Oxford open immunology最新文献

TAM receptors, composed of Tyro3, Axl, and Mertk, belong to the receptor tyrosine kinase family and are activated by binding of their cognate ligands, Gas6 and Pros1. These receptor-ligand interactions mediate critical physiological processes, including the maintenance of immunological equilibrium, thrombocyte aggregation and subsequent thrombus development, apoptotic cellular debris clearance, homeostatic regulation of endothelial and vascular smooth muscle cells, and erythrocyte production. Perturbations in TAM signaling cascades have been shown to compromise the clearance of apoptotic cells, leading to persistent inflammatory responses that can contribute to the development of various autoimmune pathologies, including multiple sclerosis, rheumatoid arthritis, Sjögren's syndrome, and systemic lupus erythematosus. We retrieved and reviewed only the primary studies addressing the roles of TAM receptors and their ligands in selected autoimmune diseases from Google Scholar, Scopus, Web of Science, and PubMed. The critical roles of TAM receptors in immune homeostasis and apoptotic cell clearance are well established. However, findings from several primary studies discussed in this review further emphasized that the loss of TAM receptor function in these processes significantly contributes to the pathogenesis and progression of autoimmune diseases. Herein, we highlight the role of TAM receptors in several autoimmune diseases, suggesting that TAM receptors are potential biomarkers for monitoring disease prognosis and therapeutic targets to improve patient outcomes.

The success of cancer immunotherapies has highlighted the importance of monitoring the anti-tumour T cell response. Patients with mesothelioma frequently present with a malignant pleural effusion (MPE) that is commonly drained regularly to alleviate symptoms. As MPE contains tumour cells, T cells and cytokines, it provides a unique opportunity to sample immune events at the tumour site. However, there is minimal information on how MPE T cells are distinct from those in the blood, and whether T cell phenotypes unique to each compartment correlate with survival. We characterised T cell populations of matched MPE and blood from 31 mesothelioma patients using flow cytometry and bulk T cell receptor beta (TCRβ) sequencing. MPE CD8⁺ and CD4⁺ T cells displayed increased expression of PD-1, TIGIT, LAG-3 and TIM-3 compared to blood, with co-expression of inhibitory receptors greatest on MPE CD8⁺ T cells with a tissue resident memory T cell phenotype (CD69⁺CD103⁺). CD8⁺ TCRβ repertoires displayed clonal overlap between MPE and blood, suggesting that a majority of T cells traffic between these compartments. Finally, we show that high expression of PD-1 on circulating CD4⁺ T cells is an independent prognostic factor for poor survival in this patient group. This work suggests that MPE T cell phenotypes differ from those in circulation, with blood-based T cell subsets more sensitive predictors of outcome in this study.

Over a decade has passed since the first commercial spectral flow cytometry (SFC) instrument was introduced. Unlike conventional flow cytometers, SFC utilizes an array of detectors to capture the full emission spectrum of fluorochromes, from which composite signatures are deconvoluted using an unmixing algorithm. This allows fluorochromes with overlapping peaks to be used within the same panel, enabling panels with up to 50 parameters. As its availability increases, more immunologists are looking to incorporate SFC into their experiments. One area of research benefiting from the larger SFC panels is the characterization of rare cells, including antigen-specific T cells identified directly ex vivo using either antigen stimulation or major histocompatibility complex-peptide multimers. In this brief review, we outline some practical considerations when combining ex-vivo T cell stimulation with SFC, drawing on our transition from conventional to SFC. Key aspects include designing the experiment and panel for stimulated cells, acquiring high-quality reference controls, strategies to manage autofluorescence and an overview of the data analysis, including both manual and computational approaches.

The SARS-CoV-2 pandemic caused an estimated 400 million people worldwide to experience Long COVID and post-COVID complications leading to significant chronic illness and disability with its devastating physical, societal and economic consequences. Since post-acute infectious syndromes have not been given adequate consideration prior to the pandemic, many millions of people with Long COVID worldwide have been left disabled as currently available therapies are largely symptomatic and only partially effective. A case of a previously healthy woman with Long COVID and post-COVID autonomic dysfunction and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is presented here from the perspective of a physician-patient relationship and a broader context of medical care and public health. Immunologic and autonomic mechanistic factors and therapies as these relate to Long COVID are highlighted. Complexities and issues pertaining to patient care, public health and education of neurologists and other specialists regarding Long COVID, dysautonomia and ME/CFS diagnosis and treatment are discussed, in conjunction with the need to develop and diversify effective therapies for people living with these highly disabling conditions.

Advances in sequencing technology have made it possible to capture complex immunogenetic loci at a scale that exceeds the capacity for manual annotation. Here we present the Annotator of Loci for ImmunoGlobulins and T cell Receptors (ALIGaToR), an automated pipeline to transfer genetic annotations from a known reference to a novel genomic assembly. We show that ALIGaToR accurately reproduces manually curated annotations and is capable of transferring labels even between distantly related species. Code and documentation for ALIGaToR, including a script reproducing all analyses in this paper, are available at https://github.com/scharch/aligator.

