Kevin Schmid, Robin P Schenk, Gabriela M Wiedemann
{"title":"Low-Input Assay for Transposase-Accessible Chromatin Identifies Epigenetic Signatures of Liver Group 1 Innate Lymphoid Cells.","authors":"Kevin Schmid, Robin P Schenk, Gabriela M Wiedemann","doi":"10.1002/eji.70066","DOIUrl":"https://doi.org/10.1002/eji.70066","url":null,"abstract":"<p><p>Assessing chromatin accessibility in rare cell populations within tissue remains a key challenge. To address this, we present a low-input ATAC workflow optimized for liver ILCs. The protocol is validated across cell numbers, Tn5 ratios, and library preparation steps and unveils unique epigenetic features of liver NK cells and ILC1s.</p>","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 10","pages":"e70066"},"PeriodicalIF":3.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145211261","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":"TNF Production or TNFR2 Expression Characterize Distinct States of Regulatory T Cells that Cooperate in Treg Expansion in Cancer and Chronic Inflammation","authors":"Gloria Tucci, Ilenia Pacella, Alessandra Pinzon Grimaldos, Alessandra Rossi, Ilenia Cammarata, Marta Zagaglioni, Giovanna Peruzzi, Valentina Tirelli, Massimo Sanchez, Giuseppe Pietropaolo, Francesca Sozio, Annalisa Del Prete, Valerio Licursi, Vincenzo Barnaba, Silvia Piconese","doi":"10.1002/eji.70062","DOIUrl":"https://doi.org/10.1002/eji.70062","url":null,"abstract":"<p>TNF is a pleiotropic cytokine with immunomodulatory functions mediated by its interaction with the receptor TNFR2, highly expressed by Tregs. However, Tregs can also produce TNF, and an autocrine TNF-TNFR2 loop has been proposed. Here, we describe that both human and mouse Tregs produce TNF in physiological conditions, in several mouse organs, and in mouse models of chronic inflammation and cancer. However, TNF production and TNFR2 expression are differentially distributed: indeed, TNFR2<sup>+</sup> and TNFR2<sup>−</sup> Treg subsets are, respectively, poor and strong TNF producers. The two subsets of TNFR2<sup>+</sup> and TNFR2<sup>−</sup> Tregs partially maintain their different ability to produce TNF when separately stimulated ex vivo. However, when cocultured, the TNFR2<sup>+</sup> cells greatly outnumber the TNFR2<sup>−</sup> counterpart and induce in TNFR2<sup>−</sup> cells the upregulation of Foxp3 and TNFR2, in association with the transfer of cytoplasmic material. Functionally, TNFR2<sup>+</sup> Tregs display superior suppressive activity and survival in vitro, both related to an improved resistance to oxidative stress. Overall, our data indicate that Tregs exist in two states, respectively committed to TNF production or TNF sensing through TNFR2, which cooperate in promoting the suppressive function of the whole Treg pool.</p>","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 9","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.70062","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111107","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}
Ziqing Wang, Tao Yang, Federico Lupo, Lara-Marie Behrens, Anika Janssen, Seth B. Coffelt, Immo Prinz, Inga Sandrock, Sarina Ravens
{"title":"Partial Compensation of IL-17 Production by Vγ1 T Cells in the Absence of Vγ4 and Vγ6 T Cells","authors":"Ziqing Wang, Tao Yang, Federico Lupo, Lara-Marie Behrens, Anika Janssen, Seth B. Coffelt, Immo Prinz, Inga Sandrock, Sarina Ravens","doi":"10.1002/eji.70061","DOIUrl":"10.1002/eji.70061","url":null,"abstract":"<p>γδ T cells are unconventional T cells that group into different subsets based on the usage of variable γδ T cell receptor (TCR) gene segments, body location, and functionality. γδ T cells that secrete the proinflammatory cytokine interleukin 17 (IL-17) predominantly express a Vγ4<sup>+</sup> or Vγ6<sup>+</sup> γδ TCR. The biology and the importance of the γδ TCR of IL-17-producing γδ T cells are not well understood. Here, we investigated the IL-17 production capability of γδ T cells in mice deficient for Vγ4<sup>+</sup> and Vγ6<sup>+</sup> γδ TCRs using flow cytometry, TCR-seq, and single-cell transcriptomics. Our data show that Vγ1 T cells only partially compensate for the loss of IL-17<sup>+</sup> Vγ4 and Vγ6 T cell subsets in lymphoid and nonlymphoid tissues. They develop pre- and postnatally and were predominantly detectable in their physiological body habitats. Collectively, the data underscore the nonredundant roles of Vγ4⁺ and Vγ6⁺ subsets in IL-17-mediated immunity.</p>","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 9","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.70061","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145090782","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}
