Andreas Radbruch, Peter K. Jani, Thomas H. Winkler, Klaus Rajewsky
{"title":"Georg Friedrich (Fritz) Melchers (27.4.1936–24.2.2025)","authors":"Andreas Radbruch, Peter K. Jani, Thomas H. Winkler, Klaus Rajewsky","doi":"10.1002/eji.202552109","DOIUrl":"https://doi.org/10.1002/eji.202552109","url":null,"abstract":"","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 6","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144264589","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}
Alvaro González-Dominguez, Shuling Zhang, Daniel Boy-Ruiz, Daniel Connors, Raquel de la Varga-Martínez, Beverly A. Mock, Mario D. Cordero
{"title":"mTOR Modulates NLRP3 Inflammasome Activation via Nuclear Translocation and STAT1 Inhibition","authors":"Alvaro González-Dominguez, Shuling Zhang, Daniel Boy-Ruiz, Daniel Connors, Raquel de la Varga-Martínez, Beverly A. Mock, Mario D. Cordero","doi":"10.1002/eji.202451176","DOIUrl":"https://doi.org/10.1002/eji.202451176","url":null,"abstract":"<div>\u0000 \u0000 <p>The NLRP3 inflammasome has emerged as an unexpected sensor of metabolic danger and stress. Their enhanced activation has been implicated in the development of major diseases such as gout, Type 2 diabetes, obesity, cancer, and neurodegenerative and cardiovascular diseases. In this study, we showed that mammalian target of rapamycin (mTOR) regulates NLRP3 inflammasome activation in the nucleus of macrophages. mTOR binds to NLRP3 under basal conditions, and this binding is reduced after lipopolysaccharides (LPS) or LPS + adenosine triphosphate (ATP) treatment. Furthermore, rapamycin-induced downregulation of mTOR expression has an inhibitory effect on NLRP3 inflammasome activation. mTOR knockdown (KD) mice exhibit reduced protein levels of inflammasome components, and their macrophages fail to activate the NLRP3 inflammasome after LPS + ATP treatment. From a mechanistic point of view, LPS + ATP treatment induced the nuclear translocation of mTOR, leading to enhanced NLRP3 inflammasome activation. However, the mTOR inhibition by rapamycin treatment increased phosphorylation of STAT1 which repressed NLRP3 activation. When rapamycin was combined with the STAT1 inhibitor fludarabine, NLRP3 inflammasome activity was restored. Taken together, these findings suggest a role for mTOR in NLRP3 regulation and identify a potential therapeutic option for controlling inflammasome activation.</p>\u0000 </div>","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 6","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144264593","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}
Christian Niehaus, Daniel Geanon, Ayesha Lietzau, Marija Jankovic, Christopher Maucourant, Benjamin Maasoumy, Ernesto Sparrelid, Heiner Wedemeyer, Julia Kahlhöfer, Christine S. Falk, Itzel Medina Andrade, Andrea Ponzetta, Niklas K. Björkström, Anke R.M. Kraft, Markus Cornberg, Benedikt Strunz
{"title":"Origin of Hypofunctional CD103+ NK Cells in Cirrhosis-Associated Ascites","authors":"Christian Niehaus, Daniel Geanon, Ayesha Lietzau, Marija Jankovic, Christopher Maucourant, Benjamin Maasoumy, Ernesto Sparrelid, Heiner Wedemeyer, Julia Kahlhöfer, Christine S. Falk, Itzel Medina Andrade, Andrea Ponzetta, Niklas K. Björkström, Anke R.M. Kraft, Markus Cornberg, Benedikt Strunz","doi":"10.1002/eji.202451311","DOIUrl":"https://doi.org/10.1002/eji.202451311","url":null,"abstract":"<p>The occurrence of ascites is a frequent complication associated with the decompensation of liver cirrhosis. While it is known that cirrhosis leads to altered immune responses in the periphery, the immunological milieu of ascites remains poorly understood. In this study, we investigate the role and origin of natural killer (NK) cells in cirrhosis-associated ascites. Using high-dimensional flow cytometry and cytokine analysis, we analyzed matched peripheral blood and ascites fluid alongside liver and duodenum samples to discern tissue-specific differences. Interestingly, a subset of peritoneal NK cells displayed high expression of the tissue-residency receptor CD103. This subset of CD103<sup>+</sup> ascites NK cells was distinct from blood, liver, and intestinal NK cells and presented with a less activated phenotype coupled with reduced effector capacity. Investigating their origin, we could identify that cytokines present in ascites, here predominantly IL-15 in synergy with IL-21 and TGFβ, can induce CD103 expression and that ascites supernatant further facilitates this process. These results indicate that the ascites in patients with decompensated liver cirrhosis harbor a heterogenous subset of CD103<sup>+</sup> NK cells that is likely induced by the cytokine milieu.</p>","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 6","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.202451311","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144264587","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}
