European Journal of Immunology最新文献

BTK-Inhibition Enhances TLR-7-Mediated Interferon-Alpha Production in pDCs by Blocking the Inhibitory BDCA-2 Pathway

IF 4.5 3区医学

European Journal of Immunology Pub Date : 2025-02-24 DOI: 10.1002/eji.202450985

Laura Ceglarek, Ramona Gerhards, Vinicius Boldrini, Christian Wichmann, Anneli Peters, Edgar Meinl

引用次数: 0

VSTM1/SIRL-1: An Inhibitory Pattern Recognition Receptor Regulating Myeloid Cells

IF 4.5 3区医学

European Journal of Immunology Pub Date : 2025-02-24 DOI: 10.1002/eji.202451465

Maaike Koops, Linde Meyaard

引用次数: 0

Survival and Developmental Progression of Unselected Thymocytes in the Absence of the T-Cell Adaptor Gads

IF 4.5 3区医学

European Journal of Immunology Pub Date : 2025-02-24 DOI: 10.1002/eji.202451000

Rose Shalah, Manal Marzouk, Enas Hallumi, Naama Klopstock, Deborah Yablonski

{"title":"Survival and Developmental Progression of Unselected Thymocytes in the Absence of the T-Cell Adaptor Gads","authors":"Rose Shalah, Manal Marzouk, Enas Hallumi, Naama Klopstock, Deborah Yablonski","doi":"10.1002/eji.202451000","DOIUrl":"https://doi.org/10.1002/eji.202451000","url":null,"abstract":"Thymocyte β-selection and positive-selection depend on TCR signaling via the immune adaptors SLP-76 and LAT. Gads bridges the recruitment of SLP-76 to LAT, yet is not required for the maturation of single positive (SP) thymocytes. To illuminate this paradox, we performed tamoxifen-induced ablation of Gads (GadsiKO), accompanied by the expression of tdTomato, and compared the development of Gads-expressing (Tom−) and Gads-ablated (Tom+) thymocytes within the same mouse. GadsiKO (Tom+) thymocytes exhibited impaired β- and positive-selection, yet δ-selection was not affected. While susceptible to apoptosis ex vivo, the marked accumulation of self-MHC nonresponding (CD5−) GadsiKO DP thymocytes suggested the possibility of impaired death by neglect in situ. Further supporting this notion, GadsiKO CD5lo DP thymocytes exhibited reduced apoptosis in situ and reduced CD8-induced apoptosis ex vivo. Most GadsiKO CD4 SP thymocytes were positively selected, yet a distinct population of unselected (CD5− TCRβneg/low CCR7lo CD24hi) CD4 SP thymocytes was seen only in the absence of Gads. This unselected population did not include Treg or TCRγδ subsets; rather, it encompassed CD44lo CD25+ cells, resembling pre-β-selection thymocytes. Our results suggest that Gads promotes passage through key TCR-driven developmental checkpoints while repressing the progression of unselected DN and DP thymocytes.","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 2","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.202451000","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143475718","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}

引用次数: 0

Trametinib Suppresses the Stimulated T Cells Through G1 Arrest and Apoptosis

IF 4.5 3区医学

European Journal of Immunology Pub Date : 2025-02-24 DOI: 10.1002/eji.202350667

Toshimasa Nakao, Takero Shindo, Hideki Takakura, Takumi Narita, Yukako Ise-Nakao, Saeko Akiyama, Yosuke Iizumi, Shogen Boku, Motoki Watanabe, Toshiyuki Sakai, Seiichi Shimizu, Masaki Yamada, Yoshihiro Sowa, Michihiro Mutoh