Stefanie Dietz-Ziegler, Samantha Kewitz, Gabriele Kaiser, Jessica Rühle, Alexander Marmé, Alexander Dalpke, Bachar Cheaib, Jan Pauluschke-Fröhlich, Melanie Henes, Ana Velic, Andreas Pich, Anneli Vollert, Martin Schaller, Felix Knab, Trim Lajqi, Christian F. Poets, Christian Gille, Natascha Köstlin-Gille
{"title":"Extracellular Vesicles Derived From the Feces of Pregnant Women Modulate T Cells Toward a Pregnancy-Supportive Phenotype In Vitro","authors":"Stefanie Dietz-Ziegler, Samantha Kewitz, Gabriele Kaiser, Jessica Rühle, Alexander Marmé, Alexander Dalpke, Bachar Cheaib, Jan Pauluschke-Fröhlich, Melanie Henes, Ana Velic, Andreas Pich, Anneli Vollert, Martin Schaller, Felix Knab, Trim Lajqi, Christian F. Poets, Christian Gille, Natascha Köstlin-Gille","doi":"10.1002/eji.70056","DOIUrl":"10.1002/eji.70056","url":null,"abstract":"<p>Pregnancy requires immune tolerance to a semi-allogeneic fetus, involving profound adaptations, particularly in the T helper (Th) cell response. The intestinal microbiome plays a crucial role in health, but its influence on immune adaptation to pregnancy remains unclear. Bacterial extracellular vesicles (BEVs), released by gut bacteria, can cross the intestinal barrier and modulate immune responses. In our study we investigated the effect of fecal EVs (fEVs) from pregnant women on Th cell composition <i>in vitro</i>. fEVs were purified from preserved stool samples, characterized, and their uptake by immune cells was analyzed. Using an <i>in vitro</i> T cell culture model, we examined Th cell phenotypes, intracellular cytokine expression, and proteomic changes after stimulation with fEVs from pregnant and non-pregnant women. We demonstrate that fEVs from preserved stool samples are rapidly taken up by T cells and modulate their phenotype. Stimulation with fEVs from pregnant women shifts Th cells toward a regulatory profile favorable for pregnancy, increasing Th2 cells while reducing Th17 cells compared to fEVs from non-pregnant controls. This study provides the first <i>in vitro</i> evidence that fecal-derived EVs influence immune adaptation to pregnancy and may offer a basis for microbiome-targeted strategies to prevent or treat immunological pregnancy complications.</p>","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 9","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.70056","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145084625","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}
Tonia Bargmann, Sebastian Konzok, Renato Liguori, Maximilian Fuchs, Charline Sommer, Dirk Schaudien, Charlotte Schob, Stephan Halle, Christopher Werlein, Patrick Zardo, Lavinia Neubert, Danny Jonigk, Hans-Gerd Fieguth, Fulvia Ferrazzi, Katherina Sewald, Susann Dehmel, Armin Braun
{"title":"Activation of CD8⁺ T Cells in the Human Ex Vivo Lung Tumor Microenvironment Using Anti-CD3/CD28 and Nivolumab","authors":"Tonia Bargmann, Sebastian Konzok, Renato Liguori, Maximilian Fuchs, Charline Sommer, Dirk Schaudien, Charlotte Schob, Stephan Halle, Christopher Werlein, Patrick Zardo, Lavinia Neubert, Danny Jonigk, Hans-Gerd Fieguth, Fulvia Ferrazzi, Katherina Sewald, Susann Dehmel, Armin Braun","doi":"10.1002/eji.70060","DOIUrl":"https://doi.org/10.1002/eji.70060","url":null,"abstract":"<p>Despite advancements in immunotherapies, the diversity of the tumor microenvironment remains a challenge for cancer treatment. To elucidate microenvironment-specific differences in antitumor responses, we established patient-derived <i>ex vivo</i> tumor-lung slices. We analyzed immune activation profiles after treatment with anti-CD3/CD28 and the checkpoint inhibitor Nivolumab. Lung slices from non-tumor, tumor-adjacent, tumor-border, and tumor-central tissue were generated and assessed for viability, cell composition, and immune competence via flow cytometry, soluble factor secretion, and bulk RNA-sequencing. The tumor-border contained the highest number of immune cells (8.3-fold vs. non-tumor), secreted tumor markers (S100 and CA15-3), and exhibited high levels of inflammatory mediators (IFNγ, IL-6, and IL-2). Treatment with anti-CD3/CD28 increased the frequency of CD137<sup>+</sup>/CD8<sup>+</sup> T cells and induced cytokine responses dominated by IFNγ, IL-2, and Granzyme B. While both non-tumor and tumor-border tissue responded to anti-CD3/CD28, the intensities of immune responses were highly varied. Notably, treatment with Nivolumab induced an inflammatory response primarily in the tumor-border evidenced by IFNγ, IL-2, and Perforin secretion alongside increased expression of CD107a on CD8<sup>+</sup> T cells, in a donor-dependent manner. Taken together, these data demonstrate how tumor-border tissue slices can be utilized to study T cell responses in the context of the patient-specific tumor microenvironment.