European Journal of Immunology最新文献

{"title":"Minor Splicing Factor RNPC3 Is Essential for the Germinal Center B Cell Response","authors":"Jing Wang,&nbsp;Gui-Xin Ruan,&nbsp;Yuxing Li,&nbsp;Xiong Xiao,&nbsp;Zhijian Zhu,&nbsp;Wenjing Chen,&nbsp;Hengjun Huang,&nbsp;Rui Zhang,&nbsp;Ruisi Wang,&nbsp;Meiyuan Chen,&nbsp;Ling Guo,&nbsp;Yan Li,&nbsp;Shengli Xu,&nbsp;Xijun Ou","doi":"10.1002/eji.202451508","DOIUrl":"https://doi.org/10.1002/eji.202451508","url":null,"abstract":"<div>\u0000 \u0000 <p>Germinal center (GC) response ensures the generation of diverse and high-affinity antibodies during the T cell-dependent (TD) immune response. This process is controlled by coordinated transcriptional and posttranscriptional gene regulatory mechanisms. Minor intron splicing is known to be involved in posttranscriptional regulation of gene expression. RNA-binding region (RNP1, RRM) containing 3 (RNPC3) is a minor spliceosome component involved in stabilizing the U11/U12 di-snRNP complex, which is essential for minor intron splicing. However, it remains unclear if RNPC3 and RNPC3-related gene regulatory mechanisms are important for the TD immune response. In this study, we conditionally ablated RNPC3 in activated B cells and showed that the mutant mice had defective antibody generation due to impaired GC B cell response. We demonstrate that RNPC3 deficiency inhibits the proliferation and promotes the apoptosis of activated B cells. Mechanistically, we show that RNPC3 regulates the development of GC B cells in a minor spliceosome-dependent manner by controlling the removal of minor introns from minor intron-containing genes associated with cell proliferation and apoptosis. Our study thus uncovers a previously unappreciated role for RNPC3 in regulating GC B cell response.</p>\u0000 </div>","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 4","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143749593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Guidelines and Advances in Basic and Applied Dendritic Cell Biology","authors":"Björn E. Clausen,&nbsp;Diana Dudziak","doi":"10.1002/eji.202551942","DOIUrl":"https://doi.org/10.1002/eji.202551942","url":null,"abstract":"&lt;p&gt;Dear Readers,&lt;/p&gt;&lt;p&gt;The Study Group Dendritic Cells (AKDC) of the German Society for Immunology (DGfI), established on September 28, 2016, during the 46th Annual Meeting in Hamburg, has become an essential forum for fostering high-quality research in dendritic cell (DC) and macrophage biology. With a current membership of 342, the group emphasizes rigorous scientific inquiry, methodological standardization, and active collaboration between young and established investigators.&lt;/p&gt;&lt;p&gt;The research interests of the AKDC cover a wide spectrum of topics within DC and macrophage biology, addressing fundamental issues from ontogeny and tissue homeostasis to T cell priming and immune regulation. Importantly, the research initiatives extend into translational applications, aiming to harness these cells in therapeutic strategies against cancer and autoimmune diseases. This integrated approach underscores the dual commitment to understanding the cellular mechanisms underpinning immune responses and translating these insights into clinical innovation.&lt;/p&gt;&lt;p&gt;A notable initiative that emerged from the activities of the AKDC is this special collection of articles on DCs. This collection compiles recent key developments and technical advances in the field, providing a critical resource for researchers to keep pace with emerging methodologies and conceptual frameworks. The series not only highlights advances in basic DC biology but also lays the groundwork for applied research, thereby serving as a bridge between laboratory discoveries and clinical application.&lt;/p&gt;&lt;p&gt;Central to the AKDC's contributions are the hands-on laboratory protocols (&lt;i&gt;Guidelines&lt;/i&gt;) that standardize the preparation and analysis of DC subsets. One set of guidelines details the preparation of single-cell suspensions from mouse lymphoid tissues—including the spleen, lymph nodes, and thymus—and describes the subsequent multiparameter flow cytometry analysis designed to differentiate DC subsets from other myeloid cells. Complementary protocols address the preparation of single-cell suspensions from mouse nonlymphoid tissues, such as skin, intestine, lung, kidney, mammary glands, oral mucosa, and transplantable tumors, ensuring that a wide range of experimental systems can benefit from reproducible methodologies.