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Showing papers in "Nature Reviews Immunology in 2016"


Journal ArticleDOI
TL;DR: It is emphasized that sex is a biological variable that should be considered in immunological studies and contribute to variations in the incidence of autoimmune diseases and malignancies, susceptibility to infectious diseases and responses to vaccines in males and females.
Abstract: Males and females differ in their immunological responses to foreign and self-antigens and show distinctions in innate and adaptive immune responses. Certain immunological sex differences are present throughout life, whereas others are only apparent after puberty and before reproductive senescence, suggesting that both genes and hormones are involved. Furthermore, early environmental exposures influence the microbiome and have sex-dependent effects on immune function. Importantly, these sex-based immunological differences contribute to variations in the incidence of autoimmune diseases and malignancies, susceptibility to infectious diseases and responses to vaccines in males and females. Here, we discuss these differences and emphasize that sex is a biological variable that should be considered in immunological studies.

3,214 citations


Journal ArticleDOI
TL;DR: Current understanding of the mechanisms by which the innate and adaptive immune systems interact with neurotransmitters and neurocircuits to influence the risk for depression are detailed.
Abstract: Crosstalk between inflammatory pathways and neurocircuits in the brain can lead to behavioural responses, such as avoidance and alarm, that are likely to have provided early humans with an evolutionary advantage in their interactions with pathogens and predators. However, in modern times, such interactions between inflammation and the brain appear to drive the development of depression and may contribute to non-responsiveness to current antidepressant therapies. Recent data have elucidated the mechanisms by which the innate and adaptive immune systems interact with neurotransmitters and neurocircuits to influence the risk for depression. Here, we detail our current understanding of these pathways and discuss the therapeutic potential of targeting the immune system to treat depression.

2,133 citations


Journal ArticleDOI
TL;DR: This Review discusses the recent developments in inflammasome research with a focus on the molecular mechanisms that govern inflammaome assembly, signalling and regulation.
Abstract: Inflammasomes are multiprotein signalling platforms that control the inflammatory response and coordinate antimicrobial host defences. They are assembled by pattern-recognition receptors following the detection of pathogenic microorganisms and danger signals in the cytosol of host cells, and they activate inflammatory caspases to produce cytokines and to induce pyroptotic cell death. The clinical importance of inflammasomes reaches beyond infectious disease, as dysregulated inflammasome activity is associated with numerous hereditary and acquired inflammatory disorders. In this Review, we discuss the recent developments in inflammasome research with a focus on the molecular mechanisms that govern inflammasome assembly, signalling and regulation.

2,084 citations


Journal ArticleDOI
TL;DR: Technological and computational approaches for investigating the microbiome, as well as recent advances in the understanding of host immunity and microbial mutualism are discussed with a focus on specific microbial metabolites, bacterial components and the immune system.
Abstract: The microbiota - the collection of microorganisms that live within and on all mammals - provides crucial signals for the development and function of the immune system. Increased availability of technologies that profile microbial communities is facilitating the entry of many immunologists into the evolving field of host-microbiota studies. The microbial communities, their metabolites and components are not only necessary for immune homeostasis, they also influence the susceptibility of the host to many immune-mediated diseases and disorders. In this Review, we discuss technological and computational approaches for investigating the microbiome, as well as recent advances in our understanding of host immunity and microbial mutualism with a focus on specific microbial metabolites, bacterial components and the immune system.

1,926 citations


Journal ArticleDOI
TL;DR: A brief refresher course on six of the major metabolic pathways involved in immunometabolism is provided, giving specific examples of how precise changes in the metabolites of these pathways shape the immune cell response.
Abstract: Immunometabolism is emerging an important area of immunological research, but for many immunologists the complexity of the field can be daunting. Here, the authors provide an overview of six key metabolic pathways that occur in immune cells and explain what is known (and what is still to be uncovered) concerning their effects on immune cell function. In recent years a substantial number of findings have been made in the area of immunometabolism, by which we mean the changes in intracellular metabolic pathways in immune cells that alter their function. Here, we provide a brief refresher course on six of the major metabolic pathways involved (specifically, glycolysis, the tricarboxylic acid (TCA) cycle, the pentose phosphate pathway, fatty acid oxidation, fatty acid synthesis and amino acid metabolism), giving specific examples of how precise changes in the metabolites of these pathways shape the immune cell response. What is emerging is a complex interplay between metabolic reprogramming and immunity, which is providing an extra dimension to our understanding of the immune system in health and disease.

