Immunology

Macrophages destroy bacteria and other microorganisms through phagocytosis-coupled antimicrobial responses, such as the generation of reactive oxygen species and the delivery of hydrolytic enzymes from lysosomes to the phagosome. However, many intracellular bacteria subvert these responses, escaping to other cellular compartments to survive and/or replicate. Such bacterial subversion strategies are countered by a range of additional direct antibacterial responses that are switched on by pattern-recognition receptors and/or host-derived cytokines and other factors, often through inducible gene expression and/or metabolic reprogramming. Our understanding of these inducible antibacterial defence strategies in macrophages is rapidly evolving. In this Review, we provide an overview of the broad repertoire of antibacterial responses that can be engaged in macrophages, including LC3-associated phagocytosis, metabolic reprogramming and antimicrobial metabolites, lipid droplets, guanylate-binding proteins, antimicrobial peptides, metal ion toxicity, nutrient depletion, autophagy and nitric oxide production. We also highlight key inducers, signalling pathways and transcription factors involved in driving these different antibacterial responses. Finally, we discuss how a detailed understanding of the molecular mechanisms of antibacterial responses in macrophages might be exploited for developing host-directed therapies to combat antibiotic-resistant bacterial infections. Macrophages are innate immune sentinels providing frontline defence against infection. This Review describes the inducible mechanisms used by macrophages to kill bacterial pathogens and/or inhibit their growth and outlines how this knowledge might be exploited in the design of host-directed therapies.

The thymus is essential for establishing adaptive immunity yet undergoes age-related involution that leads to compromised immune responsiveness. The thymus is also extremely sensitive to acute insult and although capable of regeneration, this capacity declines with age for unknown reasons. We applied single-cell and spatial transcriptomics, lineage-tracing and advanced imaging to define age-related changes in nonhematopoietic stromal cells and discovered the emergence of two atypical thymic epithelial cell (TEC) states. These age-associated TECs (aaTECs) formed high-density peri-medullary epithelial clusters that were devoid of thymocytes; an accretion of nonproductive thymic tissue that worsened with age, exhibited features of epithelial-to-mesenchymal transition and was associated with downregulation of FOXN1. Interaction analysis revealed that the emergence of aaTECs drew tonic signals from other functional TEC populations at baseline acting as a sink for TEC growth factors. Following acute injury, aaTECs expanded substantially, further perturbing trophic regeneration pathways and correlating with defective repair of the involuted thymus. These findings therefore define a unique feature of thymic involution linked to immune aging and could have implications for developing immune-boosting therapies in older individuals. Here the authors identify age-associated changes in the epithelial cell compartment of the thymus that form high-density nonproductive microenvironmental niches that contribute toward thymic involution and inhibit its repair following injury.

Eosinophils are bone marrow-derived granulocytes that are traditionally associated with type 2 immune responses, such as those that occur during parasite infections and allergy. Emerging evidence demonstrates the remarkable functional plasticity of this elusive cell type and its pleiotropic functions in diverse settings. Eosinophils broadly contribute to tissue homeostasis, host defence and immune regulation, predominantly at mucosal sites. The scope of their activities primarily reflects the breadth of their portfolio of secreted mediators, which range from cytotoxic cationic proteins and reactive oxygen species to multiple cytokines, chemokines and lipid mediators. Here, we comprehensively review basic eosinophil biology that is directly related to their activities in homeostasis, protective immunity, regeneration and cancer. We examine how dysregulation of these functions contributes to the physiopathology of a broad range of inflammatory diseases. Furthermore, we discuss recent findings regarding the tissue compartmentalization and adaptation of eosinophils, shedding light on the factors that likely drive their functional diversification within tissues. This Review by Arnold and Munitz discusses the diverse roles of eosinophils in the settings of tissue homeostasis, infection, allergy and cancer. The authors explain the molecular mechanisms that enable eosinophils to adapt to diverse tissue types and conditions, and they consider the therapeutic potential of eosinophil-depleting drugs in the clinic.

Tumours can obtain nutrients and oxygen required to progress and metastasize through the blood supply1. Inducing angiogenesis involves the sprouting of established vessel beds and their maturation into an organized network2,3. Here we generate a comprehensive atlas of tumour vasculature at single-cell resolution, encompassing approximately 200,000 cells from 372 donors representing 31 cancer types. Trajectory inference suggested that tumour angiogenesis was initiated from venous endothelial cells and extended towards arterial endothelial cells. As neovascularization elongates (through angiogenic stages SI, SII and SIII), APLN+ tip cells at the SI stage (APLN+ TipSI) advanced to TipSIII cells with increased Notch signalling. Meanwhile, stalk cells, following tip cells, transitioned from high chemokine expression to elevated TEK (also known as Tie2) expression. Moreover, APLN+ TipSI cells not only were associated with disease progression and poor prognosis but also hold promise for predicting response to anti-VEGF therapy. Lymphatic endothelial cells demonstrated two distinct differentiation lineages: one responsible for lymphangiogenesis and the other involved in antigen presentation. In pericytes, endoplasmic reticulum stress was associated with the proangiogenic BASP1+ matrix-producing pericytes. Furthermore, intercellular communication analysis showed that neovascular endothelial cells could shape an immunosuppressive microenvironment conducive to angiogenesis. This study depicts the complexity of tumour vasculature and has potential clinical significance for anti-angiogenic therapy. An atlas of tumour vasculature shows that tumour angiogenesis is initiated from venous endothelial cells and extended towards arterial endothelial cells.

