William Mouton, Sophia Djebali, Marine Villard, Omran Allatif, Cécile Chauvel, Sarah Benezech, Philippe Vanhems, Jacqueline Marvel, Thierry Walzer, Sophie Trouillet-Assant
{"title":"Immunological and Clinical Markers of Post-acute Sequelae of COVID-19: Insights from Mild and Severe Cases 6 Months Post-infection","authors":"William Mouton, Sophia Djebali, Marine Villard, Omran Allatif, Cécile Chauvel, Sarah Benezech, Philippe Vanhems, Jacqueline Marvel, Thierry Walzer, Sophie Trouillet-Assant","doi":"10.1002/eji.202551948","DOIUrl":"https://doi.org/10.1002/eji.202551948","url":null,"abstract":"<p>Post-acute sequelae of COVID-19 (PASC) are a complex clinical condition that requires a better understanding of its underlying biological mechanisms. In this study, we assessed hundreds of virological, serological, immunological, and tissue damage biomarkers in two cohorts of patients who had experienced either mild (<i>n</i> = 270) or severe (<i>n</i> = 188) COVID-19, 6 to 9 months post-initial infection, and in which 40% and 57.4% of patients, respectively, developed PASC. Blood analysis showed that the main differences observed in humoral, viral, and biological biomarkers were associated with the initial COVID-19 severity, rather than being specifically linked to PASC. However, patients with PASC displayed altered CD4<sup>+</sup> and CD8<sup>+</sup> memory T cell subsets, with higher cytokine-secreting cells and increased terminally differentiated CD45RA<sup>+</sup> effector memory T cells (TEMRA). Elevated SARS-CoV-2-specific T cells responsive to nucleocapsid/membrane proteins with a TEMRA phenotype were also observed. A random forest model identified these features and initial symptom duration as top variables discriminating PASC, achieving over 80% classification accuracy.</p>","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 7","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.202551948","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144582279","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":"Correction to “cIAP-2 and Survivin Contribute to Cytokine-Mediated Delayed Eosinophil Apoptosis”","authors":"","doi":"10.1002/eji.202570063","DOIUrl":"https://doi.org/10.1002/eji.202570063","url":null,"abstract":"<p>E. M. Vassina, S. Yousefi, D. Simon, C. Zwicky, S. Conus, and H.-U. Simon, “CIAP-2 and Survivin Contribute to Cytokine-Mediated Delayed Eosinophil Apoptosis,” <i>European Journal of Immunology</i> 36, no. 7 (2006): 1975–1984, https://doi.org/10.1002/eji.200635943.</p><p>Concerns were raised by a third party regarding duplicated image panels within Figure 2A, between the cIAP-1 and cIAP-2 normal neutrophil subpanels. The authors acknowledged the image compilation error, and as the original raw data were no longer available, they repeated the experiment. The new data confirmed that the corresponding experimental results and the overall conclusions of the paper remain unaffected. The corrected panels of Figure 2A, the full-length immunoblots, and the updated methods are below. The authors apologize for this mistake.</p><p><b>Corrected image panels of Figure</b> 2A</p><p>Lack of expression of cIAP-1 and cIAP-2 in freshly purified normal human neutrophils compared to THP-1 and HL-60 cell lines. Immunoblot analysis was performed to assess protein expression. No detectable levels of cIAP-1 or cIAP-2 were observed in normal blood neutrophils. Lysates from THP-1 and HL-60 cells served as controls. Membranes were re-probed with anti-GAPDH monoclonal antibody to confirm equal protein loading.</p><p><b>Full-length immunoblots of the repeated experiments</b></p><p>Full-length immunoblots are shown for cIAP-1, cIAP-2, and GAPDH protein expression. Each lane was loaded with 50 µg of total cell lysate derived from either human blood neutrophils or the control cell lines THP-1 and HL-60. GAPDH served as a loading control.</p><p>Peripheral blood neutrophils from control individuals were purified as described [<span>1</span>] and were >98% pure. For control experiments, the human promyelocytic leukemia cell line HL-60 clone 15 and the human monocytic leukemia cell line THP-1 (both from ATCC, Manassas, VA, USA) were used.</p><p>Cell-free extracts and immunoblotting were performed as previously described [<span>2</span>]. Briefly, cell pellets were resuspended in lysis buffer (50 mM Tris-HCl [pH 7.4], 150 mM NaCl, 10% glycerol, 1% Triton X-100, 1% NP-40, 2 mM EDTA, 2.5 mM MgCl₂, 2.5 mM NaF, 10 mM sodium pyrophosphate, and 200 µM sodium orthovanadate), freshly supplemented with protease inhibitor cocktail (Sigma-Aldrich), 1 mM PMSF (Sigma-Aldrich), and 1 × PhosSTOP phosphatase inhibitor cocktail (Roche). Cells were collected, washed with PBS, and lysed on ice for 20 min. Lysates were clarified by high-speed centrifugation (13,000 rpm, 15 min, 4 °C). Protein concentrations were determined using the Pierce BCA protein assay kit (Thermo Fisher Scientific).</p><p>Equal amounts of protein (50 µg) were denatured and separated on 12% SERVAGel TG PRiME gels (SERVA Electrophoresis, Heidelberg, Germany), followed by transfer onto Immobilon-P PVDF membranes (Merck Millipore). Membranes were blocked with 5% nonfat dry milk in TBST (20 mM Tris-HCl, 150 mM NaCl, 0.1% Tween 20","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 7","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.202570063","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144582281","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}