Jelle Folkerts, Marjolein J. W. de Bruijn, Wilfred F. J. van IJcken, Rudi W. Hendriks, Ralph Stadhouders
{"title":"Butyrate Selectively Targets Super-Enhancers and Transcriptional Networks Associated with Human Mast Cell Function","authors":"Jelle Folkerts, Marjolein J. W. de Bruijn, Wilfred F. J. van IJcken, Rudi W. Hendriks, Ralph Stadhouders","doi":"10.1002/eji.202451680","DOIUrl":"https://doi.org/10.1002/eji.202451680","url":null,"abstract":"<p>Mast cells are key drivers of allergic inflammation. We have previously shown that butyrate, a short-chain fatty acid derived from dietary fibers, inhibits human mast cell activation and degranulation. Here, we characterized the mechanisms underlying butyrate-mediated control of mast cell activity. To this end, we assessed the genome-wide impact of butyrate, a histone deacetylase (HDAC) inhibitor, on the epigenomic control of mast cell gene expression by integrating transcriptome and histone acetylation (H3K27Ac) profiles obtained from butyrate-treated primary human mast cells. Butyrate affected a selective set of genes and gene regulatory elements in mast cells. Most prominent was the hypoacetylation of promoter regions of highly expressed genes and super-enhancers controlling key mast cell identity genes. Perturbation of super-enhancer activity via pharmacological bromodomain inhibition suppressed degranulation of primary human mast cells, evoking repression of key mast cell identity genes that resembled the inhibitory effects of butyrate. Our data indicate that butyrate inhibits human mast cell activity via surprisingly selective targeting of super-enhancers to regulate the core mast cell transcriptional program.</p>","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 6","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.202451680","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144264597","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. 6'25","authors":"","doi":"10.1002/eji.202570061","DOIUrl":"https://doi.org/10.1002/eji.202570061","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 6","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.202570061","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144244778","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":"1st Symposium of HIS-YI: Emerging Challenges in Immunology: The contribution of Young Immunologists, November 21, 2024, Larissa, Greece","authors":"","doi":"10.1002/eji.202570200","DOIUrl":"https://doi.org/10.1002/eji.202570200","url":null,"abstract":"","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 S1","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144190984","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":"Inhibition of Melanoma Growth by Ex Vivo Expanded Tumor-Specific CD8+ T Cells Is Dependent on the Configuration of Nanoscale Artificial APCs","authors":"Antara Mondal, Faisal Jamal, Arpita Das, Arnab Kumar Sahoo, Khushboo Chaudhary, Sarmili Chowdhury, Aakriti Jha, Santiswarup Singha","doi":"10.1002/eji.202451676","DOIUrl":"https://doi.org/10.1002/eji.202451676","url":null,"abstract":"<div>\u0000 \u0000 <p>Adoptive T-cell therapy is an emerging immunotherapeutic strategy for treating cancer, but the compromised quality of CD8+ T-cells limits the therapeutic efficacy. Traditional methods involving polyclonal expansion of CD8+ T-cells mainly prioritize yielding a high quantity of CD8+ T-cells. However, the antigen-specificity of ex vivo expanded CD8+ T-cells and the ability to produce cytolytic molecules are the two critical determinants of therapeutic efficacy that remain poorly studied. To address this problem, we formulated nanoscale artificial antigen-presenting cells (a-APCs) displaying tumor-specific class-I peptide-major histocompatibility complexes (p-MHC-I) and co-stimulatory molecules to expand the antigen-specific CD8+ T-cells ex vivo. We found that the magnitude of ex vivo expanded T-cells was directly proportional to the valency of p-MHC coated on the a-APCs. Promisingly, a-APC with higher valency of p-MHC yielded CD8+ T-cells capable of producing a greater extent of cytolytic molecules such as granzyme B and perforin, exhibited excellent therapeutic efficacy by inhibiting the growth of aggressive murine melanoma than the CD8+ T-cells expanded by lower valency a-APCs. Our findings emphasize that the valency of p-MHC is a critical parameter for configuring nanoscale a-APCs, which governs ex vivo manufacturing of therapeutically potent antigen-specific CD8+ T-cells capable of inhibiting the growth of solid tumors.