{"title":"Trametinib Suppresses the Stimulated T Cells Through G1 Arrest and Apoptosis","authors":"Toshimasa Nakao, Takero Shindo, Hideki Takakura, Takumi Narita, Yukako Ise-Nakao, Saeko Akiyama, Yosuke Iizumi, Shogen Boku, Motoki Watanabe, Toshiyuki Sakai, Seiichi Shimizu, Masaki Yamada, Yoshihiro Sowa, Michihiro Mutoh","doi":"10.1002/eji.202350667","DOIUrl":"https://doi.org/10.1002/eji.202350667","url":null,"abstract":"<div>\u0000 \u0000 The development of efficient immunosuppressants may bring significant benefits to patients after organ/stem transplantation and those with allergies or autoimmune diseases. MEK inhibitors were originally developed as anticancer reagents, but recent reports have suggested that they may have the potential to be immunosuppressants. Trametinib is a first-in-class MEK inhibitor. Here, we examined the effects of trametinib on the immune system and revealed its mechanism. Trametinib suppressed both CD4 and CD8 T-cell proliferation and activated T cells, which expressed CD25 and TIM3, in a dose-dependent manner in vitro. Trametinib also suppressed T cell-related cytokine secretion in a dose-dependent manner. Notably, trametinib suppressed T cell proliferation through the induction of G1 arrest and apoptosis in stimulated T cells. In addition, trametinib induced regulatory T cells (Tregs). We confirmed that low concentrations of trametinib (1 and 10 nM) were not toxic toward splenic naïve T cells and normal mouse liver cells. In this study, we demonstrated whether trametinib suppressed CD4 and CD8 T cell proliferation by inducing G1 arrest and apoptosis along with suppression of cytokine secretion.\u0000 </div>","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 2","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143475717","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}

引用次数: 0

Towards the Next Generation of Data-Driven Therapeutics Using Spatially Resolved Single-Cell Technologies and Generative AI

IF 4.5 3区医学

European Journal of Immunology Pub Date : 2025-02-18 DOI: 10.1002/eji.202451234

Avital Rodov, Hosna Baniadam, Robert Zeiser, Ido Amit, Nir Yosef, Tobias Wertheimer, Florian Ingelfinger

{"title":"Towards the Next Generation of Data-Driven Therapeutics Using Spatially Resolved Single-Cell Technologies and Generative AI","authors":"Avital Rodov, Hosna Baniadam, Robert Zeiser, Ido Amit, Nir Yosef, Tobias Wertheimer, Florian Ingelfinger","doi":"10.1002/eji.202451234","DOIUrl":"https://doi.org/10.1002/eji.202451234","url":null,"abstract":"Recent advances in multi-omics and spatially resolved single-cell technologies have revolutionised our ability to profile millions of cellular states, offering unprecedented opportunities to understand the complex molecular landscapes of human tissues in both health and disease. These developments hold immense potential for precision medicine, particularly in the rational design of novel therapeutics for treating inflammatory and autoimmune diseases. However, the vast, high-dimensional data generated by these technologies present significant analytical challenges, such as distinguishing technical variation from biological variation or defining relevant questions that leverage the added spatial dimension to improve our understanding of tissue organisation. Generative artificial intelligence (AI), specifically variational autoencoder- or transformer-based latent variable models, provides a powerful and flexible approach to addressing these challenges. These models make inferences about a cell's intrinsic state by effectively identifying complex patterns, reducing data dimensionality and modelling the biological variability in single-cell datasets. This review explores the current landscape of single-cell and spatial multi-omics technologies, the application of generative AI in data analysis and modelling and their transformative impact on our understanding of autoimmune diseases. By combining spatial and single-cell data with advanced AI methodologies, we highlight novel insights into the pathogenesis of autoimmune disorders and outline future directions for leveraging these technologies to achieve the goal of AI-powered personalised medicine.","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 2","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.202451234","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143431812","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}

引用次数: 0

Tissue-Resident Regulatory T Cells Expressing CD83 Maintain Local Homeostasis and Restrict Th2 Responses in Asthma

IF 4.5 3区医学

European Journal of Immunology Pub Date : 2025-02-16 DOI: 10.1002/eji.202451525

Anita Heiß, Susanne Krammer, Christine Kuhnt, Christina Draßner, Philipp Beck, Adriana Geiger, Stefan Schliep, Carol-Immanuel Geppert, Alexander Steinkasserer, Andreas B. Wild

