Cellular &Molecular Immunology最新文献

{"title":"γδ T-cell autoresponses to ectopic membrane proteins: a new type of pattern recognition","authors":"Hongqin You, Xiangjin Zhang, Hui Chen, Chang Liu, Da Teng, Jiajia Han, Ming Chen, Yongsheng Pang, Jianmin Zhang, Menghua Cai, Yueqi Zhao, Qingqing Dong, Shuli Wang, Yi Xu, Yu Hu, Peng Dong, Wei He","doi":"10.1038/s41423-025-01258-x","DOIUrl":"10.1038/s41423-025-01258-x","url":null,"abstract":"T-cell receptor (TCR) γδ-expressing cells are conserved lymphocytes of innate immunity involved in first-line defense and immune surveillance. TCRγδ recognizes protein/nonprotein ligands without the help of the major histocompatibility complex (MHC), especially via direct binding to protein ligands, which is dependent primarily on the δ chain complementary determining region 3 (CDR3δ). However, the mechanism of protein‒antigen recognition by human γδ TCRs remains poorly defined. We hypothesize that γδ TCRs recognize self-proteins expressed ectopically on the cell membrane that are derived from intracellular components under stress. Here, we mapped 16 intercellular self-proteins among 21,000 proteins with a huProteinChip as putative ligands for Vδ1/Vδ2 TCRs, 13 for Vδ1 TCRs and 3 for Vδ2 TCRs. Functional tests confirmed that ectopic nucleolin (NCL) is a ligand for the Vδ1 TCR, whereas protein-glutamine γ-glutamyltransferase K (TGM1) is a ligand for the Vδ2 TCR. In the context of radiation exposure, the ectopic expression of intracellular proteins on the tumor cell surface is related to the increased antitumor cytotoxicity of γδ T cells both in vitro and in vivo. In conclusion, the recognition of intracellular proteins that are ectopically expressed on somatic cells by human γδ TCRs is a basic interaction mechanism that enables new types of immune pattern recognition and a novel γδ TCR-ligand-based strategy for tumor immunotherapy.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 4","pages":"356-370"},"PeriodicalIF":21.8,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41423-025-01258-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143406020","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}

{"title":"Cell-associated galectin 9 interacts with cytotoxic T cells confers resistance to tumor killing in nasopharyngeal carcinoma through autophagy activation","authors":"Ngar-Woon Kam, Cho Yiu Lau, Jeffrey Yan Ho Lau, Xin Dai, Yusi Liang, Syrus Pak Hei Lai, Michael King Yung Chung, Valen Zhuoyou Yu, Wenting Qiu, Mengsu Yang, Corey Smith, Rajiv Khanna, Kwan Ming Ng, Wei Dai, Chi Ming Che, Victor Ho-Fun Lee, Dora L. W. Kwong","doi":"10.1038/s41423-024-01253-8","DOIUrl":"10.1038/s41423-024-01253-8","url":null,"abstract":"Immune effector cells, including cytotoxic T lymphocytes (CTLs) play essential roles in eliminating cancer cells. However, their functionality is often compromised, even when they infiltrate the tumor microenvironment (TME) or are transferred to cancer patients adoptively. In this study, we focused on galectin 9 (G9), an inhibitory ligand that we observed to be predominately positioned on the plasma membrane and readily interacts with CD8 + CTL in the TME of nasopharyngeal carcinoma (NPC). We discovered that cell-cell contact between activated effector CTLs and target tumor cells (TarTC) with G9 overexpression led to cellular death defects. Despite the formation of CTL–TarTC conjugates, there is no impact on the cell number nor viability of CTL, and the release of cytolytic content and associated activity were not completely abrogated. Instead, this interaction promoted autophagy and restricted necrosis in the TarTC. Furthermore, reducing G9 expression in tumor cells enhanced the suppressive effect on tumor growth upon adoptive transfer of activated effector CTL. Additionally, inhibiting autophagy effectively controlled tumor growth in cases of G9 overexpression. Therefore, we highlight the contribution of G9 in facilitating the resistance of NPC to CTL-mediated killing by inducing a selection-cell death state in tumor cells, characterized by increased autophagy and decreased necrosis.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 3","pages":"260-281"},"PeriodicalIF":21.8,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41423-024-01253-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254825","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}

