European Journal of Immunology最新文献

Recent advances in multi-omics and spatially resolved single-cell technologies have revolutionised our ability to profile millions of cellular states, offering unprecedented opportunities to understand the complex molecular landscapes of human tissues in both health and disease. These developments hold immense potential for precision medicine, particularly in the rational design of novel therapeutics for treating inflammatory and autoimmune diseases. However, the vast, high-dimensional data generated by these technologies present significant analytical challenges, such as distinguishing technical variation from biological variation or defining relevant questions that leverage the added spatial dimension to improve our understanding of tissue organisation. Generative artificial intelligence (AI), specifically variational autoencoder- or transformer-based latent variable models, provides a powerful and flexible approach to addressing these challenges. These models make inferences about a cell's intrinsic state by effectively identifying complex patterns, reducing data dimensionality and modelling the biological variability in single-cell datasets. This review explores the current landscape of single-cell and spatial multi-omics technologies, the application of generative AI in data analysis and modelling and their transformative impact on our understanding of autoimmune diseases. By combining spatial and single-cell data with advanced AI methodologies, we highlight novel insights into the pathogenesis of autoimmune disorders and outline future directions for leveraging these technologies to achieve the goal of AI-powered personalised medicine.

Non-lymphoid tissue Tregs (NLT-Tregs) are critical for tissue homeostasis, inflammation control, and induction of tissue repair. Recent single-cell RNA sequencing data identified the expression of CD83 as part of an NLT-Treg signature, which is an essential molecule for the stability and differentiation of lymphoid Tregs. However, the biological significance of CD83 expression for NLT Tregs has not yet been elucidated. The present study explores for the first time the role of CD83 expression by lung-resident Tregs in the steady state and during asthma to understand its importance in barrier tissues. We evaluated the effect of Treg-specific CD83 deletion (CD83cKO) on the lung-resident T-cell compartment and cytokine profile. CD83-deficient lung Tregs are less differentiated but more activated, resulting in unrestrained T-cell activation. Further, CD83cKO mice were challenged in an asthma model and showed an accelerated disease progression, driven by Th2-biased T-cell responses. CD83cKO Tregs exhibited enhanced responsiveness to IL-4, leading to insufficient control of Th2-differentiation from naïve T cells. These findings underscore the pivotal role of CD83 in the NLT-Treg-mediated modulation of Th2 responses. Overall, our results highlight CD83 as a key player in tissue homeostasis and inflammatory responses, suggesting potential therapeutic implications for inflammatory disorders such as asthma.

NADPH-oxidase (NOX)-derived reactive oxygen species (ROS) have been described to play essential roles in B-cell activation processes. However, several key questions concerning NOX activity and subsequent ROS production remain unaddressed, including fundamental processes such as differentiation, functional competence, cellular metabolism, and viability. This study investigated these questions in a murine B-cell response after secondary immunization. We combined single-cell transcriptomics and single-cell detection of NOX activity and observed that various subsets of B cells dynamically express NOX1 and NOX2. The NOX⁺ cellular phenotype correlated with increased activity of metabolic pathways, augmented lactate production, lower IgG secretion rates, and markers for longevity. The NOX⁺ cellular phenotype was also associated with increased cellular stress and apoptosis, underscoring the intricate relationship between ROS and cellular survival. Consequently, these insights advance our understanding of how long-lived humoral immunity is formed.

Type I interferon (IFN) signalling induces the expression of several hundred IFN-stimulated genes (ISGs) that provide an unfavourable environment for viral replication. To prevent an overexuberant response and autoinflammatory disease, IFN signalling requires tight control. One critical regulator is the ubiquitin-like protein IFN-stimulated gene 15 (ISG15), evidenced by autoinflammatory disease in patients with inherited ISG15 deficiencies. Current models suggest that ISG15 stabilises ubiquitin-specific peptidase 18 (USP18), a well-established negative regulator of IFN signalling. USP18 also functions as an ISG15-specific peptidase that cleaves ISG15 from ISGylated proteins; however, USP18's catalytic activity is dispensable for controlling IFN signalling. Here, we show that the ISG15-dependent stabilisation of USP18 involves hydrophobic interactions reliant on tryptophan 123 (W123) in ISG15. Nonetheless, while USP18 stabilisation is necessary, it is not sufficient for the regulation of IFN signalling; ISG15 C-terminal mutants with significantly reduced affinity still stabilised USP18, yet the magnitude of signalling resembled ISG15-deficient cells. Hence, USP18 requires non-covalent interactions with the ISG15 C-terminal diGlycine motif to promote its regulatory function. It shows ISG15 is a repressor of type I IFN signalling beyond its role as a USP18 stabiliser.

