European Journal of Immunology最新文献

Changes in transcript abundance and isoforms, mediated by epigenetic and post-transcriptional mechanisms, are a hallmark of the development, activation, and effector functions of immune cells. How epigenetic and post-transcriptional processes are orchestrated to regulate transcription and pre-mRNA processing, and their interplay with metabolism, is emerging as important for immunity. DNA and histone modifications recruit RNA-binding proteins (RBPs) to mediate co-transcriptional RNA processing at specific chromatin loci. Simultaneously, RBPs influence the deposition of epigenetic modifications by regulating the expression of chromatin-modifying enzymes and enzymes that control the amounts of metabolites. These are used as substrates by chromatin-modifying enzymes and can influence RBP activity; thus, modulation of metabolic pathways represents a mechanism to regulate the epigenetic landscape and pre-mRNA processing. A body of work identifies emerging regulatory principles that address the interplay between epigenetics and RBPs in the nucleus, and of cytoplasmic post-transcriptional mechanisms that regulate metabolism and epigenetics. In this review, we focus on the interconnections between RBP-mediated processes, chromatin modifications, and metabolic pathways, highlighting the role that such circuits have in T- and B-lymphocytes, and in autoimmunity.

Severe COVID-19 is an immunological disorder characterized by a hyper-inflammatory reaction of the immune system. SARS-CoV-2 anti-spike antibodies of the IgG isotype are known to strongly contribute to this hyperinflammation by overactivation of alveolar macrophages. However, while the pathogenic function of IgG has been extensively studied, very little is known about the function of IgA, the most abundant immunoglobulin isotype in the airways. Although IgA is generally considered noninflammatory, in this study, we show that anti-spike IgA induces pronounced proinflammatory responses. We demonstrate that stimulation of macrophages with anti-spike IgA immune complexes in combination with a viral stimulus amplifies proinflammatory cytokine production. This IgA-induced inflammation is particularly driven by IgA2, the IgA subclass that is increased in the plasma of severely ill COVID-19 patients. We identified that IgA2-induced inflammation is predominantly dependent on FcαRI-Syk signaling. Mechanistically, IgA2-induced inflammation is linked to enhanced glycolysis and altered mitochondrial function, indicating subclass-specific immunometabolic reprogramming. Taken together, these data indicate a pathogenic role for IgA2 in severe COVID-19 and highlight its signaling cascades and metabolic pathways as potential druggable targets to counteract hyperinflammation in severe coronavirus infections, such as COVID-19, SARS, MERS, and potential future outbreaks.

T helper cell subsets—Th1, Th2, and Th17—coordinate pathogen-specific immune responses. Candida albicans-specific T cells include protective Th17 cells alongside other Th subsets. However, the role of alternative Th subsets remains unclear, particularly in individuals with impaired Th17 responses and recurrent candidiasis. Here, we show that patients with STAT1 gain-of-function mutations and chronic mucocutaneous candidiasis have a numerically normal but functionally altered pool of C. albicans-specific Th cells, skewed toward Th1 and Th2. This imbalance persisted even when assessing responses to the known and the newly identified immunodominant C. albicans antigens MP65 (65-kilodalton mannoprotein), HYR1 (hyphally regulated cell wall protein 1), and SAP4-6 (secreted aspartic proteinases 4–6), suggesting that antigen recognition and priming remain intact despite qualitative defects in T cell polarization. Using mucosal infection mouse models, we demonstrate that C. albicans-specific transgenic Th17 cells are sufficient to control infection, whereas Th1 and Th2 cells fail to protect, even in high numbers. Moreover, co-transfer of Th2 cells with Th17 cells impaired fungal control via an IL-4-dependent mechanism. These findings highlight the essential role of Th17 cells in protective immunity against C. albicans and reveal that non-Th17 responses are ineffective and may contribute to susceptibility in both humans and mice.

Autoimmune diseases arise from a breakdown in immune tolerance. This leads to self-reactive immune responses and chronic inflammation. Induction of antigen-specific tolerance offers a targeted approach that restores immune balance without global immunosuppression. We discuss current approaches to therapies that seek to induce tolerance. These include peptide-, immunoglobulin-, carrier-, and cell-based approaches. We review clinical trials and preclinical studies that explore novel strategies for the induction of durable (antigen-specific) tolerance as possible interventions in autoimmune disease.