{"title":"GLP1 alleviates oleic acid-propelled lipocalin-2 generation by tumor-infiltrating CD8+ T cells to reduce polymorphonuclear MDSC recruitment and enhances viral immunotherapy in pancreatic cancer","authors":"Jingyi Wu, Peng Qian, Yifeng Han, Chuning Xu, Mao Xia, Ping Zhan, Jiwu Wei, Jie Dong","doi":"10.1038/s41423-025-01260-3","DOIUrl":"10.1038/s41423-025-01260-3","url":null,"abstract":"Recruitment of polymorphonuclear MDSCs (PMN-MDSCs) in the TME suppresses the antitumor activity of tumor-infiltrating CD8+ T cells (CD8+ TILs). Little is known about the role of antitumoral CD8+ TILs in actively initiating an immune-tolerant microenvironment, particularly in the recruitment of PMN-MDSCs. In this study, we found that immunotherapy-activated CD8+ TILs significantly increased PNM-MDSC infiltration in the TME, resulting in antitumor resistance. When CD8+ T cells are activated, lipocalin-2 (LCN2) expression is strongly upregulated, which significantly enhances PMN-MDSC chemotaxis. Mechanistically, immune activation increased fatty acid synthesis in CD8+ T cells, particularly oleic acid (OA), which induced lysosomal membrane permeabilization, releasing cathepsin B and subsequently activating NF-κB to promote LCN2 expression. Moreover, we showed that glucagon-like peptide 1 (GLP1) effectively inhibited OA synthesis in activated CD8+ T cells, reducing LCN2 production. We then developed a recombinant adenovirus encoding GLP1 (AdV-GLP1), which significantly reduced PMN-MDSC infiltration and reinvigorated the antitumor activity of CD8+ TILs. In various pancreatic cancer models, including subcutaneous, orthotopic, and humanized CDX/PDX models, AdV-GLP1 displayed excellent antitumor efficacy. Our work advances the understanding of how immunotherapy-activated CD8+ TILs initiate PMN-MDSC infiltration and provides a clinically relevant strategy to target this interaction and improve cancer immunotherapy.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 3","pages":"282-299"},"PeriodicalIF":21.8,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254842","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}

{"title":"Peroxisome proliferator-activated receptor alpha is an essential factor in enhanced macrophage immune function induced by angiotensin-converting enzyme","authors":"Suguru Saito, Duo-Yao Cao, Ellen A. Bernstein, Tomohiro Shibata, Anthony E. Jones, Amy Rios, Aoi O. Hoshi, Aleksandr B. Stotland, Erika E. Nishi, Jennifer E. Van Eyk, Ajit Divakaruni, Zakir Khan, Kenneth E. Bernstein","doi":"10.1038/s41423-025-01257-y","DOIUrl":"10.1038/s41423-025-01257-y","url":null,"abstract":"Increased expression of angiotensin-converting enzyme (ACE) by myeloid lineage cells strongly increases the immune activity of these cells, as observed in ACE10/10 mice, which exhibit a marked increase in antitumor and antibactericidal immunity. We report that peroxisome proliferator-activated receptor alpha (PPARα), a transcription factor that regulates genes critical for lipid metabolism, is a key molecule in the enhanced macrophage function induced by ACE. Here, we used a Cre–LoxP approach with LysM-Cre to create a modified ACE10/10 mouse line in which macrophages continue to generate abundant ACE but in which monocyte and macrophage PPARα expression is selectively suppressed. These mice, termed A10-PPARα-Cre, have significantly increased growth of B16-F10 tumors compared with ACE10/10 mice with Cre expression. PPARα depletion impaired cytokine production and antigen-presenting activity in ACE-expressing macrophages, resulting in reduced tumor antigen-specific CD8+ T-cell generation. Additionally, the elevated bactericidal resistance typical of ACE10/10 mice was significantly reduced in A10-PPARα-Cre mice, such that these mice resembled WT mice in their resistance to methicillin-resistant Staphylococcus aureus (MRSA) infection. THP-1 cells expressing increased ACE (termed THP-1-ACE) constitute a human macrophage model with increased PPARα that shows enhanced cytotoxicity against tumor cells and better phagocytosis and killing of MRSA. RNA silencing of PPARα in THP-1-ACE cells reduced both tumor cell death and bacterial phagocytosis and clearance. In contrast, the in vivo administration of pemafibrate, a specific agonist of PPARα, to WT and A10-PPARα-Cre mice reduced B16-F10 tumor growth by 24.5% and 25.8%, respectively, but pemafibrate reduced tumors by 57.8% in ACE10/10 mice. With pemafibrate, the number of antitumor CD8+ T cells was significantly lower in A10-PPARα-Cre mice than in ACE10/10 mice. We conclude that PPARα is important in the immune system of myeloid cells, including wild-type cells, and that its increased expression by ACE-expressing macrophages in ACE10/10 mice is indispensable for ACE-dependent functional upregulation of macrophages in both mice and human cells.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 3","pages":"243-259"},"PeriodicalIF":21.8,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41423-025-01257-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254845","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}

