European Journal of Immunology最新文献

Hemophagocytic lymphohistiocytosis (HLH) is a severe inflammatory syndrome characterized by persistent activation of lymphocytes and macrophages. Recently, deleterious autosomal recessive mutations in ZNFX1 were reported to predispose pediatric patients to HLH-like disease upon viral trigger. The objective of this study was to assess the suitability of Znfx1-mutant (Znfx1^mut) mice infected with lymphocytic choriomeningitis virus (LCMV) as a model of HLH-like inflammation observed in patients. Following LCMV infection, Znfx1^mut mice were monitored for pathophysiological signs of HLH, and their cells were immunophenotyped. Furthermore, functional assays were performed in vitro on T cells and bone marrow-derived macrophages (BMDMs) to assess the cells' response to stimuli. Our experiments highlighted several hallmark features of HLH-like inflammation in Znfx1^mut mice. Immunophenotyping revealed more pronounced T cell expansion and type-1 helper (Th1) polarization in LCMV-infected Znfx1^mut mice. Znfx1^mut macrophages infiltrated the liver to a greater extent upon infection and produced greater levels of cytokines in vitro in the absence of stimulation, suggesting that these cells have a major role in driving inflammation. This novel murine model of HLH-like inflammation mirrors key aspects of the immune dysregulation observed in patients, providing a valuable tool for studying disease mechanisms in ZNFX1 deficiency.

MHC class I (MHC-I) cross-presentation involves final proteolytic peptide processing by the endosomal insulin-regulated aminopeptidase (IRAP). Reasoning that analysis of the IRAP-proximal proteome may inform about dynamic remodeling of a key cross-presentation compartment during antigen uptake, we developed a proximity biotinylation system by expressing an IRAP-TurboID fusion protein in MuTuDCs, a cell line resembling murine type 1 conventional dendritic cells. Analysis of luminal proteins associated with IRAP at steady state and during phagocytosis revealed a massive shift upon uptake of yeast but not apoptotic cells, favoring enrichment of antigen-processing machinery, MHC-I molecules, and proteins involved in ER-associated folding and trafficking. Importantly, Sec22b modulated this proteomic landscape, promoting the localization of MHC-I cross-presentation proteins (e.g., MHC-I, Tap1, Wdfy4, transferrin receptor) to the IRAP environment, while its absence favored MHC-II and ER-related proteins, suggesting a Sec22b-dependent dichotomy between pathways favoring cross-presentation versus antigen degradation. Intriguingly, uptake of apoptotic cells failed to promote cross-presentation but induced two proteins related to immune tolerance, suggesting potential adaptation of proteome modulation to the outcome of antigen presentation. These data suggest that IRAP⁺ endosomes serve as adaptive hubs integrating secretory and endocytic pathways, with Sec22b acting as a key determinant in tailoring this compartment for MHC-I-mediated cross-presentation.

Cell therapy using regulatory T cells (Tregs) holds therapeutic promise in immune-mediated diseases, but their stability and persistence after transfer into inflammatory environments remain major challenges. CD8⁺ Tregs, in particular, express multiple cytokine receptors, raising questions about their plasticity. Here, we investigated their susceptibility to pro-inflammatory signals and the role of FOXP3 in maintaining stability. Short-term culture with IL-6 and TNFα or IFNγ had no impact, but exposure to TGFβ combined with IL-6 and IL-1β or IL-21 and IL-23 induced substantial transcriptomic changes, including marked FOXP3 downregulation. Enforced FOXP3 expression via lentiviral transduction enhanced suppressive activity in vitro and stabilized phenotype under inflammation. Notably, FOXP3 knockout CD8⁺ Tregs retained suppressive function for up to 2 weeks, suggesting FOXP3 is not strictly required for short-term activity. Moreover, FOXP3 expression was boosted by transduction of mTOR regulators SESN2 or FLCN, or the SAGA complex component TAF5L, with SESN2 and TAF5L alone sufficient to enhance suppressive function. Together, these findings reveal mechanisms controlling CD8⁺ Treg stability and identify molecular targets to optimize next-generation Treg-based cell therapies for immune-mediated diseases.

