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Intravaginal anti-HIV microbicides could provide women with a self-controlled means for HIV prevention, but results from clinical trials have been largely disappointing. We postulated that unrecognized effects of intravaginal gels on the upper female reproductive tract might contribute to the lower-than-expected efficacy of HIV microbicides. Our objective was to study the effects of intravaginal gels on the immune microenvironment of the cervix and uterus. In this randomized crossover study, 27 healthy female volunteers used a nightly application of intravaginal nonoxynol-9 (N9) gel as a \"failed\" microbicide or the universal placebo gel (UPG) as a \"safe\" gel (intervention cycles), or nothing (control cycle) from the end of menses to the mid-luteal phase. At a specific time-point following ovulation, all participants underwent sample collection for measurements of T-cell phenotypes, gene expression, and cytokine/chemokine protein concentrations from 3 anatomic sites above the vagina: the cervical transformation zone, the endocervix and the endometrium. We used hierarchical statistical models to estimate mean (95% CI) intervention effects, for N9 and UPG relative to control. Exposure to N9 gel and UPG generated a common \"harm signal\" that included transcriptional up-regulation of inflammatory genes chemokine (C-C motif) ligand 20 (macrophage inflammatory factor-3alpha) and interleukin 8 in the cervix, decreased protein concentrations of secretory leukocyte protease inhibitor, and transcriptional up-regulation of inflammatory mediators glycodelin-A and osteopontin in the endometrium. These results need to be replicated with a larger sample, but underscore the need to consider the effects of microbicide agents and gel excipients on the upper female reproductive tract in studies of vaginal microbicides.

Following periods of haematopoietic cell stress, such as after chemotherapy, radiotherapy, infection and transplantation, patient outcomes are linked to the degree of immune reconstitution, specifically of T cells. Delayed or defective recovery of the T cell pool has significant clinical consequences, including prolonged immunosuppression, poor vaccine responses and increased risks of infections and malignancies. Thus, strategies that restore thymic function and enhance T cell reconstitution can provide considerable benefit to individuals whose immune system has been decimated in various settings. In this Review, we focus on the causes and consequences of impaired adaptive immunity and discuss therapeutic strategies that can recover immune function, with a particular emphasis on approaches that can promote a diverse repertoire of T cells through de novo T cell formation.Reconstitution of the immune system after depletion by chemotherapy, radiotherapy, infection or transplantation is crucial to maintain protection from infection and to respond to immune-based therapy. Here the authors describe the ways in which a diverse T cell compartment can be restored, focusing on therapeutic strategies that drive the production of new T cells.

The community of cells lining our airways plays a collaborative role in the preservation of immune homeostasis in the lung and provides protection from the pathogens and pollutants in the air we breathe. In addition to its structural attributes that provide effective mucociliary clearance of the lower airspace, the airway epithelium is an immunologically active barrier surface that senses changes in the airway environment and interacts with resident and recruited immune cells. Single-cell RNA-sequencing is illuminating the cellular heterogeneity that exists in the airway wall and has identified novel cell populations with unique molecular signatures, trajectories of differentiation and diverse functions in health and disease. In this Review, we discuss how our view of the airway epithelial landscape has evolved with the advent of transcriptomic approaches to cellular phenotyping, with a focus on epithelial interactions with the local neuronal and immune systems.In this Review, Lloyd and Hewitt describe our contemporary understanding of the airway epithelial cell landscape. They highlight the new epithelial cell types that have been recently discovered and explain how epithelial cells interact with the immune and nervous systems to shape immunity in the airways.

Key Points The cell fate decisions of developing thymocytes are coordinated by interactions with self-peptide–MHC complexes that are displayed by various types of thymic antigen presenting cells (APCs). Different thymic APCs use cell type-specific strategies of self antigen sampling and processing. Cortical thymic epithelial cells (cTECs) use unique proteolytic pathways to generate MHC class I-bound and MHC class II-bound peptides, and these 'private' peptides expressed by cTECs are critical for the positive selection of a fully functional T cell repertoire. Several types of haematopoieteic and non-haematopoietic APCs cooperatively present self antigens for central tolerance induction. Medullary thymic epithelial cells (mTECs) promiscuously express peripheral self antigens and autonomously present these to thymocytes. Different subsets of dendritic cells sample blood-borne and mTEC-derived self antigens within the thymus or transport peripheral self antigens into the thymus. Here, the authors describe the key characteristics of the different antigen-presenting cell (APC) populations that govern T cell development in the thymus. They discuss how the interactions that occur between thymocytes and thymic APCs shape the mature T cell repertoire, and how they subsequently affect the nature of peripheral immune responses. The fate of developing T cells is specified by the interaction of their antigen receptors with self-peptide–MHC complexes that are displayed by thymic antigen-presenting cells (APCs). Various subsets of thymic APCs are strategically positioned in particular thymic microenvironments and they coordinate the selection of a functional and self-tolerant T cell repertoire. In this Review, we discuss the different strategies that these APCs use to sample and process self antigens and to thereby generate partly unique, 'idiosyncratic' peptide–MHC ligandomes. We discuss how the particular composition of the peptide–MHC ligandomes that are presented by specific APC subsets not only shapes the T cell repertoire in the thymus but may also indelibly imprint the behaviour of mature T cells in the periphery.

