Macrophages are active participants of tissue repair and when normal repair processes fail, fibrosis can ensue, which leads to major organ dysfunction and affects nearly a billion people worldwide. Here we focus on macro...Macrophages are active participants of tissue repair and when normal repair processes fail, fibrosis can ensue, which leads to major organ dysfunction and affects nearly a billion people worldwide. Here we focus on macrophages in the spatiotemporal control of fibrosis, drawing on our understanding of the roles of these cells in organogenesis, adult organ homeostasis and wound repair. We describe recent insights from single-cell transcriptomics studies of human and mouse tissues that reveal macrophage heterogeneity in healthy and fibrotic niches, as well as the pathways underlying macrophage-fibroblast cooperation during progression from inflammation to fibrosis. Finally, we propose a model to explain how macrophage activity over time and across different tissues controls tissue fibrosis, we discuss therapeutic initiatives based on regulation of macrophage activity and we recommend future research directions.
Many inhibitory receptors that regulate immune cell function recognize a limited number of specific ligands. However, a subgroup of so-called inhibitory pattern recognition receptors (iPRRs) can bind a much larger array...Many inhibitory receptors that regulate immune cell function recognize a limited number of specific ligands. However, a subgroup of so-called inhibitory pattern recognition receptors (iPRRs) can bind a much larger array of ligands of structural similarity. Leukocyte-associated immunoglobulin-like receptor 1 (LAIR1) is one such iPRR that is expressed by most immune cells and recognizes a common structural pattern present in collagens and collagen domain-containing proteins. LAIR1 signalling regulates diverse immune cell populations and is currently the focus of multiple clinical trials for the treatment of cancer. We here review the current literature on LAIR1, as a prototypic example of how inhibitory PRRs contribute to immune balance and of how these receptors are regulated. We discuss the function of LAIR1 in homeostasis, infection, inflammation and cancer, and consider the advantages and potential pitfalls of targeting this receptor in human disease.
Chimeric antigen receptor (CAR)-engineered immune cell therapy represents an important advance in cancer treatments. However, the complex ex vivo cell manufacturing process and stringent patient selection criteria curtai...Chimeric antigen receptor (CAR)-engineered immune cell therapy represents an important advance in cancer treatments. However, the complex ex vivo cell manufacturing process and stringent patient selection criteria curtail its widespread use. In vivo CAR engineering is emerging as a promising off-the-shelf therapy, providing advantages such as streamlined production, elimination of patient-specific manufacturing, reduced costs and simplified logistics. A large set of preclinical findings has inspired further investigation into treatments for hard-to-treat diseases such as solid tumours and has facilitated the development of advanced products to enhance in vivo CAR engineering efficacy, the persistence of the cellular therapeutic and safety. In this Review, we summarize current in vivo CAR engineering strategies, including nanoparticle-based and viral delivery systems as well as bioinstructive implantable scaffolds, and discuss their advantages and disadvantages. Additionally, we provide a systematic comparison between in vivo and conventional ex vivo CAR engineering methods and address the challenges and future prospects of in vivo CAR engineering.
The central nervous system (CNS) has a unique relationship with the immune system, referred to as immune privilege. For many years it was thought that immune privilege was due to isolation of the CNS from the immune syst...The central nervous system (CNS) has a unique relationship with the immune system, referred to as immune privilege. For many years it was thought that immune privilege was due to isolation of the CNS from the immune system, but recent findings have shown that this theory is flawed and that there is substantial neuroimmune communication, particularly at border sites that encase the CNS. These border sites include perivascular and subarachnoid spaces, the choroid plexus, the meninges and the vasculature, including the recently discovered meningeal lymphatic vessels. CNS border tissues have extensive interaction with the cerebrospinal fluid, which acts as an immune mediator, allowing the immune system at the CNS borders to respond to challenges within the CNS parenchyma. Together, CNS border tissues enable immune surveillance and protection against infections while preventing inflammatory damage to the parenchyma. A better understanding of the mechanisms of immune privilege as an accord, as opposed to isolation, between the two systems would help us obtain effective immunotherapies for neurological diseases.
Cytotoxic lymphocytes counter intracellular pathogens and cancer by recognizing and destroying infected or transformed target cells. The basis for their function is the cytolytic immune synapse, a structurally stereotype...Cytotoxic lymphocytes counter intracellular pathogens and cancer by recognizing and destroying infected or transformed target cells. The basis for their function is the cytolytic immune synapse, a structurally stereotyped cell-cell interface through which lymphocytes deliver toxic proteins to target cells. The immune synapse is a highly dynamic contact capable of exerting nanonewton-scale forces against the target cell. In recent years, it has become clear that the interplay between these forces and the biophysical properties of the target influences the entirety of the cytotoxic response, from the initial activation of cytotoxic lymphocytes to the release of dying target cells. As a result, cellular cytotoxicity has become an exemplar of the ways in which biomechanics can regulate immune cell activation and effector function. This Review covers recent progress in this area, which has prompted a reconsideration of target cell killing from a more mechanobiological perspective.
Transposable elements (TEs) are mobile repetitive nucleic acid sequences that have been incorporated into the genome through spontaneous integration, accounting for almost 50% of human DNA. Even though most TEs are no lo...Transposable elements (TEs) are mobile repetitive nucleic acid sequences that have been incorporated into the genome through spontaneous integration, accounting for almost 50% of human DNA. Even though most TEs are no longer mobile today, studies have demonstrated that they have important roles in different biological processes, such as ageing, embryonic development, and cancer. TEs influence these processes through various mechanisms, including active transposition of TEs contributing to ongoing evolution, transposon transcription generating RNA or protein, and by influencing gene regulation as enhancers. However, how TEs interact with the immune system remains a largely unexplored field. In this Perspective, we describe how TEs might influence different aspects of the immune system, such as innate immune responses, T cell activation and differentiation, and tissue adaptation. Furthermore, TEs can serve as a source of neoantigens for T cells in antitumour immunity. We suggest that TE biology is an important emerging field of immunology and discuss the potential to harness the TE network therapeutically, for example, to improve immunotherapies for cancer and autoimmune and inflammatory diseases.