European Journal of Immunology最新文献

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.

Interactions between T- and B cells in the germinal center reaction are instrumental for the initiation, maintenance, and downregulation of the human adaptive immune response, leading to the production of antigen-specific antibodies and long-lasting immunological memory. Replicating the human immune system remains challenging, with an over-reliance on animal models with limited translational accuracy. There is an increasing need for new tools that accurately model human immune function. This review evaluates existing 2D and 3D in vitro and ex vivo human models for their ability to reproduce the germinal center reaction, with a particular focus on T- and B-cell interaction. We conclude that although current models are able to replicate certain features of the germinal center reaction, no current model is able to completely replicate the complex human GC process. We outline the challenges in recreating a fully functional germinal center and suggest future directions of research to improve existing models, ultimately bringing us closer to completely reproducing the human lymph node.

The study examined the relationship between rubella virus (RV)-induced gene expression and proinflammatory cytokine/chemokine secretion in females previously vaccinated with MMR. Gene clusters enriched for functional pathways of innate immune system activation and antiviral responses were found to predict RV-specific MCP-1, MCP-4, IP-10, and IL-2 secretion.

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.