European Journal of Immunology最新文献

Lipid nanoparticles (LNPs) have emerged as the preeminent nonviral drug delivery vehicles for nucleic acid therapeutics, as exemplified by their usage in the mRNA COVID-19 vaccines. As a safe and highly modular delivery platform, LNPs are attractive for a wide range of applications. In addition to vaccines, LNPs are being utilized as platforms for other immunoengineering efforts, especially as cancer immunotherapies by modulating immune cells and their functionality via nucleic acid delivery. In this review, we focus on the methods and applications of LNP-based immunotherapy in five cell types: T cells, NK cells, macrophages, stem cells, and dendritic cells. Each of these cell types has wide-reaching applications in immunotherapy but comes with unique challenges and delivery barriers. By combining knowledge of immunology and nanotechnology, LNPs can be developed for improved immune cell targeting and transfection, ultimately working toward novel clinical therapeutics.

G protein-coupled receptors (GPCRs) are vital cell surface receptors that govern a myriad of physiological functions. Despite their crucial role in regulating antitumor immunity and tumorigenesis, therapeutic applications targeting GPCRs in oncology are currently limited. This review offers a focused examination of selected protumorigenic chemokine and metabolite-sensing GPCRs. Specifically, the review highlights five GPCRs able to orchestrate tumor immunobiology at three main levels: tumor immunity, cancer cell expansion, and blood vessel development. The review culminates by illuminating emerging therapies and discussing innovative strategies to harness the full potential of GPCR-targeted treatments, by applying a multireceptor and patient-specific logic.

Therapeutic interventions in the complement system, a key immune-inflammatory mediator and contributor to a broad range of clinical conditions, have long been considered important yet challenging or even unfeasible to achieve. Almost 20 years ago, a spark was lit demonstrating the clinical and commercial viability of complement-targeted therapies. Since then, the field has experienced an impressive expansion of targeted indications and available treatment modalities. Currently, a dozen distinct complement-specific therapeutics covering several intervention points are available in the clinic, benefiting patients suffering from eight disorders, not counting numerous clinical trials and off-label uses. Observing this rapid rise of complement-targeted therapy from obscurity to mainstream with amazement, one might ask whether the peak of this development has now been reached or whether the field will continue marching on to new heights. This review looks at the milestones of complement drug discovery and development achieved so far, surveys the currently approved drug entities and indications, and ventures a glimpse into the future advancements yet to come.

COVID-19, the disease caused by SARS-CoV-2, particularly causes severe inflammatory disease in elderly, obese, and male patients. Since both aging and obesity are associated with decreased testosterone and estradiol expression, we hypothesized that decreased hormone levels contribute to excessive inflammation in the context of COVID-19. Previously, we and others have shown that hyperinflammation in severe COVID-19 patients is induced by the production of pathogenic anti-spike IgG antibodies that activate alveolar macrophages. Therefore, we developed an in vitro assay in which we stimulated human macrophages with viral stimuli, anti-spike IgG immune complexes, and different sex hormones. Treatment with levels of testosterone reflecting young adults led to a significant reduction in TNF and IFN-γ production by human macrophages. In addition, estradiol significantly attenuated the production of a very broad panel of cytokines, including TNF, IL-1β, IL-6, IL-10, and IFN-γ. Both testosterone and estradiol reduced the expression of Fc gamma receptors IIa and III, the two main receptors responsible for anti-spike IgG-induced inflammation. Combined, these findings indicate that sex hormones reduce the inflammatory response of human alveolar macrophages to specific COVID-19-associated stimuli, thereby providing a potential immunological mechanism for the development of severe COVID-19 in both older male and female patients.

In vitro cultures remain crucial for studying the fundamental mechanisms of human T-cell development. Here, we introduce a novel in vitro cultivation system based on ThymoSpheres (TS): dense spheroids consisting of DLL4-expressing stromal cells and human hematopoietic precursor cells, in the absence of thymic epithelial cells. These spheroids are subsequently cultured at the air–liquid interphase. TS generate large numbers of mature T cells, are easy to manipulate, scalable, and can be repeatably sampled to monitor T-cell differentiation. The mature T cells generated from primary human hematopoietic precursor cells were extensively characterized using single-cell RNA and combined T-cell receptor (TCR) sequencing. These predominantly CD8α T cells exhibit transcriptional and TCR CDR3 characteristics similar to the recently described human polyclonal αβ unconventional T cell (UTC) lineage. This includes the expression of hallmark genes associated with agonist selection, such as IKZF2 (Helios), and the expression of various natural killer receptors. The TCR repertoire of these UTCs is polyclonal and enriched for CDR3-associated autoreactive features and early rearrangements of the TCR-α chain. In conclusion, TS cultures offer an intriguing platform to study the development of this human polyclonal UTC lineage and its inducing selection mechanisms.