Caitlín Ní Chasaide, Pauline Schmitt, Béré K. Diallo, Lisa Borkner, Charlotte M. Leane, Seyed Davoud Jazayeri, Sreeram Udayan, Eoin O'Neill, Lucy M. Curham, Barry Moran, Mieszko M. Wilk, Kingston H. G. Mills
{"title":"Acellular Pertussis Vaccines Induce CD8+ and CD4+ Regulatory T Cells That Suppress Protective Tissue-Resident Memory CD4+ T Cells, in Part via IL-10","authors":"Caitlín Ní Chasaide, Pauline Schmitt, Béré K. Diallo, Lisa Borkner, Charlotte M. Leane, Seyed Davoud Jazayeri, Sreeram Udayan, Eoin O'Neill, Lucy M. Curham, Barry Moran, Mieszko M. Wilk, Kingston H. G. Mills","doi":"10.1002/eji.202451630","DOIUrl":"https://doi.org/10.1002/eji.202451630","url":null,"abstract":"<p>Tissue-resident memory T (T<sub>RM</sub>) cells play a key role in sustained protective immunity against <i>Bordetella pertussis</i> infection of the nasal mucosa. Current alum-adjuvanted acellular pertussis (aP) vaccines protect against severe pertussis disease but fail to prevent nasal infection with <i>B. pertussis</i>. Here we demonstrate that immunization of mice with an aP vaccine failed to generate respiratory T<sub>RM</sub> cells, but did induce antigen-specific CD4<sup>+</sup> Treg cells that expressed Foxp3, CD49b, PD-1 and LAG-3, and CD8<sup>+</sup> Treg cells that expressed CD122, PD-1, and IL-10. <i>B. pertussis</i>-specific CD4<sup>+</sup> and CD8<sup>+</sup> T cell lines established from aP-immunized mice expressed the regulatory markers and suppressed activation of Th1 and Th17 cells. Blockade of IL-10 signaling during aP immunization or <i>B. pertussis</i> challenge promoted the induction of IL-17-secreting CD4<sup>+</sup> T<sub>RM</sub> responses and enhanced bacterial clearance from the nose. Addition of the adjuvant LP-GMP, comprising TLR2 and STING agonists, to the aP vaccine and delivery by the nasal route promoted the induction of antigen-specific IL-17-producing CD4<sup>+</sup> T<sub>RM</sub> cells and enhanced vaccine efficacy. Our findings demonstrate that aP vaccines suppress the induction of protective T<sub>RM</sub> cells in part through the induction of CD4<sup>+</sup> and CD8<sup>+</sup> Treg cells, which can be overcome using a potent adjuvant and delivery of the vaccine intranasally.</p>","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 7","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.202451630","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144582206","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}
Joseph Clarke, Jeremy Pike, David Bending, Dylan Owen, David C. Wraith, Alicia J. El Haj
{"title":"Remote Force Modulation of the T-Cell Receptor Reveals an NFAT-Threshold for CD4+ T-Cell Activation","authors":"Joseph Clarke, Jeremy Pike, David Bending, Dylan Owen, David C. Wraith, Alicia J. El Haj","doi":"10.1002/eji.202451716","DOIUrl":"https://doi.org/10.1002/eji.202451716","url":null,"abstract":"<p>Mechano-modulation of cell surface proteins to influence cell activation has been shown as a promising new advanced therapy for regenerative medicine applications. These strategies rely on the manipulation of mechanosensitive cell surface receptors to initiate intracellular signal transduction. The cell surface receptor of T lymphocytes (TCR), which recognises peptide-MHC molecules central to driving the adaptive immune response, has recently been suggested to be mechano-responsive. Despite this advance, little is known as to whether the TCR can be mechanically modulated to achieve TCR signalling and subsequent T-cell activation, and whether these characteristics can be exploited for immunotherapies. Here, we describe a magnetic particle-based platform for mechanical modulation of the TCR and outline how this platform can be utilised to achieve CD4<sup>+</sup> T-cell activation. We demonstrate that mechanical manipulation of the TCR induces cell surface clustering of the TCR and downstream TCR signalling, leading to eventual TCR downregulation and T-cell activation. We investigate the temporal relationship between mechanical modulation of the TCR and subsequent T-cell activation, thereby identifying that accumulation of signalling events within the NFAT pathway is required to reach the threshold required for CD4<sup>+</sup> T-cell activation, outlining an axis which controls the CD4<sup>+</sup> T-cell response to external mechanical cues. These findings identify how CD4<sup>+</sup> T cells can modulate their function in response to such cues while also outlining a remote-magnetic particle-based platform that may be used for the control of T-cell responses.