&lt;/p&gt;&lt;p&gt;The guidelines further extend into human studies, where protocols for the preparation of single-cell suspensions from human lymphoid and nonlymphoid tissues are detailed. These protocols include detailed gating strategies for flow cytometric analysis and cell sorting, thereby enhancing the resolution at which primary human DC subpopulations can be examined. In addition, state-of-the-art protocols for multiparameter fluorescence microscopy have been developed to facilitate the visualization and quantitative analysis of DC subsets within tissue sections, further advancing our capacity to analyze these cells in situ.&lt;/p&gt;&lt;p&gt;Beyond these technical protocols, the article collection","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 4","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.202551942","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143749372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IgA2 ACPA Drives a Hyper-Inflammatory Phenotype in Macrophages via ATP Synthase and COX2","authors":"Luís Almeida,&nbsp;Alice Bacon,&nbsp;Mohan Ghorasaini,&nbsp;Alwin J. van der Ham,&nbsp;René E. M. Toes,&nbsp;Martin Giera,&nbsp;Bart Everts","doi":"10.1002/eji.202451586","DOIUrl":"https://doi.org/10.1002/eji.202451586","url":null,"abstract":"<p>IgA can form immune complexes (ICs) and activate myeloid cells via Fc alpha receptor-mediated signalling to secrete pro-inflammatory cytokines. It was previously described that of the two IgA subclasses (IgA1 and IgA2), IgA2 is more inflammatory than IgA1. However, the mechanisms underlying this differential pro-inflammatory potential remain poorly defined. Using anti-citrullinated protein IgA1 and IgA2 antibodies (ACPA) that are commonly found in rheumatoid arthritis (RA) patients and linked to chronic inflammation, we show here that, in macrophages, IgA2-ICs boost TLR-induced TNF and IL6 secretion, COX2 expression, and production of COX2-dependent lipid mediators to a higher level than IgA1-ICs. Metabolically, we found the amplification of TLR-induced cytokine production and COX2 induction by IgA2-ICs to be dependent on mitochondrial ATP synthesis, but not glycolysis. Finally, we found the potentiation of TLR-induced cytokine production by IgA-ICs to be COX2-dependent. Together this work points towards a key role for mitochondrial ATP synthesis in driving COX2 expression and subsequent IgA2-IC-dependent potentiation of TLR-induced cytokine production by macrophages. As such, our work provides new insights into the mechanisms underlying IgA2-induced inflammation in the context of RA. Thus, this may hold novel clues to be explored as therapeutic possibilities to target antibody-driven inflammation in chronic inflammatory diseases.</p>","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 4","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.202451586","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143749595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modulation of Host Immunity by Microbiome-Derived Indole-3-Propionic Acid and Other Bacterial Metabolites","authors":"Burkhard Schütz,&nbsp;Felix F. Krause,&nbsp;R. Verena Taudte,&nbsp;Mario M. Zaiss,&nbsp;Maik Luu,&nbsp;Alexander Visekruna","doi":"10.1002/eji.202451594","DOIUrl":"https://doi.org/10.1002/eji.202451594","url":null,"abstract":"<p>In recent years, we have witnessed a rapidly growing interest in the intricate communications between intestinal microorganisms and the host immune system. Research on the human microbiome is evolving from merely descriptive and correlative studies to a deeper mechanistic understanding of the bidirectional interactions between gut microbiota and the mucosal immune system. Despite numerous challenges, it has become increasingly evident that an imbalance in gut microbiota composition, known as dysbiosis, is associated