European Journal of Immunology最新文献

This study presents the discovery and first functional characterization of chicken lipid-reactive Natural Killer T (NKT)-like cells, resolving a long-standing knowledge gap in avian immunology. Using purified TCRVβ2⁺ lymphocytes, we demonstrate through rigorous experiments combining shRNA-mediated gene silencing, pharmacological pathway blockade, primary MACS-purified co-cultures, and intracellular cytokine flow cytometry that these cells are activated by CpG-ODN-stimulated antigen-presenting cells (APCs). Activation selectively depends on APC-driven glycosphingolipid (GSL) biosynthesis, with CpG-ODN significantly upregulating key biosynthetic enzymes (ST3GAL1 and ST3GAL5) in APCs. Silencing of enzymes involved in this pathway or chemical inhibition of GSL synthesis abrogated T cell activation. We identify GM3 as a potent, functional lipid ligand activating TCRVβ2⁺ lymphocytes. In parallel, IL-12 and IL-18 trigger IFN-γ production from TCRVβ2⁺ lymphocytes, crucially requiring live APC interactions. Upon activation of splenocytes with GM3, the cells expressed chIL-2, chIL-4, chIL-17, Granzyme A, and Perforin. By establishing functional, nonpeptide lipid-reactive T cells in chickens, these findings redefine the conceptual framework of avian innate-like T cell immunology. This discovery unlocks a highly translatable, universal target for lipid-adjuvanted poultry vaccines to enhance global animal health and food security.

Regulatory T cells (Tregs) are essential for immune tolerance, with cAMP metabolism central to their suppressive function. Inducible cAMP early repressor (ICER) is a negative regulator of cAMP signalling. However, its role in Treg biology is not fully understood. Here we generated Foxp3-specific ICER knockout mice to assess ICER's function in Tregs. We found that ICER deficiency does not impair Treg development or suppression of effector T cell proliferation under homeostatic conditions. However, ICER-deficient Tregs display enhanced Foxp3 stability, increased glycolysis and proliferation but exhibit impaired suppression of IFN-γ production by effector T cells. In a dextran sodium sulphate-induced colitis model, loss of ICER in Tregs led to aggravated intestinal inflammation and tissue damage, without, however, a marked effect on gross disease parameters. These results identify ICER as a context-dependent modulator of Treg metabolism and inflammatory cytokine control, highlighting its potential role in regulating immune responses during inflammation.

Juvenile idiopathic arthritis (JIA) is a common inflammatory rheumatic disease of childhood, yet the mechanisms driving immune activation in affected joints remain unclear. In this study, we analyzed synovial fluid (SF) immune cells from patients with JIA using two complementary methodologies, single-cell multiomics and flow cytometry. SF displayed a markedly altered immune landscape compared with blood. Both myeloid and plasmacytoid dendritic cells were enriched in SF, and SF monocytes exhibited signs of macrophage differentiation. B cells were strikingly rare in SF, and the few B cells present were predominantly CD21^lo age-associated B cells. In contrast, CD56^hiCD16⁻ NK cells and CD161⁻ γδ T cells were strongly enriched in SF. Among SF CD4⁺ T cells, regulatory T cells, T peripheral helper cells, and CD161⁺ T cells were most abundant, while CD8⁺ T cells exhibited a tissue-resident memory phenotype with a broad expression of different granzymes. Immune cell frequencies in SF correlated poorly with matched blood samples, and no clear association between SF immune cell composition and JIA subtype or selected clinical parameters was detected. This comprehensive characterization of the SF immune environment provides a foundation for future studies aimed at defining the roles of specific immune cell subsets in JIA pathogenesis.

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.

Autoimmune diseases represent a major and growing health burden, particularly among young adults. Emerging evidence suggests that changes in the environment and diet may contribute to disease. Experimental studies have demonstrated that excessive salt intake can modulate immune function by inducing pathogenic pro-inflammatory T helper 17 cells (Th17) and impairing anti-inflammatory regulatory T cell (Treg) function both in vitro and in vivo, thereby promoting autoimmunity. Serum/glucocorticoid-regulated kinase 1 (SGK1) has been identified as a central mediator of immune function in response to high salt. Additionally, alterations in immunometabolism and epigenetic modulations have been linked to immune dysfunction under high-sodium conditions. Understanding the complex interplay between inflammatory processes, immunometabolism, and epigenetic regulation is essential for deciphering how ionic disturbances may shape T cell immunity and disease. Despite strong evidence from animal models linking sodium intake and shifts in the ionic microenvironment to immunomodulation and disease, evidence from human studies remains limited, largely due to small cohort sizes and methodological constraints. This review provides a comprehensive overview of sodium-induced immune alterations and underscores the need for larger and more standardized clinical studies to further clarify the role of sodium and changes in the ionic microenvironment in autoimmunity.

