatory response. We found that depleting tissue-resident macrophages rather than disrupting the recruitment of monocyte-derived macrophages attenuated lung injury after trauma or stroke. Our findings revealed that the release of circulating alarmins from sites of distant sterile tissue damage triggered an inflammatory response in lung-resident macrophages by binding to receptor for advanced glycation end products (RAGE) on the membrane, which activated epidermal growth factor receptor (EGFR). Mechanistically, ligand-activated RAGE triggered EGFR activation through an interaction, leading to Rab5-mediated RAGE internalization and EGFR phosphorylation, which subsequently recruited and activated P38; this, in turn, promoted RAGE translation and trafficking to the plasma membrane to increase the cellular response to RAGE ligands, consequently exacerbating inflammation. Our study also showed that the loss of RAGE or EGFR expression by adoptive transfer of macrophages, blocking the function of RAGE with a neutralizing antibody, or pharmacological inhibition of EGFR activation in macrophages could protect against trauma- or stroke-induced remote lung injury. Therefore, our study revealed that targeting the RAGE-EGFR signaling pathway in tissue-resident macrophages is a potential therapeutic approach for treating secondary complications of sterile damage.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":null,"pages":null},"PeriodicalIF":24.1,"publicationDate":"2024-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139477531","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：