Natural killer (NK) cells are innate lymphoid cells that protect a host from viral infections and malignancies. MicroRNA-146a (miR-146a) is an important regulator of immune function that is highly expressed in NK cells and is further upregulated during murine cytomegalovirus (MCMV) infection. Here we utilized mice with a global targeted deletion of miR-146a to understand its impact on the innate immune responses to MCMV infection. MiR-146a^−/− mice were protected from lethal MCMV infection, which was intrinsic to the hematopoietic compartment based on bone marrow chimera experiments. NK cell depletion abrogated this protection, implicating NK cells as critical for the miR-146a^−/− protection from MCMV. Surprisingly, NK cells from miR-146a-deficient mice were largely similar to control NK cells with respect to development, maturation, trafficking, and effector functions. However, miR-146a^−/− mice had increased NK cell numbers and frequency of the most mature Stage IV (CD27⁻CD11b⁺) NK cells in the liver at baseline, enhanced STAT1 phosphorylation, and increased selective expansion of Ly49H⁺ NK cells and T cells during MCMV infection. This study demonstrates a critical role for miR-146a in the host response to MCMV, arising from mechanisms that include increased NK cell numbers and early T-cell expansion.

The neuroimmune axis has been the focus of many studies, with special emphasis on the interactions between the central nervous system and the different immune cell subsets. T cells are namely recognized to play a critical role due to their interaction with nerves, by secreting cytokines and neurotrophins, which regulate the development, function, and survival of neurons. In this context, γδ T cells are particularly relevant, as they colonize specific tissues, namely the meninges, and have a wide variety of complex functions that balance physiological systems. Notably, γδ T cells are not only key components for maintaining brain homeostasis but are also responsible for triggering or preventing inflammatory responses in various pathologies, including neurodegenerative diseases as well as neuropsychiatric and developmental disorders. Here, we provide an overview of the current state of the art on the contribution of γδ T cells in neuropathophysiology and delve into the molecular mechanisms behind it. We aim to shed light on γδ T cell functions in the central nervous system while highlighting upcoming challenges in the field and providing new clues for potential therapeutic strategies.

Ascertaining the presence of weakly positive anti-HLA donor-specific antibodies (DSA) in organ transplantation with multiplex single antigen beads assays may be challenging despite their high sensitivity due to technical variability issues. Through extensive datasets of Next-Generation Sequencing HLA typings and single antigen analyses, we reassessed the mean fluorescence intensity (MFI) positivity threshold of the assay to enhance accuracy. By showing that some beads were more prone to false positivity than others, we propose a nuanced approach that accounts for nonspecific intrinsic reactivities at the HLA antigen level, that is, on a bead-by-bead basis, as it enhances assay precision and reliability. This is substantiated by a comprehensive statistical analysis of MFI values and the implementation of the determination of a “Quantile Adjusted Threshold 500” (QAT500) value for each bead. Applied to DSA detection during patients’ follow-up, this approach discriminated better and earlier low-strength DSA that would later raise their MFI above the clinically relevant threshold of 3000. Moving from a subjective interpretation to a more objective and precise methodology allows for standardizing HLA antibody and DSA detection. The study emphasizes the need for further research with real clinical data to validate and refine this approach.

Detailed knowledge of human B-cell development is crucial for the proper interpretation of inborn errors of immunity and malignant diseases. It is of interest to understand the kinetics of protein expression changes during development, but also to properly interpret the major and possibly alternative developmental trajectories. We have investigated human samples from healthy individuals with the aim of describing all B-cell developmental trajectories. We validated a 30-parameter mass cytometry panel and demonstrated the utility of “vaevictis” visualization of B-cell developmental stages. We used the trajectory inference tool “tviblindi” to exhaustively describe all trajectories leading to all developmental ends discovered in the data. Focusing on Natural Effector B cells, we demonstrated the dynamics of expression of nuclear factors (PAX-5, TdT, Ki-67, Bcl-2), cytokine and chemokine receptors (CD127, CXCR4, CXCR5) in relation to the canonical B-cell developmental stage markers. We observed branching of the memory development, where follicular memory formation was marked by CD73 expression. Lastly, we performed an analysis of two example cases of abnormal B-cell development caused by mutations in RAG-1 and Wiskott–Aldrich syndrome gene in patients with primary immunodeficiency. In conclusion, we developed, validated, and presented a comprehensive set of tools for the investigation of B-cell development in the bone marrow compartment.

The pathobiology of IL-17 in lung fibrogenesis is controversial. Here we examined the role of IL-17A/F in bleomycin (BLM) and adenoviral TGF-β1-induced lung fibrosis in mice. In both experimental models, WT and IL17af^−/− mice showed increased collagen contents and remodeled lung architecture as assessed by histopathological examination, suggesting that IL-17A/F is dispensable for lung fibrogenesis. However, IL17af^−/− mice responded to the BLM challenge with perturbed lung leukocyte subset recruitment. More specifically, bleomycin triggered angiocentric neutrophilic infiltrations of the lung accompanied by increased mortality of IL17af^−/− but not WT mice. WT bone marrow transplantation failed to correct this phenotype in BLM-challenged IL17af^−/− mice. Conversely, IL17a/f^−/− bone marrow transplantation → WT did not perturb lung leukocytic responses upon BLM. At the same time, IL17af^−/− mice treated with recombinant IL-17A/F showed an attenuated lung inflammatory response to BLM. Together, the data show that the degree of BLM-driven acute lung injury was critically dependent on the presence of IL-17A/F, while in both models, the fibrotic remodeling process was not.