with the development and progression of various metabolic, immune, cancer, and neurodegenerative disorders. A growing body of evidence highlights the importance of small molecules produced by intestinal commensal bacteria, collectively referred to as gut microbial metabolites. These metabolites serve as crucial diffusible messengers, translating the microbial language to host cells. This review aims to explore the complex and not yet fully understood molecular mechanisms through which microbiota-derived metabolites influence the activity of the immune cells and shape immune reactions in the gut and other organs. Specifically, we will discuss recent research that reveals the close relationship between microbial indole-3-propionic acid (IPA) and mucosal immunity. Furthermore, we will emphasize the beneficial effects of IPA on intestinal inflammation and discuss its potential clinical implications.</p>","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 4","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.202451594","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143749625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cover Story: Eur. J. Immunol. 4'25","authors":"","doi":"10.1002/eji.202570041","DOIUrl":"https://doi.org/10.1002/eji.202570041","url":null,"abstract":"<p>Our cover features images related to flow cytometry techniques widely used for analysis of function and phenotypes of major human and murine immune cell subsets, superimposed on a multidimensional immune cell population scatter plot. These images are taken from the third edition of EJI's Flow Cytometry Guidelines by Cossarizza et al., a comprehensive resource prepared by flow cytometry and immunology research experts from around the world.\u0000\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 4","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.202570041","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143741059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interleukin-8/Matrix Metalloproteinase-9 Axis Impairs Wound Healing in Type 2 Diabetes through Neutrophil Extracellular Traps-Fibroblast Crosstalk","authors":"Dimitrios Tsilingiris,&nbsp;Anastasia-Maria Natsi,&nbsp;Efstratios Gavriilidis,&nbsp;Christina Antoniadou,&nbsp;Ioanna Eleftheriadou,&nbsp;Ioanna A. Anastasiou,&nbsp;Anastasios Tentolouris,&nbsp;Evangelos Papadimitriou,&nbsp;Evgenios Eftalitsidis,&nbsp;Panagiotis Kolovos,&nbsp;Victoria Tsironidou,&nbsp;Alexandra Giatromanolaki,&nbsp;Maria Koffa,&nbsp;Nikolaos Tentolouris,&nbsp;Panagiotis Skendros,&nbsp;Konstantinos Ritis","doi":"10.1002/eji.202451664","DOIUrl":"https://doi.org/10.1002/eji.202451664","url":null,"abstract":"<p>Neutrophils interact with and activate fibroblasts through the release of neutrophil extracellular traps (NETs). We investigated the role of NETs-fibroblast crosstalk in the cutaneous wound healing of type 2 diabetes (T2D). Neutrophils/NETs, serum, and primary human skin fibroblasts (HSFs) were obtained from individuals with T2D and age/sex-matched controls. NET-stimulation studies were performed on neutrophils/HSFs, with and without specific inhibitors, while HSF healing capacity was assessed using a scratch wound healing assay. T2D HSFs display a profibrotic phenotype, showing increased CCN2/CTGF, α-smooth muscle actin, and collagen release, albeit with impaired healing capacity, elevated type I collagen C-terminal telopeptide, and collagen degradation associated with increased (∼3.5-fold) matrix metalloproteinase-9 (MMP-9) in T2D neutrophils/NETs. IL-8 induced the expression of MMP-9 in neutrophils/NETs. Moreover, T2D neutrophils/NETs exhibited increased IL-8 content, which acted in an autocrine/paracrine fashion to further augment its production by neutrophils/HSFs. The findings were validated in normoglycemic individuals during a hyperglycemic clamp with concomitant lipid infusion and further corroborated immunohistochemically in diabetic plantar ulcer biopsies. This novel, vicious circle of NETs/interleukin-8/MMP-9/HSFs was hindered by IL-8 or MMP-9 blockade via specific inhibitors or by dismantling the NET-scaffold with DNase I, suggesting candidate therapeutic targets in wound healing impairment of T2D.