European Journal of Immunology最新文献

Our expanding knowledge of innate lymphoid cells (ILCs) over the last two decades has demonstrated the pivotal role these cells play in homeostasis and host defense. Recent work suggests that the observed heterogeneity within different ILC types can be linked to their ontogeny in early life, indicating that the fetal environment likely influences ILC development and function. In this review, we aim to summarize the current understanding of how cell-extrinsic factors shape ILC emergence in early life. By examining the combined effects of progenitor cell origin and the signals they receive, we highlight the major environmental cues important for establishing ILC potential. Furthermore, we summarize the key factors for the production of each of the three groups of ILCs, while identifying outstanding questions regarding when and how these signals influence ILC development. Altogether, this review describes our evolving understanding of the interplay between ILC ontogenic origin and environmental signals in early life, and establishes key areas for further work to clarify how specific signals drive ILC development.

Glucocorticoids (GCs) regulate diverse physiological processes, comprising metabolism, immune responses, stress adaptation, and inflammation. Synthetic GCs are widely used for their powerful anti-inflammatory and immunosuppressive effects, in the treatment of autoimmune diseases, allergies, and inflammation. Here, we investigated the role of the glucocorticoid receptor (GR) in B cell development and survival using both B cell-specific GR-deficient mice and continuous in vivo GR agonist treatments. Deletion of the GR in B cells altered splenic B cell subpopulations, increasing follicular and CD21^lo B cells and leading to the accumulation of IgM⁻/IgD⁻ B cells. In vivo treatment with GR agonists, such as Dexamethasone (Dex) and Prednisolone (Pred), selectively depleted IgD^hi follicular while enriching IgM^hi marginal zone B cells. IgM^hi B cells, which were more resistant to GC-induced cell death, showed an increased expression of IL-10 and genes involved in survival, suggesting a potential regulatory function. In vitro, B cell activation via CpG or lipopolysaccharide (LPS) altered IgM/IgD expression and B cell sensitivity to GR agonists, thereby leading to improved B cell survival and increased plasma cell differentiation. Together, these findings suggest that IgD downregulation and IgM upregulation are critical for B cell survival under GC exposure and that GR agonists promote the enrichment of IgM^hi cells resistant to apoptosis.

Autoimmunity causes damage to organs targeted by the effector function of the immune response. The dynamics of autoimmunity in human peripheral tissues are not well understood due to the limited access to tissue samples. As cellular metabolism controls immune function, studying the crosstalk between the environment and cells within a tissue may provide information on how the metabolism of immune cells drives autoimmunity in peripheral tissues. In this review, I discuss some of the work that explored the complexity of the tissue environment, its sensing by cells in the tissue, and the consequences this has on cell and tissue functions, highlighting implications for autoimmune diseases. I also suggest a framework to study immunometabolism in tissues, contextualizing the metabolic choices of immune cells within the diversity of the extracellular environment they encounter.

Rheumatoid arthritis (RA) represents a major global public health challenge, with approximately 1% of the world's population suffering from this disease. In the absence of a cure, patients require ongoing and very often lifelong treatment. While environmental, genetic, and epigenetic factors have all been linked to the development of RA, a key, universally accepted initiating factor in disease development is the loss of immunological tolerance to self-antigens. Currently, most treatment approaches utilise agents that suppress the immune system or inflammatory response. However, there is no currently available treatment to re-establish self-tolerance, the key driving factor in the initiation of the disease. In this review, we will explore how peripheral tolerance mechanisms fail in RA, leading to disease initiation and progression. We will explore how dendritic cells (DCs), a central and nonredundant cell type in maintaining immune tolerance, contribute to RA and discuss molecular strategies to switch these immunogenic and self-reactive cells to tolerogenic cells. Finally, in addition to understanding the fundamental mechanisms of how peripheral tolerance mechanisms are lost, it is also important to know where this dysregulation occurs. Therefore, in this review, we will also discuss emerging research on sites of disease initiation in the context of tolerance.

We report the case of a stage 4 mantle cell lymphoma patient, resistant to conventional first- and second-line therapies, treated with CAR-T cells. The therapy was initially efficacious, with an appreciable CAR-T cells expansion in vivo. However, downregulation of CD19 expression on malignant B cells led to sudden therapy failure.

The primary function of MHC-E—human leukocyte antigen (HLA)-E in humans and Mamu-E in rhesus macaques—relates to immune surveillance via CD94/NKG2x receptors expressed on NK cells. However, a secondary role where MHC-E presents immunogenic peptides to CD8⁺ T cells that provide protective immunity in specific settings has also been described. Given the high sequence homologies between HLA-E and Mamu-E molecules, peptide binding similarities are assumed but not systematically explored, with most studies prioritising HLA-E. Here, we have optimised and developed two complementary techniques to explore the peptide repertoires of specific HLA-E and Mamu-E subtypes. We established a label-free, high-throughput nano-differential scanning fluorimetry (nDSF)-based method, where peptide binding strength is measured through thermal stability (T_m). This method revealed shared repertoires with occasional subtype-specific peptide binding hierarchies for the MHC-E types studied here, HLA-E*01:03 and Mamu-E*02:04. When combined with a fluorescence polarisation (FP) peptide competition assay, we show that half maximal inhibitory concentrations (IC₅₀) correlate exponentially with nDSF-acquired T_m data, revealing that modest T_m increments equate to marked IC₅₀ differences, and hence substantial differences in relative peptide binding strengths. Collectively, these methodologies offer high-throughput, scalable approaches to provide detailed peptide binding information for rhesus and human MHC-E types.

