European Journal of Immunology最新文献

Lymphoid follicles in the human gut are critical immune hubs, yet their role in Crohn's disease pathogenesis remains poorly understood. Here, we apply multiplexed imaging mass cytometry to spatially profile Peyer's patches and lymphoid follicles in biopsies from healthy controls and Crohn's disease patients with ileitis, isolated colonic involvement, or in remission. Despite tissue heterogeneity, our optimized preprocessing pipeline enabled robust tissue annotation, single-cell phenotyping, and neighbourhood-level analysis. While conventional analysis based on cell frequencies did not distinguish disease states, spatial analysis revealed disease-associated remodelling of lymphoid architecture. Biopsies from colonic Crohn's disease patients showed, within follicles, increased frequencies of activated CD8⁺ T cells and a reduction in naïve T cells, alongside enrichment of B cell–T cell interaction neighbourhoods. These alterations were most pronounced in smaller B-cell patches, suggesting more functionally dynamic immune-cell interactions in compact lymphoid structures. In contrast, Crohn's disease ileitis samples closely resembled healthy tissue, with minimal structural or immune cell perturbations. Our data support a model in which Peyer's patches and lymphoid follicles undergo structural and functional remodelling in response to colonic inflammation. These findings underscore the value of spatially resolved immune profiling to uncover tissue-specific immune dynamics in inflammatory bowel disease.

The cover image is based on the article Activation of CD8⁺ T cells in the human ex vivo lung tumor microenvironment using anti-CD3/CD28 and Nivolumab by Tonia Bargmann et al., https://doi.org/10.1002/eji.70060

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.

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⁺ and TNFR2⁻ Treg subsets are, respectively, poor and strong TNF producers. The two subsets of TNFR2⁺ and TNFR2⁻ Tregs partially maintain their different ability to produce TNF when separately stimulated ex vivo. However, when cocultured, the TNFR2⁺ cells greatly outnumber the TNFR2⁻ counterpart and induce in TNFR2⁻ cells the upregulation of Foxp3 and TNFR2, in association with the transfer of cytoplasmic material. Functionally, TNFR2⁺ 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.

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⁺ or Vγ6⁺ 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⁺ and Vγ6⁺ 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⁺ 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.

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.