</p>","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 4","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.202451664","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143749592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Issue Information: Eur. J. Immunol. 4'25","authors":"","doi":"10.1002/eji.202570042","DOIUrl":"https://doi.org/10.1002/eji.202570042","url":null,"abstract":"","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 4","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.202570042","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143741060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interleukin-18 Binding Protein (IL-18BP) Deficiency Affects Lymphocyte Activation and IL-18 Expression in a Mouse Model of Liver Inflammation","authors":"Christelle Devisme,&nbsp;Marie Stosskopf,&nbsp;Claire Piquet-Pellorce,&nbsp;Gaby Palmer,&nbsp;Cem Gabay,&nbsp;Jacques Le Seyec,&nbsp;Michel Samson,&nbsp;Céline Raguenes-Nicol","doi":"10.1002/eji.202451579","DOIUrl":"https://doi.org/10.1002/eji.202451579","url":null,"abstract":"&lt;p&gt;The liver is a vital detoxification organ, continuously exposed to injury from xenobiotics, infections, and metabolic disturbances. It plays an important immunological role, with NK and NKT cells as major actors, and serves as the primary source of acute-phase proteins during inflammation [&lt;span&gt;1&lt;/span&gt;]. Understanding the immune processes in acute hepatitis is essential for better characterizing the disease and helping recovery. A key player in inflammation regulation is interleukin (IL)-18. Produced mainly by innate immune cells, IL-18 is synthesized as proIL-18 in the cytosol, cleaved by caspase-1 upon inflammasome activation, and released. IL-18 activates NK and NKT cells and induces interferon-gamma (IFN-γ) production by T helper 1 cells [&lt;span&gt;2&lt;/span&gt;]. Elevated IL-18 levels are linked to inflammatory disease [&lt;span&gt;3&lt;/span&gt;] as well as liver pathologies, including acute hepatitis C virus (HCV) infection, metabolic-associated liver disease, and poor prognosis in hepatocarcinoma [&lt;span&gt;4&lt;/span&gt;]. Mutations in the IL-18 binding protein (IL-18BP), a soluble receptor inhibiting the activity of IL-18, are associated in humans with fulminant hepatitis [&lt;span&gt;5&lt;/span&gt;]. Studies in IL-18BP-deficient mice revealed that IL-18BP contributes to maintaining steady-state levels of circulating IL-18 [&lt;span&gt;6&lt;/span&gt;] and that IL-18-induced IFN-γ upregulates IL-18BP, forming a negative feedback loop to resolve inflammation [&lt;span&gt;3&lt;/span&gt;]. In this study, we investigated the IL-18/IL-18BP axis in acute mouse liver inflammation induced by concanavalin A (ConA) injection, a T cell- and macrophage-dependent liver injury model [&lt;span&gt;7&lt;/span&gt;], or induced by coronavirus mouse hepatitis virus 3 (MHV-3), which mimics fulminant viral hepatitis [&lt;span&gt;7&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;Using these models, we compared wild-type (WT) and &lt;i&gt;Il18bp&lt;/i&gt;-deficient (KO) mice. Both genotypes showed elevated mean ALT levels upon stimulation and weight loss starting at 60 h postinfection (hpi) (Figure S1). However, some MHV-3 injected mice exhibited ALT levels within the uninfected range at 72 hpi (gray dots in charts). Given the low dose of the virus used to avoid death before day 7, these animals might have cleared the virus more efficiently at the early stages. Focusing on immune-cell infiltration in the liver, we observed no significant differences in cell counts or population proportions between WT and KO mice (Figure 1A,B). We found that MHV-3-infected mice with normal ALT levels had a higher proportion of neutrophils (Figure S2A). Most strikingly, the percent of activated CD69&lt;sup&gt;+&lt;/sup&gt; lymphocytes was markedly reduced in the liver and spleen of MHV-3 infected KO mice (Figure 1C–F; Figure S2) compared with WT or ConA-treated mice.