{"title":"mRNA 3ʹUTR length matters: alternative polyadenylation shapes autophagy and inflammatory responses in macrophages","authors":"Wenjun Cai, Emiliano P. Ricci","doi":"10.1038/s41423-024-01252-9","DOIUrl":"10.1038/s41423-024-01252-9","url":null,"abstract":"","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 3","pages":"336-338"},"PeriodicalIF":21.8,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000795","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}

{"title":"Increasing evidence for the pathogenic role of keratinocytes in lupus","authors":"Benjamin Klein, Allison C. Billi, J. Michelle Kahlenberg","doi":"10.1038/s41423-024-01254-7","DOIUrl":"10.1038/s41423-024-01254-7","url":null,"abstract":"","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 3","pages":"333-335"},"PeriodicalIF":21.8,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000812","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}

{"title":"Author Correction: A special RELationship between sugar and tumor-infiltrating regulatory T cells","authors":"Ingo Schmitz","doi":"10.1038/s41423-025-01256-z","DOIUrl":"10.1038/s41423-025-01256-z","url":null,"abstract":"","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 3","pages":"340-340"},"PeriodicalIF":21.8,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41423-025-01256-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000786","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}

{"title":"Author Correction: A spike protein S2 antibody efficiently neutralizes the Omicron variant","authors":"Jia Hu, Xiang Chen, Xingbing Lu, Lijuan Wu, Liyuan Yin, Lingling Zhu, Hao Liang, Feng Xu, Qinghua Zhou","doi":"10.1038/s41423-025-01255-0","DOIUrl":"10.1038/s41423-025-01255-0","url":null,"abstract":"","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 3","pages":"339-339"},"PeriodicalIF":21.8,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41423-025-01255-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000805","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}

{"title":"Myelin debris as an initiator of microglial dysfunction and neuropathology in Alzheimer’s disease","authors":"Joshua D. Samuels, John R. Lukens","doi":"10.1038/s41423-024-01243-w","DOIUrl":"10.1038/s41423-024-01243-w","url":null,"abstract":"","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 2","pages":"208-210"},"PeriodicalIF":21.8,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142982724","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}

{"title":"Demyelination-derived lysophosphatidylserine promotes microglial dysfunction and neuropathology in a mouse model of Alzheimer’s disease","authors":"Yubo Zhou, Zonghui Huang, Bolong Lin, Ming Ma, Yize Hao, Juanjuan Liu, Wen Xu, Guangming Huang, Wei Mo, Xiaqiong Wang, Wei Jiang, Rongbin Zhou","doi":"10.1038/s41423-024-01235-w","DOIUrl":"10.1038/s41423-024-01235-w","url":null,"abstract":"Microglia dysfunction-associated neuroinflammation is an important driver of Alzheimer’s disease (AD), but the mechanism is poorly understood. Here, we show that demyelination promotes neuroinflammation and cognitive impairment via the lysophosphatidylserine (LysoPS)-GPR34 axis in AD. Demyelination is observed at the early stage and is accompanied by an increase in LysoPS in myelin debris in a 5xFAD mouse model of AD. Reducing the content of LysoPS in myelin or inhibiting its receptor GPR34 via genetic or pharmacological approaches can reduce microglial dysfunction and neuroinflammation and improve microglial Aβ phagocytosis, subsequently resulting in less Aβ deposition and memory restoration in 5xFAD mice. Furthermore, increased LysoPS production and microglial GPR34 expression were also observed in the brains of AD patients. These results reveal the pathogenic role of demyelination-derived LysoPS in microglial dysfunction and AD pathology and suggest that blocking GPR34 as a therapeutic strategy beyond targeting Aβ.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 2","pages":"134-149"},"PeriodicalIF":21.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909156","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}