Proinflammatory cytokines and chemokines play a crucial role in regulating the inflammatory response, which is essential for the proper functioning of our immune system. When infections or threats to the body’s defense mechanisms are detected, the innate immune system takes the lead. However, an excessive inflammatory response can lead to the production of high concentrations of cytotoxic molecules, resulting in tissue damage. Inflammasomes are significant contributors to innate immunity, and one of the most extensively studied inflammasome complexes is NOD-like receptor 3 (NLRP3). NLRP3 has a wide range of recognition mechanisms that streamline immune activation and eliminate pathogens. These cytosolic multiprotein complexes are composed of effector, adaptor, and sensor proteins, which are crucial for identifying intracellular bacterial breakdown products and initiating an innate immune cascade. To understand the diverse behavior of NLRP3 activation and its significance in the development of lifestyle-related diseases, one must delve into the study of the immune response and apoptosis mediated by the release of proinflammatory cytokines. In this review, we briefly explore the immune response in the context of lifestyle associated disorders such as obesity, hyperlipidemia, diabetes, chronic respiratory disease, oral disease, and cardiovascular disease. NOD-like receptors (NLRs - proteins that help our immune system fight off harmful invaders) are vital for our health. Their function in T and B cells (types of white blood cells) is less clear. Scientists have found 22 kinds of NLRs in humans, which start different immune and inflammation responses. This study is a detailed review of NLRs, examining their structure, how they are activated, and their role in diseases like obesity, diabetes, and heart problems. It emphasizes that NLRs, particularly the NLRP3 inflammasome (a protein complex involved in inflammation), are key in lifestyle diseases by causing inflammation. The review proposes that focusing on NLRP3 could lead to new treatments for these diseases. This research is a big step in understanding how our natural immune system contributes to chronic diseases and offers potential for new treatments. Future research could further explore the complexities of NLRs and their potential as treatment targets. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

Dendritic cells (DCs) are crucial gatekeepers of the balance between immunity and tolerance. They exist in two functional states, immature or mature, that refer to an information-sensing versus an information-transmitting state, respectively. Historically, the term DC maturation was used to describe the acquisition of immunostimulatory capacity by DCs following their triggering by pathogens or tissue damage signals. As such, immature DCs were proposed to mediate tolerance, whereas mature DCs were associated with the induction of protective T cell immunity. Later studies have challenged this view and unequivocally demonstrated that two distinct modes of DC maturation exist, homeostatic and immunogenic DC maturation, each with a distinct functional outcome. Therefore, the mere expression of maturation markers cannot be used to predict immunogenicity. How DCs become activated in homeostatic conditions and maintain tolerance remains an area of intense debate. Several recent studies have shed light on the signals driving the homeostatic maturation programme, especially in the conventional type 1 DC (cDC1) compartment. Here, we highlight our growing understanding of homeostatic DC maturation and the relevance of this process for immune tolerance. Dendritic cells (DCs) act as gatekeepers between immunity and tolerance. Initially, it was postulated that mature DCs promote effector T cell responses and immature DCs promote tolerance. Recent studies have shown instead that two distinct modes of DC maturation exist — homeostatic and immunogenic. Here, Bosteels and Janssens discuss our current understanding of homeostatic DC maturation and how this contributes to immune tolerance, with a focus on the cDC1 compartment.

Antibodies are exceptionally versatile molecules with remarkable flexibility in their binding properties. Their natural targets range from small-molecule toxins, across viruses of different sizes, to bacteria and large multicellular parasites. The molecular determinants bound by antibodies include proteins, peptides, carbohydrates, nucleic acids, lipids and even synthetic molecules that have never existed in nature. Membrane-anchored antibodies also serve as receptors on the surface of the B cells that produce them. Despite recent structural insights, there is still no unifying molecular mechanism to explain how antibody targets (antigens) trigger the activation of these B-cell receptors (BCRs). After cognate antigen encounter, somatic hypermutation and class-switch recombination allow BCR affinity maturation and immunoglobulin class-specific responses, respectively. This raises the fundamental question of how one receptor activation mechanism can accommodate a plethora of variant receptors and ligands, and how it can ensure that individual B cells remain responsive to antigen after somatic hypermutation and class switching. There is still no definite answer. Here we give a brief historical account of the different models proposed to explain BCR triggering and discuss their merit in the context of the current knowledge of the structure of BCRs, their dynamic membrane distribution, and recent biochemical and cell biological insights. The mechanisms by which antigen triggers B-cell activation are incompletely understood. In this Review, Degn and Tolar discuss the different models of B-cell receptor triggering that have been proposed over the years in the light of recent insights.