Mucosal immunization represents a promising approach to protect against pathogens that enter through mucosal surfaces. This review provides a practical overview of the mucosal immune system's main features and explores the benefits of mucosal vaccination, including its capacity to induce both local and systemic immune responses. Key challenges-such as mechanical barriers, the tolerogenic nature of mucosal immunity and variability due to environmental influences-are examined in detail. Strategies to overcome mucosal tolerance, improve antigen uptake and enhance immunogenicity are discussed, alongside recent advances that combine multiple mucosal routes or explore less conventional pathways. The review also outlines practical considerations for optimizing vaccine delivery and evaluating immune responses, offering a user-oriented guide to the current landscape and future directions in mucosal vaccine development.

Immune function varies widely across humans. Biological sex is a key factor underlying human immune variability, with men presenting with more severe infections and increased cancer rates, while women exhibit higher vaccine responses and prevalence of autoimmunity. Intrinsic biological sex differences arise from varying contributions of chromosomal sex, and sex hormone sensing and downstream signaling to different cell types. This complex regulation presents a unique opportunity for the exploration of human immune sex differences using systems-level methods of investigation. Here we analyze the current literature and the applications of systems immunology in elucidating the immune sex differences in humans. We examine mechanisms of biological sex modulation of human immunity via sex chromosomes, and particularly emphasize the role of sex hormones. We then focus on how systems immunology has been advancing our understanding of how sex impacts the healthy immune system at steady state, ranging from cell composition, transcriptomics, epigenomics, metabolomics, spatial and cell-cell interactions, to plasma proteomics. We also examine systems-level applications to investigating sex differences upon immune perturbations and give an overview of key future directions for the field. Systems immunology provides a powerful framework to decode biological sex-regulated pathways in immunity, paving the way for more precise, sex-informed therapeutic interventions to address sex differences in immune-related conditions.

The immune system is a complex network of cells, tissues and organs that protects the body against harmful pathogens. Characterization of the immune system is essential for understanding the complex interactions underlying pathophysiology and providing insights to enable therapeutic targeting for modern drug development. Tissue and peripheral sampling report on important biomarkers, but may not adequately sample complex, heterogeneous systemic diseases. Imaging has been extensively used in the study of immune diseases, largely relying upon structural measurements of disease manifestation (e.g. X-ray for joint space narrowing in rheumatoid arthritis). These measurements are downstream from drug action, offering no insight into the intricacies of the immune system. Molecular imaging, particularly through Positron Emission Tomography has the potential to map the immune system at the whole-body level, providing non-invasive, quantitative readouts. Adoption of PET clinically and for drug development purposes for studying immune processes has been limited to date, lagging use in neuroscience and oncology. Emerging technical developments are likely to create new opportunities for immune system monitoring: (i) A broad set of clinical probes to study immune cells and associated processes are in development, (ii) The advent of TotalBody PET able to capture high-sensitivity measurements from all tissues with reduced radiation dose burden. This review explores the potential applications of PET for immune drug development, the technology advancements and suggests how adoption barriers can be overcome. The immune toolset of the future will likely demand an integrated approach, using tissue and peripheral readouts combined with immune-specific imaging.

The molecular complexity of cancer presents significant challenges to traditional therapeutic approaches, necessitating the development of innovative treatment strategies capable of addressing the disease's dynamic nature and resistance mechanisms. Data-driven methodologies, particularly those employing Artificial Intelligence (AI), hold substantial promise by advancing a comprehensive understanding of the intricate molecular and cellular mechanisms underlying cancer and supporting the development of adaptive, patient-specific therapeutic strategies. Initiated through the Mertelsmann Foundation, the Collaborative Research Institute Intelligent Oncology (CRIION) in Freiburg im Breisgau, Germany, aims to drive progress in AI-driven oncology. CRIION fosters global collaboration through initiatives like the Intelligent Oncology Symposium and supports multidisciplinary projects designed to integrate AI innovations into clinical workflows.

Class I and II human leukocyte antigens (HLA-I and HLA-II) present peptide antigens for immunosurveillance by T cells. HLA molecules also form ligands for a plethora of innate, germline-encoded receptors. Many of these receptors engage HLA molecules in a peptide sequence independent manner, with binding sites outside the peptide binding groove. However, some receptors, typically expressed on natural killer (NK) cells, engage the HLA presented peptide directly. Remarkably, some of these receptors display exquisite specificity for peptide sequences, with the capacity to detect sequences conserved in pathogens. Here, we review evidence for peptide-specific NK cell receptors (PSNKRs) and discuss their potential roles in immunity.