Atypical chemokine receptors (ACKRs) are a subclass of chemokine receptors that internalise and degrade chemokines instead of eliciting chemotaxis. Scavenging by ACKRs reduces the local bioavailability of chemokines and can thus reshape chemokine gradients that direct leukocyte trafficking during inflammation and anticancer responses. In pancreatic ductal adenocarcinoma (PDAC), chemokine axes, such as CXCL12-CXCR4, are co-opted by cancer-associated fibroblasts (CAFs) for tumour growth and escape, and immunosuppression. Here, we explore the use of ACKRs to reshape chemokine gradients within the PDAC tumour microenvironment. ACKR2, previously only known to scavenge inflammatory CC chemokines, was recently shown to be able to interact with CXCL10 and CXCL14. Here, using a chemokine binding assay and cytometric bead arrays, we reveal that ACKR2 scavenges additional CXC chemokines CXCL12 and CXCL1. ACKR2 scavenges CXCL12 with reduced efficiency compared to ACKR3, previously reported to bind CXCL12. Finally, we demonstrate that the overexpression of ACKR2 on bystander cells protects primary murine cytotoxic T lymphocytes from PDAC CAF-mediated chemoattraction. These findings reveal new CXC chemokine ligands of ACKR2 and indicate that ACKR overexpression may protect T cells from misdirection by CAFs.

Anti-cyclic citrullinated peptide2 (CCP2) antibody positivity in rheumatoid arthritis (RA) and in the predisease phase, together with the success of B-cell depletion, support a crucial role for B cells in RA pathogenesis. Yet, knowledge of B cells in the transition from autoimmunity to RA is limited, and therefore we here investigated B-cell changes during the risk-RA phase. B-cell phenotypes in 18 CCP2-positive risk-RA individuals with musculoskeletal complaints were studied, parallel with ten CCP2-positive RA patients and nine healthy controls. Nine of the risk-RA individuals progressed to RA. B-cell phenotypes were investigated using spectral flow cytometry. The results demonstrate that unswitched and switched memory B-cell frequencies in the risk-RA cohort were more similar to controls than RA patients. Yet, risk-RA progressors displayed an early activation profile amongst naïve B cells. Deeper characterization of the memory compartment revealed expansion of CD27-negative IgG+ B cells both in RA compared with controls (p = 0.0172) and in risk-RA progressors versus non-progressors (p = 0.0295). Overall, we demonstrate that the phenotypic distribution of B cells is altered in the risk-RA phase. This includes changes in CD27-negative class-switched B cells, which have been attributed to autoreactive and anergic features implicating a possible contribution to RA development.

The immunosuppressed state of transplant patients allows opportunistic pathogens such as human cytomegalovirus (HCMV) to cause severe disease. Therefore, inducing and boosting immunity against HCMV in recipients prior to organ transplantation is highly desirable, and accordingly, the development of an HCMV vaccine has been identified as a clinically relevant priority. Such vaccines need to be highly attenuated while eliciting specific and protective immune responses. We tested the concept of expressing the NKG2D ligand (NKG2D-L) ULBP2 by HCMV vaccine candidates to achieve NK cell activation, and, thereby viral attenuation. ULBP2 expression was found on HCMV-infected cells, reflecting the promotor strengths used to drive ULBP2 transgene expression. Moreover, significantly increased shedding of soluble ULBP2 (sULBP2) was detected for these mutants mirroring the surface expression levels. No negative effect of sULBP2 on NK cell function was observed. NK cells efficiently controlled viral spread, which was further increased by additional triggering of the activating receptor NKG2D. Engagement of NKG2D was also confirmed by its downregulation depending on ULBP2 surface density. Finally, expression of ULBP2 significantly enhanced NK cell cytotoxicity, which was independent of KIR-ligand mismatch as well as the presence of T cells. This NKG2D-L-based approach represents a feasible and promising strategy for HCMV vaccine development.