Balanced immune responses in the eyes are crucial to preserve vision. The ocular immune system has long been considered distinct, owing to the so-called ‘immune privilege’ of its component tissues. More recently, intravital imaging and transcriptomic techniques have reshaped scientific understanding of the ocular immune landscape, such as revealing the specialization of immune cell populations in the various tissues of the eye. As knowledge of the phenotypes of corneal and retinal immune cells has evolved, links to both the systemic immune system, and the central and peripheral nervous systems, have been identified. Using intravital imaging, T cells have recently been found to reside in, and actively patrol, the healthy human cornea. Disease-associated retinal microglia with links to retinal degeneration have also been identified. This Review provides an updated guide to the ocular immune system, highlighting current knowledge of the immune cells that are present in steady-state and specific diseased ocular tissues, as well as evidence for their relationship to systemic disease. In addition, we discuss emerging intravital imaging techniques that can be used to visualize immune cell morphology and dynamics in living human eyes and how these could be applied to advance understanding of the human immune system. This Review provides an overview of the immune system of the eye at steady state and in ocular disease, and it describes the links between ocular immunology and systemic disease. It highlights the intravital imaging techniques that have provided insights into immune cell morphology and dynamics in living human eyes.

Antibody-dependent enhancement (ADE) of infectious disease is a phenomenon whereby host antibodies increase the severity of an infection. It is well established in viral infections but ADE also has an underappreciated role during bacterial, fungal and parasitic infections. ADE can occur during both primary infections and re-infections with the same or a related pathogen; therefore, understanding the underlying mechanisms of ADE is critical for understanding the pathogenesis and progression of many infectious diseases. Here, we review the four distinct mechanisms by which antibodies increase disease severity during an infection. We discuss the most established mechanistic explanation for ADE, where cross-reactive, disease-enhancing antibodies bound to pathogens interact with Fc receptors, thereby enhancing pathogen entry or replication, ultimately increasing the total pathogen load. Additionally, we explore how some pathogenic antibodies can shield bacteria from complement-dependent killing, thereby enhancing bacterial survival. We interrogate the molecular mechanisms by which antibodies can amplify inflammation to drive severe disease, even in the absence of increased pathogen replication. We also examine emerging roles for autoantibodies in enhancing the pathogenesis of infectious diseases. Finally, we discuss how we can leverage these insights to improve vaccine design and future treatments for infectious diseases. This Review discusses the different mechanisms of antibody-dependent enhancement (ADE) of infectious disease, including how antibodies can increase the pathogen load, protect bacteria from the immune system and amplify inflammation. The authors also highlight the role of autoantibodies and consider how a better understanding of ADE can be used to improve vaccines and treatments for infectious diseases.

Summary. There is an intriguing dichotomy in the function of cytokine interleukin-15—at low levels, it is required for the homeostasis of the immune system

Written by Claire Kowalick A breakthrough for biomedical research promises new insight into immunotherapy development and disease modeling. Scientists at The University of Texas Health Science Center at San Antonio have created a humanized mouse model with a human immune system and a human-like gut microbiome that is capable of mounting specific antibody responses. The scientists […]

Natural killer (NK) cells are innate lymphoid cells (ILCs) that serve as a first line of defense against pathogens and tumors. Historically, their classification hinged on a limited array of surface protein markers. However, recent advancements in single-cell technologies, such assingle-cell RNA sequencing (scRNA-seq) and cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq), have unveiled a more complex and nuanced understanding of NK cells. This has led to variations in nomenclature and inconsistencies across scientific literature. In our study, we utilized these technologies to dissect the heterogeneity of NK cells in healthy human blood. We identified three prominent NK cell subsets: NK1, NK2 and NK3, further differentiated into six distinct subgroups. All subsets were present in all donors, irrespective of their human cytomegalovirus (HCMV) status. Our findings delineate the unique molecular characteristics, key transcription factors, principal biological functions, significant metabolic traits, and cytokine responses of each subgroup. These data also suggest two separate ontogenetic origins for NK cells, leading to divergent transcriptional trajectories. We explore these pathways in depth and propose a comprehensive, standardized nomenclature for NK cells. This standardized terminology aims at fostering clarity and consistency in future research, thereby improving cross-study comparisons.

Summary. Basophils are the rarest leukocytes, but they have essential roles in protection against helminths, allergic disorders, autoimmune diseases, and s