</p>","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 9","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.70060","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058005","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}
Antonia Geisse, Tao Zhang, Jonathan Schreiber, Kristina Markova, Sophie Burkhalter, Hedda Wardemann, Andrew J. Macpherson, Tim Rollenske
{"title":"Efficient Expression and Purification of Recombinant Mouse Dimeric IgA","authors":"Antonia Geisse, Tao Zhang, Jonathan Schreiber, Kristina Markova, Sophie Burkhalter, Hedda Wardemann, Andrew J. Macpherson, Tim Rollenske","doi":"10.1002/eji.70055","DOIUrl":"https://doi.org/10.1002/eji.70055","url":null,"abstract":"<p>Immunoglobulin (Ig) A is the main antibody isotype found on mucosal surfaces in mammals, where it is predominantly present as a dimer. Here we provide an easy, scalable, efficient, and broadly applicable method to produce and purify monoclonal mouse dimeric IgA from single B cell Ig transcripts to study mucosal antibody responses at single-cell level.\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 9","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.70055","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058003","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":"What We Know and What We Don't Know About the Function of γδ T Cells","authors":"Immo Prinz, Anja Meyer","doi":"10.1002/eji.70058","DOIUrl":"https://doi.org/10.1002/eji.70058","url":null,"abstract":"<p>γδ T cells, long regarded as unconventional relatives of αβ T cells, have emerged as pivotal players in immunity, with unique biology and therapeutic promise. Recent advances in single-cell multiomics, refined mouse models, and human cohort studies have deepened insights into their TCR–ligand interactions, developmental pathways, and context-dependent functions. This mini-review synthesizes current understanding from structural studies of γδ TCR recognition and developmental regulation—including inborn errors of immunity—to adaptive-like clonal expansions shaped by infection, aging, and environmental cues. It also highlights their dual roles in cancer, where subsets can exert potent cytotoxicity or promote tumor progression, and discusses strategies to optimize their antitumor potential through checkpoint blockade, metabolic modulation, and engineered receptors. Beyond immunity to malignancy, γδ T cells contribute to tissue homeostasis, repair, and regulation of inflammatory processes in diverse organs, influencing outcomes in neuroinflammation, autoimmunity, and fibrotic diseases. Together, these perspectives form the foundation of a special issue in the <i>European Journal of Immunology</i> (https://onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1521-4141.T-cells) dedicated to advancing the understanding of γδ T cell biology and clinical potential.</p>","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 9","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.70058","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058004","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}
Shumei Cao, Jiao Jiang, Haoyuan Yin, Xiaoyu Su, Qilin Li, Junhui Wu, Wenrui Li, Lai Wang, Qianjin Lu
{"title":"Aberrant Nutrient Metabolism in T Cells: Pathogenesis Insight and Therapeutic Target for Autoimmune Diseases","authors":"Shumei Cao, Jiao Jiang, Haoyuan Yin, Xiaoyu Su, Qilin Li, Junhui Wu, Wenrui Li, Lai Wang, Qianjin Lu","doi":"10.1002/eji.70059","DOIUrl":"https://doi.org/10.1002/eji.70059","url":null,"abstract":"<p>Abnormal T-cell activation and differentiation are pivotal in the pathogenesis of autoimmune disorders. Traditionally, T cell activation is orchestrated by three canonical signals: antigen recognition through the T-cell receptor (TCR) and major histocompatibility complex (MHC) interaction, co-stimulatory signals, and cytokine signaling. Recent studies have highlighted nutrients as a key fourth signal in modulating T cell immunity. T cell metabolism is integral to regulating cell proliferation, survival, and differentiation. Dysregulation of nutrient metabolism, including glucose, amino acids, and lipids, has been considered a crucial determinant of T cell activation, differentiation, and function, and may lead to the disease progression of autoimmune disorders, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS). This review aims to elucidate the impact of T cell metabolic reprogramming on autoimmune disease development and explore potential therapeutic approaches targeting nutrient metabolism for treating autoimmune disorders.