The gut microbiota plays a key role in shaping and educating host immunity, and it may also influence the central nervous system (CNS). Changes in the composition and function of commensal microbes can trigger inflammation and abnormal immune activation, contributing to disorders such as multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), autoimmune encephalitis (AIE), neuropsychiatric lupus (NPSLE), and narcolepsy. The microbiota has been linked to disease risk or protection via the production of its metabolites, products, or antigens that could modulate host immune responses, consequently causing CNS inflammation. This review highlights patient studies investigating the mechanisms through which the human microbiota is involved in CNS autoimmunity by modulating the host immune system. Future research should focus on defining causal relationships, elucidating molecular mechanisms, and addressing the different members of the intestinal microbiota to translate microbiota modulation into clinical interventions for CNS autoimmune diseases.

CD83 is critical for CD4⁺ T cell selection. It regulates MHC II ubiquitination and turnover at the surface of thymic epithelial cells (TECs). The role of UBL3, a recently identified adaptor molecule for MHC II ubiquitination, is unknown in thymic selection. Here we demonstrate that UBL3 regulates MHC II in TECs and participates in CD4⁺ T cell selection. Deleting UBL3 in CD83 loss-of-function mice (Cd83^anu/anu Ubl3^-/-) increases MHC II on the surface of Cd83^anu/anu TECs. This increase in surface MHC II correlates with increased positive selection of CD4⁺ T cells. Analysis of Cd83^anu/anu and Cd83^anu/anu Ubl3^-/- mice identifies the CD4⁺ CD8^low CD69⁺ stage of positive selection as the origin of the CD4⁺ T cell selection defect in Cd83^anu/anu mice. This stage of CD4⁺ T cell positive selection is also impacted by UBL3. The positive selection defect in the absence of CD83 also manifests as alterations in CCR7⁺ CD4 single-positive (SP) thymocytes. At the later stages of CD4⁺ T cell development, a role for UBL3 is no longer detected. In summary, through in-depth phenotyping of thymocyte populations, a role for CD83 and UBL3 in regulating the early stages of CD4⁺ T cell positive selection has been identified.

Owing to their immunoprotective properties, natural killer (NK) cells are critical for the innate immune response to pathogens, as well as a new wave of cancer immunotherapy that harnesses natural cytotoxicity. We sought to study the genetic and epigenetic drivers behind human-specific NK cell receptors, so that we can better understand the underlying cellular function. Here, we present a transcriptomic, proteomic (CITE-seq), and chromatin (single nuclei ATAC-seq) profiling of human peripheral NK cell subsets, which was then compared with genomic databases. Through integrative multi-omics, we demonstrate that CD56^bright versus CD56^dim NK cell subsets have differential distal regulatory element (DRE) landscapes, with fewer accessible DREs in the CD56^dim NK cells. We combine our epigenetic data, deposited Hi-C, and human genetic data to show mechanisms governing the NCAM1 (encoding CD56) and the killer cell immunoglobulin-like receptors (KIRs) loci. We identify an NCAM1 DRE that binds STAT3 in most NK cells, while identifying a genetic cohort that has motifs for binding repressive BLIMP1 at the DRE and resulting in less CD56 expression. Together, our findings reveal novel epigenetic and transcriptomic systems for the regulation of NK cell receptors driving NK cell cytotoxicity and diversity.

We identified RANK (TNFRSF11a) expression in human thymic FOXP3⁺ Tregs, revealing a previously unknown role for the RANK-RANKL axis in human tTreg development. We show that IL-2 and IL-15 can drive RANK expression in CD4⁺ tTregs, which in turn may modulate their maturation and proliferation within the thymic environment. Created in BioRender. Biorender, I. (2026) https://BioRender.com/gbrjlpa.

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.