</p>\u0000 </div>","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 5","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144171745","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":"Advances in Regulatory Cell Therapy for Type 1 Diabetes: Emerging Strategies and Future Directions","authors":"Laura Passerini, Aurora Forlani, Silvia Gregori","doi":"10.1002/eji.202451722","DOIUrl":"https://doi.org/10.1002/eji.202451722","url":null,"abstract":"<p>Type 1 diabetes (T1D) is an autoimmune disorder characterized by the destruction of insulin-producing β-cells in the pancreas. Despite advances in insulin therapy and β-cell replacement, a definitive cure addressing the underlying cause of the disease, that is the loss of immune tolerance to β-cells remains elusive. Emerging strategies to reshape the immune response to pancreatic autoantigens include the adoptive transfer of ex vivo cultured regulatory cells, either mesenchymal stem cells (MSCs), regulatory T cells (Tregs), or dendritic cells (DCs), collectively known as regulatory cell therapy. This review aims to provide an overview of the regulatory cell-based approaches for T1D currently under development. Although several clinical trials have demonstrated the safety of in vivo administration of regulatory cells to T1D patients, only mild signs of efficacy have been reported. The most promising results were observed in patients with shorter disease duration and higher residual β-cell mass, suggesting that early interventions may result in clinical benefit. Significant challenges remain, including the long-term efficacy and stability of the infused products. In the future, approaches combining regulatory cell-based therapies with immunomodulatory agents or strategies to restore the damaged insulin-producing cells may hold the key to achieving a functional cure for T1D.</p>","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 5","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.202451722","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144148566","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}
Mohamad Basem Alkassab, Fareeha Ajmal Shaikh, Caroline Hamm, Mir Munir A. Rahim
{"title":"Adaptive NKG2C+ NK cells in cytomegalovirus seropositive individuals predominantly lack NKR-P1A receptor expression","authors":"Mohamad Basem Alkassab, Fareeha Ajmal Shaikh, Caroline Hamm, Mir Munir A. Rahim","doi":"10.1002/eji.202451562","DOIUrl":"https://doi.org/10.1002/eji.202451562","url":null,"abstract":"<p>The impact of cytomegalovirus (CMV) infection in shaping natural killer (NK) cell receptor (NKR) repertoire highlights the importance of NKRs in immunity against CMV. NKR-P1A (CD161) is an inhibitory NKR, whose expression is lost during CMV infection, but its role in NK cell responses during CMV infection is not known. Here, we show selective expansion of adaptive NKG2C<sup>+</sup> NK cells lacking NKR-P1A receptor (NKR-P1A<sup>‒</sup>) due to their increased activation and proliferation compared with NKR-P1A<sup>+</sup> NK cells in CMV-infected individuals. <i>In vitro</i> stimulation of PBMCs showed similar inherent proliferative capacity in both NKR-P1A<sup>+</sup> versus NKR-P1A<sup>‒</sup> NK cells in steady state and upregulation, but not loss of NKR-P1A receptor expression, in sorted NK cells. Furthermore, CMV infection induced differential gene expression profiles in NKR-P1A<sup>+</sup> versus NKR-P1A<sup>‒</sup> NK cells, and only NKR-P1A<sup>‒</sup> NK cells exhibited transcriptome signatures associated with adaptive NK cells in CMV-infected individuals. This study further highlights the impact of CMV infection in shaping NK cell receptor repertoire and exclusion of NK cells that express the NKR-P1A receptor from the adaptive NKG2C<sup>+</sup> NK cell population that expands during CMV infection.</p>","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 5","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.202451562","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144148567","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}