</p>","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 6","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.202451716","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144473166","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":"γδ T Cells and Inborn Errors of Immunity","authors":"Sagar, Stephan Ehl","doi":"10.1002/eji.202451457","DOIUrl":"https://doi.org/10.1002/eji.202451457","url":null,"abstract":"<p>Gamma delta (γδ) T cells are pivotal in diverse immune responses, encompassing defense against infections, cancer surveillance, and tissue repair. Inborn errors of immunity (IEI) are rare genetic conditions disrupting human immune system development and function, with some impacting γδ T cells. In this review, we focus on IEI leading to a relative increase or decrease of γδ T cells compared to αβ T cells. We discuss how these disorders provide unique insights, in particular concerning the importance of signaling pathways for human αβ versus γδ T cell development, function, and homeostasis. Wherever suitable, we also include data from respective mouse models of IEIs that corroborate patient observations but also illustrate relevant species differences. This comparative approach identifies gaps in knowledge and defines areas for future research. Overall, this review underscores the relevance of IEIs in elucidating the development and function of human γδ T cells with potential implications for diagnosing and treating patients with immune disorders.</p>","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 6","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.202451457","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144473171","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}
Elizabeth Balint, Marie Joe Adaimy, Amelia Montemarano, Ana L. Portillo, Ali A. Ashkar
{"title":"Biological Sex Influences Human Bystander CD8+ T Cell Activation","authors":"Elizabeth Balint, Marie Joe Adaimy, Amelia Montemarano, Ana L. Portillo, Ali A. Ashkar","doi":"10.1002/eji.202451673","DOIUrl":"https://doi.org/10.1002/eji.202451673","url":null,"abstract":"<div>\u0000 \u0000 <p>The recent COVID-19 pandemic has highlighted a significant sex bias in disease outcome, where male sex is associated with greater disease severity and mortality. Interestingly, studies have also identified a role for antigen-independent “bystander-activated” CD8<sup>+</sup> T cells in the severity of COVID-19 and other viral infections. However, whether biological sex contributes to the magnitude of bystander T cell activation has not been investigated. To assess sex differences in bystander CD8<sup>+</sup> T cell activation, we isolated PBMCs from age-matched male and female donors and stimulated the cells with cytokines IL-12/15/18 to induce bystander T cell activation. Male CD8<sup>+</sup> T cells stimulated with IL-15 exhibited greater bystander activation, including increased NKG2D expression and greater antigen-independent cytotoxicity against tumor cells compared with female CD8<sup>+</sup> T cells. In contrast, IL-12/18 and IL-12/15/18 stimulation of CD8<sup>+</sup> T cells did not reveal evidence of sex differences in bystander IFN-γ production. Our data suggest that underlying sex differences in bystander CD8<sup>+</sup> T cell activation and cytotoxicity may contribute to the observed sex biases in disease severity of viral infections.</p>\u0000 </div>","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 6","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144367423","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}
Anna-Mari Schroderus, Andrea Hanel, Céline Vandamme, Viola Pitkänen, Marja Rytkönen-Nissinen, Merja Heinäniemi, Mikael Knip, Riitta Veijola, Jorma Toppari, Jorma Ilonen, Johanna Lempainen, Tuure Kinnunen
{"title":"The Frequency but not the Phenotype of Circulating Peripheral T Helper Cells is Increased at Later Stages of Progression to Type 1 Diabetes","authors":"Anna-Mari Schroderus, Andrea Hanel, Céline Vandamme, Viola Pitkänen, Marja Rytkönen-Nissinen, Merja Heinäniemi, Mikael Knip, Riitta Veijola, Jorma Toppari, Jorma Ilonen, Johanna Lempainen, Tuure Kinnunen","doi":"10.1002/eji.202451704","DOIUrl":"https://doi.org/10.1002/eji.202451704","url":null,"abstract":"<p>Circulating follicular (cTfh) and peripheral (cTph) T helper cells have been demonstrated to be expanded in several autoimmune diseases, including type 1 diabetes (T1D). Here, we examined the frequencies and phenotypes of these cells at different stages of T1D development and addressed their phenotypic and clonal relationships by analyzing samples from 27 children with newly diagnosed T1D, 29 autoantibody-positive (AAb<sup>+</sup>) children who later progressed to T1D and 57 healthy, age-matched controls. Higher frequencies of cTph cells were