Key Points Hypoxia and inflammation are frequently co-incidental microenvironmental features of sites of concentrated physiological or pathological immune activity. Hypoxia activates hypoxia-inducible factor, which is a major regulator of multiple aspects of immune cell function. Consequently, hypoxia plays a key role in the regulation of immunity and inflammation. The impact of hypoxia on immunity and inflammation is site-specific and cell type-specific. Pharmacological hydroxylase inhibition, which activates hypoxia-sensitive pathways, is profoundly protective in multiple models of inflammation. Hypoxia is a microenvironmental feature that is associated with physiological and pathological immunological niches. In this Review, Taylor and Colgan summarize the effects of physiological and pathological hypoxia on immune cells and processes and discuss the possibility of therapeutically targeting hypoxia-sensitive pathways. Immunological niches are focal sites of immune activity that can have varying microenvironmental features. Hypoxia is a feature of physiological and pathological immunological niches. The impact of hypoxia on immunity and inflammation can vary depending on the microenvironment and immune processes occurring in a given niche. In physiological immunological niches, such as the bone marrow, lymphoid tissue, placenta and intestinal mucosa, physiological hypoxia controls innate and adaptive immunity by modulating immune cell proliferation, development and effector function, largely via transcriptional changes driven by hypoxia-inducible factor (HIF). By contrast, in pathological immunological niches, such as tumours and chronically inflamed, infected or ischaemic tissues, pathological hypoxia can drive tissue dysfunction and disease development through immune cell dysregulation. Here, we differentiate between the effects of physiological and pathological hypoxia on immune cells and the consequences for immunity and inflammation in different immunological niches. Furthermore, we discuss the possibility of targeting hypoxia-sensitive pathways in immune cells for the treatment of inflammatory disease.

Tissue-resident memory T (T RM ) cells are non-recirculating cells that exist throughout the body. Although T RM cells in various organs rely on common transcriptional networks to establish tissue residency, location-specific factors adapt these cells to their tissue of lodgment. Here we analyze T RM cell heterogeneity between organs and find that the different environments in which these cells differentiate dictate T RM cell function, durability and malleability. We find that unequal responsiveness to TGFβ is a major driver of this diversity. Notably, dampened TGFβ signaling results in CD103 − T RM cells with increased proliferative potential, enhanced function and reduced longevity compared with their TGFβ-responsive CD103 + T RM counterparts. Furthermore, whereas CD103 − T RM cells readily modified their phenotype upon relocation, CD103 + T RM cells were comparatively resistant to transdifferentiation. Thus, despite common requirements for T RM cell development, tissue adaptation of these cells confers discrete functional properties such that T RM cells exist along a spectrum of differentiation potential that is governed by their local tissue microenvironment. Tissue-resident memory T (T RM ) cells are distributed throughout the body as relatively sessile populations. Mackay and colleagues find that the tissue in which T RM cells are generated dictates their properties and is in turn defined according to T RM -cell-intrinsic sensitivity to signaling via the cytokine TGFβ.

Tissue-resident memory T cells (T RM cells) are critical for cellular immunity to respiratory pathogens and reside in both the airways and the interstitium. In the present study, we found that the airway environment drove transcriptional and epigenetic changes that specifically regulated the cytolytic functions of airway T RM cells and promoted apoptosis due to amino acid starvation and activation of the integrated stress response. Comparison of airway T RM cells and splenic effector-memory T cells transferred into the airways indicated that the environment was necessary to activate these pathways, but did not induce T RM cell lineage reprogramming. Importantly, activation of the integrated stress response was reversed in airway T RM cells placed in a nutrient-rich environment. Our data defined the genetic programs of distinct lung T RM cell populations and show that local environmental cues altered airway T RM cells to limit cytolytic function and promote cell death, which ultimately leads to fewer T RM cells in the lung. Kohlmeier and colleagues showed that the airway environment drove transcriptional and epigenetic changes that regulated the cytolytic functions of airway T RM cells and promoted their apoptosis due to amino acid starvation and activation of the integrated stress response.

