European Journal of Immunology最新文献

Natural clearance of hepatitis C virus (HCV) infection occurs in about 25% of primary infections, but offers only partial protective immunity against re-infections. This study hypothesised that long-lived polyfunctional HCV-specific CD8+ memory stem T cells (T_SCM) contribute to protective immunity in rare super-clearer subjects who repeatedly clear viraemia. Six super-clearers and four clearer-chronic subjects who resolved a primary infection but subsequently developed chronic infection were studied at multiple timepoints. The T_SCM population (CCR7+CD45RA+CD95+) was bulk sorted, labelled with CellTrace Violet (CTV), and stimulated in vitro for five days with cognate HCV peptide, IL-2/IL-15, and autologous PBMCs. Functionality of the expanded HCV-specific T_SCM was assessed via the proliferation, multi-potency, and stemness indices. Total HCV-specific CD8+ T cells from super-clearers exhibited enhanced proliferative recall capability compared with clearer-chronics. Furthermore, super-clearers exhibited higher HCV-T_SCM frequencies post-expansion (22.35 ± 34.35 vs. 2.41 ± 9.83; p = 0.0066). Notably, HCV-T_SCM in clearer-chronics had ‘stemness’ indices of zero in samples before the re-infection (i.e., no ability to generate T_SCM as progeny), whereas super-clearers consistently retained this key functional property. These findings suggest that the maintenance of self-renewing HCV-specific T_SCM may underpin long-term protective immunity against re-infection and could inform vaccine design strategies targeting durable cellular memory.

Type 1 and type 2 diabetes are associated with increased severity and mortality from respiratory virus infections. Vaccination in the general population significantly reduces the risk of severe respiratory viral infection and triggers a strong, polyfunctional, and lasting T cell response in healthy individuals. However, vaccine effectiveness in people with type 1 diabetes is unclear. Here, we studied the magnitude and functional characteristics of vaccine-specific CD4⁺ and CD8⁺ T cell responses to vaccination in people with type 1 and type 2 diabetes and compared them to those of people living without diabetes, using the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine as a model. We found defects in both CD4⁺ and CD8⁺ T cell memory maintenance and the functionality of the vaccine-specific T cells in people with diabetes compared with people without. In those individuals with type 1 and type 2 diabetes who harbored detectable vaccine-specific T cells, they displayed an unfocused, tolerogenic phenotype characterized by increased expression of IL-10 and IL-13 compared with people without diabetes. These results have implications for vaccination strategies for people with diabetes.

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.