{"title":"Tissue-Resident Regulatory T Cells Expressing CD83 Maintain Local Homeostasis and Restrict Th2 Responses in Asthma","authors":"Anita Heiß, Susanne Krammer, Christine Kuhnt, Christina Draßner, Philipp Beck, Adriana Geiger, Stefan Schliep, Carol-Immanuel Geppert, Alexander Steinkasserer, Andreas B. Wild","doi":"10.1002/eji.202451525","DOIUrl":"https://doi.org/10.1002/eji.202451525","url":null,"abstract":"Non-lymphoid tissue Tregs (NLT-Tregs) are critical for tissue homeostasis, inflammation control, and induction of tissue repair. Recent single-cell RNA sequencing data identified the expression of CD83 as part of an NLT-Treg signature, which is an essential molecule for the stability and differentiation of lymphoid Tregs. However, the biological significance of CD83 expression for NLT Tregs has not yet been elucidated. The present study explores for the first time the role of CD83 expression by lung-resident Tregs in the steady state and during asthma to understand its importance in barrier tissues. We evaluated the effect of Treg-specific CD83 deletion (CD83cKO) on the lung-resident T-cell compartment and cytokine profile. CD83-deficient lung Tregs are less differentiated but more activated, resulting in unrestrained T-cell activation. Further, CD83cKO mice were challenged in an asthma model and showed an accelerated disease progression, driven by Th2-biased T-cell responses. CD83cKO Tregs exhibited enhanced responsiveness to IL-4, leading to insufficient control of Th2-differentiation from naïve T cells. These findings underscore the pivotal role of CD83 in the NLT-Treg-mediated modulation of Th2 responses. Overall, our results highlight CD83 as a key player in tissue homeostasis and inflammatory responses, suggesting potential therapeutic implications for inflammatory disorders such as asthma.","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 2","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.202451525","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143423888","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}

引用次数: 0

MAPK and STAT3 Inhibitors Modulate FoxP3 Expression and Regulatory T Cell Function

IF 4.5 3区医学

European Journal of Immunology Pub Date : 2025-02-16 DOI: 10.1002/eji.202451225

Nuria García-Díaz, Elise Solli, Ehsan Hajjar, Selma Cornillot-Clément, Johannes Landskron, Rafi Ahmad, Qian Wei, Kjetil Taskén

{"title":"MAPK and STAT3 Inhibitors Modulate FoxP3 Expression and Regulatory T Cell Function","authors":"Nuria García-Díaz, Elise Solli, Ehsan Hajjar, Selma Cornillot-Clément, Johannes Landskron, Rafi Ahmad, Qian Wei, Kjetil Taskén","doi":"10.1002/eji.202451225","DOIUrl":"https://doi.org/10.1002/eji.202451225","url":null,"abstract":"<div>\u0000 \u0000 Regulatory T cells (Tregs) are a subset of T cells defined by the expression of Forkhead box protein P3 (FoxP3) playing a crucial role in regulating effector T cell activity. Tregs accumulate in the tumor microenvironment facilitating tumor growth. Thus, targeting FoxP3+ Tregs could improve cancer immunotherapies. Here, we conducted a high-throughput, phenotypic screening of a drug repurposing library to identify compounds downregulating FoxP3 expression in human primary T cells. We identified the tyrosine kinase inhibitor bosutinib and the STAT3 inhibitor nifuroxazide effectively downregulating FoxP3 expression. To identify more potent compounds, structural analogs of these two compounds were searched and validated. These analogs were found to reduce FoxP3 expression in a similar- or more potent manner than the original hits. All compounds inhibited Treg suppressive functions and reduced the expression of Treg activation markers. Importantly, bosutinib disrupted FAK and CaMKII signaling more potently in Tregs, whilst nifuroxazide and its analog NA16 targeted STAT3 protein levels more effectively in Tregs. Additionally, bosutinib and NA16 targeted effector Tregs more effectively than other Treg subsets. In summary, bosutinib, nifuroxazide, and their analogs inhibited FoxP3 expression, Treg suppressive abilities, and Treg activation effectively, which could serve as tools for the improvement of current cancer immunotherapies.\u0000 </div>","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 2","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143424003","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}

引用次数: 0

Dynamic Activation of NADPH Oxidases in Immune Responses Modulates Differentiation, Function, and Lifespan of Plasma Cells

IF 4.5 3区医学

European Journal of Immunology Pub Date : 2025-02-11 DOI: 10.1002/eji.202350975

Olivia T. M. Bucheli, Daniela Rodrigues, Carolin Ulbricht, Anja E. Hauser, Klaus Eyer