Changes in cellular metabolism are associated with the activation of diverse immune subsets. These changes are fuelled by nutrients including glucose, amino acids and fatty acids, and are closely linked to immune cell fate and function. An emerging concept is that nutrients are not equally available to all immune cells, suggesting that the regulation of nutrient utility through competitive uptake and use is important for controlling immune responses. This review considers immune microenvironments where nutrients become limiting, the signalling alterations caused by insufficient nutrients, and the importance of nutrient availability in the regulation of immune responses. Immune cells adapt distinct metabolic strategies to accommodate specific functions associated with cell types or differentiation stages. Here in this review the authors discuss the nutrients, sensors, and mediators of such a metabolic adaption in nutrient-limiting immune microenvironments such as tumors or infections.

Extracellular vesicles such as exosomes, microvesicles, apoptotic bodies, and large oncosomes have been shown to participate in a wide variety of biological processes and are currently under intense investigation in many different fields of biomedicine. One of the key features of extracellular vesicles is that they have relatively large surface compared to their volume. Some extracellular vesicle surface molecules are shared with those of the plasma membrane of the releasing cell, while other molecules are characteristic for extracellular vesicular surfaces. Besides proteins, lipids, glycans, and nucleic acids are also players of extracellular vesicle surface interactions. Being secreted and present in high number in biological samples, collectively extracellular vesicles represent a uniquely large interactive surface area which can establish contacts both with cells and with molecules in the extracellular microenvironment. Here, we provide a brief overview of known components of the extracellular vesicle surface interactome and highlight some already established roles of the extracellular vesicle surface interactions in different biological processes in health and disease.

Key Points Optimized interstitial migration of leukocytes is necessary for their timely arrival at sites of tissue injury and microbial assault. This process is regulated by a multitude of cell-intrinsic and environmental factors. Intravital imaging studies have shed new light on the dynamics and regulation of interstitial leukocyte migration in non-lymphoid organs. These studies are discussed in this Review, with a focus on neutrophils and T cells. The actin cytoskeleton regulates the formation of a polarized cellular shape, which defines the 'amoeboid' migration mode of leukocytes in the interstitial space. Transendothelial migration of leukocytes and their entry into the interstitial space is regulated by the perivascular extravasation unit (PVEU), which is composed of endothelial cells, pericytes, perivascular macrophages, mast cells and the basement membrane. The PVEU provides physical and biochemical guidance for leukocytes during and after diapedesis. Neutrophil migration towards a focus of tissue injury is regulated by a multistep process defined by scouting, amplification and stabilization phases. Scouting is the initial process whereby scarce neutrophils accumulate at the focus. In a feedforward loop, these cells then attract waves of additional neutrophils, which form a cluster around the focus in order to contain tissue injury and pathogens. Directional decision making by migrating neutrophils is mediated by temporally and spatially coordinated gradients of chemoattractants and chemorepellents within tissues, and by physical guidance structures provided, for example, by pericytes. Multiple competing signals are integrated by intracellular signalling molecules in crawling neutrophils. Migrating effector T cell populations scan tissues for the presence of antigen. Signals delivered by the T cell receptor regulate both migratory stops — which are necessary for target cell interactions — and also the highly active migratory phenotype of T cells. Investigation of T cell population dynamics suggests that Lévy walk behaviour underlies the search strategies of T cells, and optimizes target screening behaviour. Functional impairment of T cells, such as a tolerized or exhausted state, is paralleled by impaired migration. Co-stimulatory and co-inhibitory pathways have been implicated in regulating the migration of functionally impaired T cells. A variety of innate immune cell subsets display active screening behaviour in non-lymphoid organs, which underlies the rapid detection of tissue debris or pathogens. This Review follows neutrophils and T cells as they journey from the blood into tissues in search of sites of infection or injury. It highlights the mediators, which form temporally and spatially coordinated gradients within the tissues, and the mechanisms, including physical structures, that guide this directional migration. Leukocyte migration through interstitial tissues is essential for mounting a successful immune response. Interstitial motility is governed by a vast array of cell-intrinsic and cell-extrinsic factors that together ensure the proper positioning of immune cells in the context of specific microenvironments. Recent advances in imaging modalities, in particular intravital confocal and multi-photon microscopy, have helped to expand our understanding of the cellular and molecular mechanisms that underlie leukocyte navigation in the extravascular space. In this Review, we discuss the key factors that regulate leukocyte motility within three-dimensional environments, with a focus on neutrophils and T cells in non-lymphoid organs.