European Journal of Immunology最新文献

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.

Chronic antigen exposure drives CD4⁺ T cell senescence, yet how autoimmunity and persistent viral infections differentially shape T cell differentiation and function remains unclear. Using cytomegalovirus (CMV) and rheumatoid arthritis (RA) as models of chronic immune activation, we performed high-dimensional mass cytometry and functional assays to define their impact on CD4⁺ T cells. In CMV-seropositive individuals, CD27⁻CD28⁻ CD4⁺ T cells were abundant and exhibited a predominantly cytotoxic, nonproliferative phenotype. Only a minor fraction was CMV-reactive, suggesting that bystander-driven differentiation contributes to this subset. In the absence of CMV, senescent CD4⁺ T cells were infrequent and phenotypically distinct, though they still exhibited low proliferative capacity. EBV and HSV did not independently increase CD27⁻CD28⁻ CD4⁺ T cell frequency. Similarly, RA had little effect on their abundance but instead tuned the functional quality of senescent cells. In CMV-seropositive RA patients, senescent CD4⁺ T cells produced less pro-inflammatory cytokines and showed impaired cytotoxic degranulation. Central memory CD4⁺ and CD27⁻CD28⁻ CD8⁺ T cell functions were preserved, with no evidence for CMV reactivation, suggesting maintained viral control by unaffected T cell responses. These findings highlight distinct, nonredundant effects of CMV and RA on CD4⁺ T cell senescence and reveal RA-specific functional defects in senescent CD4⁺ T cells.

The metabolic programs of immune cells influence their activation, differentiation, and effector functions. While much of immunometabolism has focused on cell-intrinsic regulation, it is now clear that metabolic activity is profoundly influenced by the surrounding tissue environment. In tumors and other inflammatory settings, immune cells are shaped by nutrient gradients, hypoxia, and immunoregulatory metabolites, factors that are spatially heterogeneous and often poorly captured by traditional methods. This review highlights recent technological advances that enable spatially resolved analysis of immune metabolism, with an emphasis on multimodal integration and cancer as a model system. Mass spectrometry imaging (MALDI, DESI), high-resolution platforms like SIMS, and vibrational imaging approaches such as Raman microscopy enable direct visualization of metabolites in tissue. Transcriptomic and proteomic data can be used to infer metabolic states, and computational models are being developed to integrate these diverse data layers. Together, these technologies are transforming the study of immunometabolism from dissociated cells to the intact tissue context. Key challenges remain in resolution, annotation, and data integration, but spatial immunometabolism holds particular promise for illuminating mechanisms of immune regulation in health and disease.

CD8⁺ T cells target infected or malignant cells via the production of pro-inflammatory cytokines and direct target cell killing. Members of the ZFP36-family of RNA-binding proteins, ZFP36 and ZFP36L1, regulate these functions in T cells via the regulation of mRNA stability and protein translation. We investigate the regulation of ZFP36 and ZFP36L1 expression using in vitro differentiated OT1 TCR transgenic memory-like T cells. We characterise the differential kinetics and sensitivity of ZFP36 and ZFP36L1 to antigen affinity and PMA versus ionomycin stimulation. By selectively inhibiting TCR-induced signalling pathways, we find that p38 MAPK, MEK1/2, and PKC contribute to inducing both ZFP36 and ZFP36L1 expression. By contrast, inhibition of calcineurin using cyclosporin A potently inhibits ZFP36L1 expression while increasing and prolonging ZFP36 expression. The Zfp36 promoter contains many binding sites for the transcription factors ELK-1/4 and few binding sites for NFAT, while the Zfp36l1 promoter contains many NFAT binding sites and few ELK1/4 binding sites. Our findings suggest that the regulation of divergent transcription factors enables calcineurin to act as a signalling node that mediates the differential regulation of ZFP36 and ZFP36L1 during T cell activation.

Prostaglandin E2 (PGE2) is one important immunosuppressive factor within the tumor microenvironment (TME). Signaling through E-prostanoid receptor type 2 (EP2) and EP4, PGE2 promotes suppressive immune cell phenotypes and impairs antitumor immunity. Blocking PGE2 signaling with EP2 and EP4 antagonists is explored to counteract tumor-induced immunosuppression. While tumor-derived PGE2 is known to modulate human myeloid cell subsets, its specific effects on macrophages remain poorly defined. While murine models show PGE2 induces a protumorigenic macrophage phenotype, the role of PGE2-EP2/4 signaling on human macrophages is unclear. This study evaluates the impact of PGE2 on human macrophage phenotype and function, and the effectiveness of targeting EP2 and EP4 with soluble and nanoparticle-encapsulated antagonists. We show that PGE2 exposure during differentiation of monocytes to macrophages induces a distinct phenotype and affects macrophage functions. Tumor-derived PGE2 predominantly signals through EP2; however, dual blockade of EP2 and EP4 more effectively counteracts PGE2-induced changes. Notably, encapsulation of EP2/4 antagonists enhances the blockade of tumor-derived PGE2 signaling on the macrophage phenotype and their ability to modulate T cell proliferation within patient-derived tumor organoids. These findings underscore the influence of tumor-derived PGE2 on human macrophages and support targeting the PGE2-EP2/4 axis in cancer treatment.