&lt;/p&gt;&lt;p&gt;To investigate the cause of this lack of activation, we measured cytokine production by quantifying a panel of inflammatory cytokines using a bead-based immunoassay. We observe the distinct effect of MHV-3 and ConA challenges on cytokine levels ","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 4","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.202451579","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143749373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic Regulation of CD8+ Effector T Cell Differentiation by PDCD5","authors":"Lixue Jin,&nbsp;Xin Zhang,&nbsp;Jingyi Wang,&nbsp;Yujia Wang,&nbsp;Ke Wang,&nbsp;Zhuolin Wang,&nbsp;Pingzhang Wang,&nbsp;Xiuyuan Sun,&nbsp;Jie Hao,&nbsp;Rong Jin,&nbsp;Dan Lu,&nbsp;Qing Ge","doi":"10.1002/eji.202451388","DOIUrl":"10.1002/eji.202451388","url":null,"abstract":"<p>Epigenetic modification plays a crucial role in establishing the transcriptional program that governs the differentiation of CD8⁺ effector T cells. However, the mechanisms by which this process is regulated at an early stage, prior to the expression of master transcription factors, are not yet fully understood. In this study, we have identified PDCD5 as an activation-induced molecule that is necessary for the proper differentiation and expansion of antigen-specific CD8⁺ effector T cells in a mouse model of chronic viral infection. The genetic deletion of <i>Pdcd5</i> resulted in impaired differentiation and function of effector T cells, while T-cell activation, metabolic reprogramming, and the differentiation of memory/exhausted T cells were largely unaffected. At the molecular level, we observed reduced chromatin accessibility and transcriptional activity of <i>Tbx21</i> and its regulated genes in <i>Pdcd5</i>^−/− CD8⁺ T cells. We further identified that PRDM9 facilitates the H3K4me3 modification of genes associated with the effector phenotype in CD8⁺ T cells. The interaction between PDCD5 and PRDM9 promotes the nuclear translocation and lysine methyltransferase activity of PRDM9. Collectively, these findings highlight the crucial role of the PDCD5/PRDM9 axis in epigenetic reprogramming during the early stages of fate determination for effector CD8⁺ T cell fate.</p>","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 3","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11924876/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143661752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ICAM-1 Is Overexpressed by Cancers and Negatively Impacts Antibody-Based Therapies Including Antibody–Drug Conjugates","authors":"J. Bradford Kline,&nbsp;Luigi Grasso,&nbsp;Nicholas C. Nicolaides","doi":"10.1002/eji.202451611","DOIUrl":"10.1002/eji.202451611","url":null,"abstract":"<div>\u0000 \u0000 <p>Humoral immunity utilizes antibodies and immune effector cells to mediate dysregulated cancer cell killing. These mechanisms are referred to as Humoral Immuno-Oncology (HIO). HIO immunosuppression is mediated by tumor-produced proteins called HIO factors. Using a combination of patient serum analysis and literature searches, we screened a number of samples to determine if they suppressed HIO. Herein, we identified that ICAM-1 (intercellular adhesion molecule 1) can bind IgG1-type antibodies and suppress their immune effector activity. Through a series of mutagenesis, we identified a unique motif within the IgG1CH3 domain essential for ICAM-1 binding, which inhibits antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Conservative amino acid substitutions within the CH3 domain were able to abrogate ICAM-1 binding and overcome ICAM-1 mediated immune effector suppression. Additionally, isogenic tumor cell lines with silenced ICAM-1 expression were more susceptible to antibody–drug conjugate (ADCs) cytotoxicity than parental cells. This effect appeared to correlate with membrane ICAM-1 binding to the IgG1 component that reduced ADC internalization, a function important for maximal target cell killing. These findings highlight a novel mechanism by which tumors can suppress the host's immune system for survival and offer new concepts for engineering antibody-based therapeutics that are refractory to ICAM-1 immunosuppression.</p>\u0000 </div>","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 3","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143661756","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}