Family of Sequence Similarity 83H (FAM83H/SACK1H) is primarily expressed in epithelial cells, where it interacts with casein kinase 1 (CK1) and keratins to regulate cytoskeletal organization, cell proliferation, and vesicular trafficking. Mutations in FAM83H are known to cause amelogenesis imperfecta, highlighting its critical role in enamel formation. We generated Fam83h-deficient mice (Fam83h^{em2(IMPC)Ccpcz}, Fam83h^−/−) and mice lacking a part of the N-terminal CK1-binding domain (Fam83h^∆87/∆87). Consistent with other Fam83h-deficient models, these mice are subviable, smaller in size, and exhibit a sparse, scruffy coat, scaly skin, general weakness, and hypoactivity. Notably, both strains show impaired lymphoid cell development in early postnatal life. In the thymus, Fam83h expression is confined to thymic epithelial cells (TECs), and its deficiency in stromal cells results in disrupted thymic architecture and a severe block in the expansion of double-negative stage 3 (DN3) T cells, ultimately leading to insufficient T cell production. Single-cell transcriptomic analysis reveals that Fam83h^−/− cortical TECs (cTECs) express reduced levels of the TEC master regulator Foxn1, and its multiple downstream target genes, suggesting a critical role for FAM83H, likely in coordination with CK1, in cTEC maturation.

Lactate is a metabolite with immunoregulatory functions. We evaluated lactate secretion and its effects on B cells from individuals with different body composition: Y_LEAN, Y_OBESE, and E_LEAN individuals. Results show higher serum metabolic profiles in Y_OBESE and E_LEAN versus Y_LEAN individuals, evaluated by levels of lactate dehydrogenase, the enzyme that converts pyruvate into lactate, which is associated with increased secretion of lactate in blood-derived B cells. Double negative (DN) B cells, which expand in the blood of Y_OBESE and E_LEAN individuals, are the major contributors to this metabolic profile. When lactate was added in vitro to B cells from Y_LEAN, Y_OBESE, and E_LEAN individuals, we found increased secretion of pathogenic autoimmune antibodies in B cells from Y_LEAN, compared to those from Y_OBESE and E_LEAN individuals, likely because B cells from Y_OBESE or E_LEAN individuals have already been exposed to, and chronically stimulated by lactate in vivo, becoming refractory to further stimulation. Mechanistically, the effects of lactate are mediated by phosphorylated signal transducer and activator of Transcription 3 (p-STAT3). These effects are inhibited in the presence of a neutralizing antibody that blocks the lactate transporter SLC5A12, responsible for lactate uptake and activation of inflammatory and pathogenic responses, and p-STAT3.

R. Nadafi, W. Dong, and V.W. van Beusechem, “Immunological Impact of Oncolytic Adenoviruses on Cancer Therapy: Clinical Insights,” European Journal of Immunology 55 (2025): e70024.

After the online publication of the article, we found that Reference 67 was mistakenly included in the paragraph discussing ORCA-010, as it does not support the statement and the appropriate supporting references are currently missing from the manuscript. Therefore, the mentioned paragraph should contain the following references:

An improved variant of Ad5-Δ24.RGD, ORCA-010, has been engineered to enhance both its safety and therapeutic efficacy [DOI: 10.1089/hum.2013.229]. In addition to the Ad5-Δ24 and RGD modifications, ORCA-010 includes a potency-enhancing T1 mutation [DOI: 10.1158/0008-5472.CAN-08-1145].

We apologize for this error.

The tonsil is a highly compartmentalized organ in which different microanatomical structures orchestrate designated (immune) functions. We use this already well-studied tissue to survey imaging-based spatial transcriptomics data for studying immune responses in native tissue context, and, to demonstrate its advantages for faithfully recapitulating cellular composition in direct comparison with single-cell RNA sequencing. While these data still pose many analytical challenges and lack standardization, we established a versatile analysis pipeline focused on their profitable particularities: considering organization (microenvironment), interactions (signaling), and function (higher order structures) across scales. Specifically, we resolve $�\sim$2M cells into 52 subpopulations across immune and, in particular, structural compartments. Various spatial niches partition tonsillar tissue into architecturally and functionally distinct regions, which we characterize through cell–cell colocalization and communication analyses, while performing various nonstandard analyses at the level of spatial features. These topological readouts may help elucidate where certain immunological processes occur (e.g., class switch recombination), and, where signaling pathways are active (e.g., TNF and galectin, which have been implicated in diverse lymphomas).

In all, we provide an analytical framework for spatial immunology, and showcase alternative views that such techniques and concomitant computational approaches can bring on tissue composition and architecture.