Autoimmunity can be initiated by autoreactive T cells that escaped central and peripheral tolerance induction. Peripheral tolerance in lymph nodes (LNs) is maintained by fibroblastic reticular cells (FRCs) via self-antigen presentation in major histocompatibility complex (MHC) class II. FRCs can be divided into various subsets, with specific markers, functions, and locations. FRCs located in the T-cell zone (TRCs) can express genes for antigen presentation in MHC class-II, for example, H2-Ab1 and Cd74, as well as the immune inhibitory ligand Cd200. However, whether this can be linked to MHC class-II protein expression and thus tolerance is unknown. By combining scRNAseq on murine FRCs with protein staining for extracellular MHC class-II, we confirm that murine TRCs have the highest MHC class-II transcript levels, while protein levels are elevated in multiple FRC subsets. Gene expression for MHC class-II, as well as Bst1 and Cd200, gradually increases along the pseudotime trajectory, with TRCs representing the end, indicating maturation. Finally, we validated in fresh LN cell suspensions that MHC class-II protein expression is associated with murine BST1⁺ FRCs, independent of CD200, and with human BST1⁺CD200⁺ TRCs. This mature FRC subset, equipped to maintain peripheral tolerance, could be an interesting target for therapies against autoimmune diseases.

Recent studies add to our understanding of T cell residency in the human bone marrow (BM). In the May 2025 issue of EJI, Schneider Revueltas et al. demonstrate that CD69⁻ CD4⁺ and CD8+ memory T cells, presumed to be recirculating, have a distinct transcriptional cluster profile and a distinct TCR repertoire from their blood counterparts. These findings are in line with CD69⁻ memory T cells taking up residence in the BM, similar to their CD69⁺ counterparts. In parallel, Pulvirenti et al. identify a subset of CD69⁺EOMES⁺GzmK⁺ Tr1-like cells in the BM maintained by IL-15. Together, these studies refine our understanding of the BM as a heterogeneous immune niche and suggest a broader definition of resident cells within this tissue.

Zinc finger E-box binding protein 2 (ZEB2) is a key factor in the differentiation of naïve CD8⁺ T cells into effector and memory T cells. However, the precise regulatory role of ZEB2 in cytotoxic CD8⁺ T cells remains unknown. Our recent DNA methylation analysis of cytomegalovirus (CMV)-specific human CD8⁺ T cells revealed two differentially methylated regions (DMRs) within the ZEB2 locus. In the present study, we show that these ZEB2 DMRs undergo pronounced demethylation during T cell differentiation. In particular, terminally differentiated CD8⁺ T cells and cytotoxic CD4⁺ T cells show an almost complete demethylation. Demethylation of the ZEB2 DMRs correlates strongly with ZEB2 expression in all T cell subsets. Furthermore, DNA methylation patterns remain stable during long-term in vitro culture. ZEB2 knockout in CD8⁺ effector T cells results in altered gene expression profiles, affecting genes related to cell–cell adhesion and impairing the cytotoxic capacity in CMV-specific killing assays. Our data show that ZEB2 expression contributes to the differentiation of naïve CD8⁺ T cells into effector and memory T cells and regulates the functional properties of virus-specific cytotoxic CD8⁺ T cells.

“Chen Q, Zheng J, Wang D, Liu Q, Kang L, Gao X, Lin Z. Nitrosonisoldipine is a selective inhibitor of inflammatory caspases and protects against pyroptosis and related septic shock. Eur J Immunol. 2021; 51(5):1234-1245.”

In Figure 4B of this article, the upper photo of “+10 µM nigericin” is wrongly labeled; it should be “+ 5 mM ATP”, which is consistent with the figure legends and description in the main text. We also found that an image of “−” negative control group and an image of “+ 5 mM ATP” positive control group were incorrectly used. In addition, we moved the upper group of images to the lower panel in the corrected figure to match the statistical results. It does not affect our results. The correct figure and figure legend are as follows:

We apologize for this error.