{"title":"Dynamic Activation of NADPH Oxidases in Immune Responses Modulates Differentiation, Function, and Lifespan of Plasma Cells","authors":"Olivia T. M. Bucheli, Daniela Rodrigues, Carolin Ulbricht, Anja E. Hauser, Klaus Eyer","doi":"10.1002/eji.202350975","DOIUrl":"https://doi.org/10.1002/eji.202350975","url":null,"abstract":"NADPH-oxidase (NOX)-derived reactive oxygen species (ROS) have been described to play essential roles in B-cell activation processes. However, several key questions concerning NOX activity and subsequent ROS production remain unaddressed, including fundamental processes such as differentiation, functional competence, cellular metabolism, and viability. This study investigated these questions in a murine B-cell response after secondary immunization. We combined single-cell transcriptomics and single-cell detection of NOX activity and observed that various subsets of B cells dynamically express NOX1 and NOX2. The NOX+ cellular phenotype correlated with increased activity of metabolic pathways, augmented lactate production, lower IgG secretion rates, and markers for longevity. The NOX+ cellular phenotype was also associated with increased cellular stress and apoptosis, underscoring the intricate relationship between ROS and cellular survival. Consequently, these insights advance our understanding of how long-lived humoral immunity is formed.","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 2","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.202350975","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143380562","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}

引用次数: 0

Toll-Like Receptor Blockage by TIP-1 and MIP-2 Treatment Mitigates Inflammation in a Mouse Model of Adult-Onset Still's Disease or Still's Disease

IF 4.5 3区医学

European Journal of Immunology Pub Date : 2025-02-11 DOI: 10.1002/eji.202451227

Mi-Hyun Ahn, Yang Seon Choi, Sang-Won Lee, Sangdun Choi, Hyoun-Ah Kim

{"title":"Toll-Like Receptor Blockage by TIP-1 and MIP-2 Treatment Mitigates Inflammation in a Mouse Model of Adult-Onset Still's Disease or Still's Disease","authors":"Mi-Hyun Ahn, Yang Seon Choi, Sang-Won Lee, Sangdun Choi, Hyoun-Ah Kim","doi":"10.1002/eji.202451227","DOIUrl":"https://doi.org/10.1002/eji.202451227","url":null,"abstract":"<div>\u0000 \u0000 The inflammatory response triggered by Toll-like receptors (TLRs) may implicated in the development of the pathogenesis of adult-onset Still's disease (AOSD). This study evaluated the efficacy of TLR inhibitor peptides, specifically TLR inhibitor peptide 1 (TIP-1) and MAL/MyD88 inhibitory peptide 2 (MIP-2) in animal models of AOSD. THP-1 cells were stimulated with TLR agonists and treated with TIP-1 or MIP-2. Interferon (IFN)-γ knock-out mice were induced with AOSD-like symptoms using Mycobacterium mixed with Freund's complete adjuvant (CFA), then treated with the peptides. THP-1 cells treated with TIP-1 and MIP-2 showed significantly decreased expression of TLRs agonist-induced MyD88 and phosphorylated NF-κB, except TLR9 agonists. Furthermore, the peptides resulted in a significant decrease in the concentrations of interleukin (IL)-1β and IL-6 in the culture supernatants, except TLR9 agonists. In animal models of AOSD, treatment with inhibitor peptides significantly improved their clinical symptoms. The administration of these peptides resulted in a significant decrease in serum levels of IL-1β and IL-18. The expression of inflammatory cytokines were downregulated in the spleen and lymph node of TIP-1 and MIP-2 treated mice. These findings suggest that TIP-1 and MIP-2 may be effective candidates for AOSD treatment, as they have broad specificity for TLRs.\u0000 </div>","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 2","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143380560","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}

引用次数: 0

IQGAP1 Influences Neutrophil Maturation and Its Effector Functions

IF 4.5 3区医学

European Journal of Immunology Pub Date : 2025-02-11 DOI: 10.1002/eji.202451349

Lifei Hou, Alan Hsu, Hongbo Luo, Koichi Yuki

引用次数: 0