The immune system is deeply shaped by its anatomical context, with spatial organization emerging as a fundamental principle of immune regulation. Recent advances in spatial omics technologies—encompassing transcriptomics, proteomics, metabolomics, lipidomics, and phosphoproteomics—have revolutionized our ability to study immune processes within intact tissue environments. By preserving spatial coordinates while capturing high-dimensional molecular data, these technologies offer unprecedented insight into how immune cell states and functions are governed by local cues and tissue architecture. In this review, we provide an overview of the major spatial omics platforms, emphasizing methodologies that have gained traction within the immunology community and in our own research. We then illustrate how these tools have begun to elucidate the logic of immune compartmentalization across anatomically complex tissues. While not exhaustive, we highlight selected examples from the intestine, secondary lymphoid organs, and liver to show how spatial omics has uncovered region-specific immune programs, microenvironmental niches, and context-dependent signaling pathways. Together, these studies demonstrate how spatial omics technologies are redefining immunological inquiry—shifting the focus from isolated cell types to their spatially embedded roles in tissue physiology and pathology.

Equine asthma (EA) is the most prevalent chronic lung disease in horses. Neutrophils are the main effector cells in severe EA. Neutrophil extracellular traps (NETs) have been described as contributors to severity in human asthma and chronic obstructive pulmonary disease. Thus, we aimed to investigate if NET-related factors in equine neutrophils, blood and bronchoalveolar lavage fluid (BALF) allow us to differentiate EA severities and to identify NET-related mechanistic insights in EA. We quantified NETs and NET-related factors in the blood and BALF of eight healthy horses and 18 horses with differing EA severities. The proportion of activated cells in BALF increased with EA severity, accompanied by dysregulation of local NET regulators in severe EA. Furthermore, circulating anti-neutrophil cytoplasmic antibodies (ANCAs = NET-autoantibodies) were found elevated in severely diseased horses. In line with these findings, NET formation by circulating neutrophils was found to depend on the severity of EA. Finally, we analysed the cholesterol content of circulating neutrophils and identified an asthma-severity-dependent decrease in cellular cholesterol, which correlated with increased NET formation and hypoxia. Local and systemic modifications—particularly in neutrophil cellular cholesterol content—provide further insight into the partially understood pathogenesis of EA and point to a systemic cholesterol-associated inflammatory component fuelling disease progression.

Cellular metabolism intricately directs the differentiation, stability, and function of regulatory T cells (Tregs), which are pivotal in immune regulation. Metabolic reprogramming enables Tregs to adapt to diverse tissue environments; however, it can also disturb immune equilibrium, driving their conversion into unfavorable states like exTregs that hinder regulation in autoimmunity and transplantation. Purine metabolism has emerged as a critical but underexplored regulator of Treg biology. Beyond their traditional roles in nucleotide synthesis and energy balance, purine metabolites also serve as potent second messengers shaping Treg phenotype, suppressive capacity, and adaptability in inflammatory, autoimmune, and transplant environments. Extracellular ATP promotes inflammation, while adenosine supports Treg-mediated immunosuppression, highlighting a dual and context-dependent nature of purinergic signaling. This review outlines current findings on intracellular and extracellular purine metabolism in Tregs, emphasizing key enzymes and purinergic receptors that sustain Treg phenotype and resilience. It discusses disruptions in purine signaling compromising Treg functions, identifies knowledge gaps, and proposes future research directions for potential therapeutic strategies in immune-related ailments.

Peripherally derived regulatory T cells (pTregs) have a prominent role in maintaining intestinal immune homeostasis. In cases of phosphoinositide-3-kinase δ (PI3Kδ) inactivation, such as in patients receiving PI3Kδ inhibitor idelalisib as a cancer treatment, breakdown of intestinal immune tolerance occurs frequently in the form of diarrhea and colon inflammation. In a mouse model of systemic PI3Kδ inactivation, both enhancement of antitumor immunity and colitis have been described as a result of Treg impairment. However, in view of the critical role for Tregs in the prevention of systemic autoimmunity, the basis for such tissue-restricted breach of immune tolerance upon loss of PI3Kδ function is not yet understood. We report here that mice lacking PI3Kδ activity do not suffer a general defect in Treg immunosuppression, but specifically fail to develop Helios⁻ pTregs in the colon. We demonstrate reduced extrathymic Treg induction, in vitro and in vivo, from naïve CD4⁺ T cells with inactive PI3Kδ, along with dysregulation of a tissue-resident phenotype. These results suggest a nonredundant role for PI3Kδ-dependent pTreg differentiation in maintaining tolerance to commensal microbial antigens in the gut.