European Journal of Immunology最新文献

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 in vitro. fEVs were purified from preserved stool samples, characterized, and their uptake by immune cells was analyzed. Using an in vitro 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 in vitro 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.

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 ex vivo 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⁺/CD8⁺ 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⁺ 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.

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.

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 European Journal of Immunology (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.

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.

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_IA) 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_IA 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_IA fashion, adoptive transfer of in vitro-induced T_IA cells in mice yielded a TCR-independent IFN-γ response during the innate phase of a Legionella pneumophila infection. Our data thus shows that CD4 T_IA cells are more ubiquitous than anticipated and could therefore be involved in more settings than expected.

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.

IL-1 family members and their signaling receptors are key drivers of inflammation in sterile or infectious conditions, as well as polarization of the innate and adaptive immunity. Deregulated or excessive activation of the IL-1 system is associated with detrimental inflammatory reactions. Beside signaling receptors, IL-1-family receptors comprise decoy or negative regulatory receptors, which regulate cell activation mediated by IL-1 family ligands. IL-1-family negative regulatory receptors, which include IL-1R8 and IL-1R2, have peculiar structural features and functions essential to the self-regulation of the IL-1 system. IL-1R8 and IL-1R2 emerge as regulatory molecules whose function is context-dependent, spanning from negative regulation of inflammation in infections or conditions of sterile inflammation and cell damage, including cancer-related inflammation, to skewing of myeloid and lymphoid cells, modulation of anti-tumor immunity, and immune checkpoint activity. This review reports new insights into the physio-pathological roles of these two negative regulatory IL-1 family members, emphasizing their mechanisms of action and potential for innovative therapeutic interventions.

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.

Dysbiosis of the vaginal microbiome is associated with increased inflammation in the female genital tract. Microbiota associated with bacterial vaginosis (BV), such as Gardnerella vaginalis, Megasphaera elsdenii, and Prevotella timonensis, replace the health-associated bacterium Lactobacillus crispatus and cause inflammation affecting mucosal integrity and immunity. However, it remains unclear how these BV-associated bacteria modulate immune cells and enhance inflammation. Here, we investigated whether BV-associated bacteria directly affected dendritic cell (DC) function. Notably, P. timonensis but not M. elsdenii induced cell–cell clustering between monocytic cell lines and, importantly, between primary DCs and primary CD4 T cells. Our data indicate that this increased clustering is independent of LFA-1. Moreover, P. timonensis enhanced DC-mediated CD4 T cell proliferation. Altogether, these results suggest that P. timonensis-induced cell–cell clustering contributes to the elevated mucosal inflammation observed during bacterial vaginosis.