detected in children with T1D and AAb<sup>+</sup> children by flow cytometry, but no phenotypic alterations compared with cTph cells from healthy children were observed. Through a single-cell multiomics approach, we demonstrate that cTph cells appear phenotypically more heterogeneous compared with cTfh cells and that they exhibit phenotypic and clonal sharing with both cTfh as well as CXCR5<sup>−</sup>PD-1<sup>lo</sup> memory T cells. Finally, the frequencies of cTph or cTfh cells did not differ in 17 children analyzed during seroconversion for T1D-associated autoantibodies, the earliest detectable time point for autoimmunity. Collectively, our data demonstrate that cTph cells are a highly heterogeneous population partially sharing features with cTfh cells and that their frequency but not phenotype is altered at later stages of progression to clinical T1D.</p>","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 6","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.202451704","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144323445","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}
Roberta Turiello, Susanna S. Ng, Elisabeth Tan, Gemma van der Voort, Nazhifah Salim, Michelle C. R. Yong, Malika Khassenova, Johannes Oldenburg, Heiko Rühl, Jan Hasenauer, Laura Surace, Marieta Toma, Tobias Bald, Michael Hölzel, Dillon Corvino
{"title":"NKG7 is a Stable Marker of Cytotoxicity Across Immune Contexts and Within the Tumor Microenvironment","authors":"Roberta Turiello, Susanna S. Ng, Elisabeth Tan, Gemma van der Voort, Nazhifah Salim, Michelle C. R. Yong, Malika Khassenova, Johannes Oldenburg, Heiko Rühl, Jan Hasenauer, Laura Surace, Marieta Toma, Tobias Bald, Michael Hölzel, Dillon Corvino","doi":"10.1002/eji.202551885","DOIUrl":"https://doi.org/10.1002/eji.202551885","url":null,"abstract":"<p>Cytotoxicity is a cornerstone of immune defense, critical for combating tumors and infections. This process relies on the coordinated action of granzymes and pore-forming proteins, with granzyme B (GZMB) and perforin (<i>PRF1</i>) being key markers and the most widely studied molecules pertaining to cytotoxicity. However, other human granzymes and cytotoxic components remain underexplored, despite growing evidence of their distinct, context-dependent roles. Natural killer cell granule protein 7 (NKG7) has recently emerged as a crucial cytotoxicity regulator, yet its expression patterns and function are poorly understood. Using large publicly available single-cell RNA sequencing atlases, we performed a comprehensive profiling of cytotoxicity across immune subsets and tissues. Our analysis highlights NKG7 expression as a strong marker of cytotoxicity, exhibiting a strong correlation with overall cytotoxic activity (<i>r</i> = 0.97) and surpassing traditional markers such as granzyme B and perforin in reliability. Furthermore, NKG7 expression is notably consistent across diverse immune subsets and tissues, reinforcing its versatility and robustness as a cytotoxicity marker. These findings position NKG7 as an invaluable tool for evaluating immune responses and a reliable indicator of cytotoxic functionality across biological and clinical contexts.</p>","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 6","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.202551885","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144323415","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":"Narrowing Down Key Players in Autoimmunity via Single-Cell Multiomics","authors":"Altea Gjurgjaj, Cecilia Domínguez Conde","doi":"10.1002/eji.202451233","DOIUrl":"https://doi.org/10.1002/eji.202451233","url":null,"abstract":"<p>Autoimmune diseases encompass a range of conditions in which our own immune system reacts against molecules encoded by our own genome. This phenomenon is mediated by the action of antigen receptors expressed by T and B cells. Identifying the molecular events that trigger these responses as well as the effector cells that underlie them is at the heart of autoimmunity research. In this review, we discuss how single-cell multiomics techniques applied to healthy and patient tissues are shedding light on the mechanisms underpinning autoimmune conditions, specifically by identifying disease-associated cell states and cellular communication networks, including those linked to specific autoimmunity susceptibility genetic loci. Furthermore, we dive into the unprecedented resolution achieved in mapping autoreactive lymphocytes, a key component of autoimmune responses. We conclude with a perspective on key bottlenecks and promising future directions leveraging the latest advances in single-cell sequencing with orthogonal methods.</p>","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"55 6","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.202451233","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144314960","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}