</p>","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 9","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.70059","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145038208","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}
Nima Yassini, Eva Goljat, Camilla Panetti, Matthias Rath, Nicole Joller
{"title":"CD4 T Cells Acquire Innate Capability Upon Classical T Cell Activation","authors":"Nima Yassini, Eva Goljat, Camilla Panetti, Matthias Rath, Nicole Joller","doi":"10.1002/eji.70054","DOIUrl":"https://doi.org/10.1002/eji.70054","url":null,"abstract":"<p>Memory T cells, a sizable compartment of the mature immune system, enable enhanced responses upon re-infection with the same pathogen. We have recently shown that virus-experienced innate acting T (T<sub>IA</sub>) cells can modulate infectious or autoimmune diseases through TCR-independent IFN-γ production. However, how these cells arise remains unclear. Here, we show that CD4 T<sub>IA</sub> cells are present in various disease settings hinting towards a disease-agnostic nature. TCR stimulation and CD28 co-stimulation are sufficient to induce naïve murine and human CD4 T cells to become capable of cytokine-mediated, TCR-independent IFN-γ responses. In true T<sub>IA</sub> fashion, adoptive transfer of in vitro-induced T<sub>IA</sub> cells in mice yielded a TCR-independent IFN-γ response during the innate phase of a <i>Legionella pneumophila</i> infection. Our data thus shows that CD4 T<sub>IA</sub> cells are more ubiquitous than anticipated and could therefore be involved in more settings than expected.</p>","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 9","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.70054","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145012703","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}
Valentin Mandin, Amandine Dupuy, Adrien Tissot, Nicolas Degauque, Richard Danger, Hoa Le Mai, Sophie Brouard
{"title":"Extracellular Vesicles in Lung Transplantation: Biomarkers, Pathophysiological Players, and Therapeutic Weapons?","authors":"Valentin Mandin, Amandine Dupuy, Adrien Tissot, Nicolas Degauque, Richard Danger, Hoa Le Mai, Sophie Brouard","doi":"10.1002/eji.70042","DOIUrl":"https://doi.org/10.1002/eji.70042","url":null,"abstract":"<p>In the field of lung transplantation (LTx), the survival of lung transplant recipients (LTRs) is limited by events such as primary graft dysfunction (PGD), infections, and acute rejection (AR), which promote the development of chronic lung allograft dysfunction (CLAD). Extracellular vesicles (EVs), including exosomes and microvesicles, have emerged as key players in LTx because of their roles in immune regulation, inflammation, and antigen presentation. EVs carry immunologically active molecules such as MHC class I/II proteins, cytokines, and lung self-antigens (SAgs), suggesting their involvement in infections and both AR and CLAD. Recent studies indicate that EVs have diagnostic and prognostic potential. EVs expressing HLA-G and SAgs correlate with graft outcomes, while circulating EV-associated miRNAs are being evaluated as noninvasive biomarkers of rejection. In addition to their diagnostic potential, mesenchymal stem cell-derived EVs show promise in managing PGD by reducing inflammation, mitigating ischemia‒reperfusion injury, and enhancing lung repair. In conclusion, EVs contribute to pathogenesis, have potential as biomarkers, and hold promise as tools for improving LTx outcomes as therapeutic agents, yet further research is needed to validate their clinical application in the prediction and management of CLAD.</p>","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 9","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.70042","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145012363","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}