The TAM receptor Axl is essential for efferocytosis and inflammatory regulation, but its role in macrophage immunometabolic homeostasis remains unclear. Here, we combined phenotypic, functional, metabolomic, and bioenergetic analyses to define how Axl deficiency alters peritoneal macrophages (PMs) under steady-state conditions. Axl^−/− PMs exhibited reduced cell numbers, downregulation of resident macrophage markers, and increased Ly6C expression, indicating a shift toward a less mature, monocyte-like phenotype. Functionally, these cells showed impaired inflammatory activation, with reduced nitrite release, diminished LPS-induced ROS production, and lower mitochondrial ROS. Metabolomic profiling revealed broad disruption of central carbon metabolism, including reduced glycolytic intermediates, depletion of tricarboxylic acid (TCA) cycle metabolites, and decreased NAD⁺/NADH and NADP⁺/NADPH pools. Despite reduced glycolytic flux, preserved pyruvate levels suggested compensatory carbon utilization. Bioenergetic assessment demonstrated pronounced mitochondrial dysfunction, characterized by reduced maximal respiration, elevated proton leak, and limited oxidative phosphorylation flexibility. Redox balance was also impaired, with decreased GSH, GSSG, and dehydroascorbic acid and increased ophthalmic acid, consistent with elevated oxidative stress. Systemically, Axl^−/− mice displayed hepatic redox imbalance and biochemical signs of liver dysfunction. Collectively, these findings identify Axl as a central regulator of macrophage identity, mitochondrial performance, and redox resilience, required for maintaining local and systemic homeostasis.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung-scarring disease in which epithelial injury, consequent release of alarmins such as interleukin (IL)-33, and immune activation contribute to extracellular matrix deposition. The intestinal helminth Heligmosomoides polygyrus bakeri (Hpb) secretes immunomodulators that suppress type 2 immunity, including HpARI2, which binds IL-33, and HpBARI_Hom2, which blocks the IL-33 receptor ST2. Here, we test this parasite-derived dual blockade strategy in the bleomycin (BLM) mouse model, moving from live Hpb infection to administration of total Hpb excretory/secretory products (HES), and finally administering recombinant HpARI2 and HpBARI_Hom2 proteins. Hpb infection and HES treatment prevented BLM-induced lung fibrosis when administered during the early inflammatory phase. Recombinant HpARI2+HpBARI_Hom2 reproduced this protection, reduced collagen deposition and hydroxyproline accumulation, and dampened ILC2, eosinophil, macrophage, and neutrophil responses. In contrast, HES or HpARI2+HpBARI_Hom2 administration failed to reverse established fibrosis when administered later in the model. Similarly, administration of the IL-33trap fusion protein could replicate these effects, suppressing fibrosis when administered in the early inflammatory, but not later fibrotic phases of this model. These findings identify parasite-derived inhibition of the IL-33 axis as a defined molecular mechanism by which helminth products can prevent early inflammatory fibrogenesis, while also demonstrating that IL-33 blockade is unlikely to reverse established lung scarring.

Neutralizing antibodies (NAbs) play a central role in antiviral protection and are increasingly considered for prophylactic or therapeutic use, particularly against viruses lacking effective antiviral treatments. While research has predominantly focused on NAbs targeting the envelope proteins of enveloped viruses, nonenveloped viruses remain major human pathogens for which broad antibody responses are less well characterized. Recent work has identified several cross- and broadly neutralizing antibodies generated during human infection with nonenveloped viruses, revealing different mechanisms of action and new structural vulnerabilities. This review provides an overview of these NAbs, summarizes their mechanisms of action when these have been identified, and highlights recent advances relevant to antiviral antibody development and vaccine research.