1,857 citations


Journal ArticleDOI
TL;DR: The mechanisms that fine-tune immune signalling to maintain immune homeostasis are described and how the innate ability of plant cells to monitor the integrity of key immune components can lead to autoimmune phenotypes following genetic or pathogen-induced perturbations of these components are discussed.
Abstract: Plants depend on cell-autonomous innate immune mechanisms for protection against infection and these pathways are activated in response to pattern recognition receptor (PRR) engagement. However, as is the case in mammals, PRR signalling in plants must be tightly controlled to avoid pathological outcomes; this Review focuses on the mechanisms that regulate plant PRR signalling.

841 citations


Journal ArticleDOI
TL;DR: The molecular and cellular characteristics of IL-33 are highlighted, together with its major role in health and disease and the potential therapeutic implications of these findings in humans are highlighted.
Abstract: Interleukin-33 (IL-33) - a member of the IL-1 family - was originally described as an inducer of type 2 immune responses, activating T helper 2 (TH2) cells and mast cells. Now, evidence is accumulating that IL-33 also potently stimulates group 2 innate lymphoid cells (ILC2s), regulatory T (Treg) cells, TH1 cells, CD8+ T cells and natural killer (NK) cells. This pleiotropic nature is reflected in the role of IL-33 in tissue and metabolic homeostasis, infection, inflammation, cancer and diseases of the central nervous system. In this Review, we highlight the molecular and cellular characteristics of IL-33, together with its major role in health and disease and the potential therapeutic implications of these findings in humans.

721 citations


Journal ArticleDOI
TL;DR: This Review discusses the major advances and the emerging concepts in this field, summarizes what is known about the differentiation and the protective functions of tissue-resident memory T cells in different tissues in the body and highlights key unanswered questions.
Abstract: T cells have crucial roles in protection against infection and cancer. Although the trafficking of memory T cells around the body is integral to their capacity to provide immune protection, studies have shown that specialization of some memory T cells into unique tissue-resident subsets gives the host enhanced regional immunity. In recent years, there has been considerable progress in our understanding of tissue-resident T cell development and function, revealing mechanisms for enhanced protective immunity that have the potential to influence rational vaccine design. This Review discusses the major advances and the emerging concepts in this field, summarizes what is known about the differentiation and the protective functions of tissue-resident memory T cells in different tissues in the body and highlights key unanswered questions.

709 citations


Journal ArticleDOI
TL;DR: The different cues within tissues that mediate neutrophil forward and reverse migration in response to injury or infection are discussed and the implications of these mechanisms to human disease are discussed.
Abstract: Neutrophil migration and its role during inflammation has been the focus of increased interest in the past decade. Advances in live imaging and the use of new model systems have helped to uncover the behaviour of neutrophils in injured and infected tissues. Although neutrophils were considered to be short-lived effector cells that undergo apoptosis in damaged tissues, recent evidence suggests that neutrophil behaviour is more complex and, in some settings, neutrophils might leave sites of tissue injury and migrate back into the vasculature. The role of reverse migration and its contribution to resolution of inflammation remains unclear. In this Review, we discuss the different cues within tissues that mediate neutrophil forward and reverse migration in response to injury or infection and the implications of these mechanisms to human disease.

673 citations


Journal ArticleDOI
TL;DR: This Review focuses on human HDPs and explores the diverse immunomodulatory effects of HDPs from a systems biology perspective, which highlights the interconnected nature of the effect (or effects) ofHDPs on the host.
Abstract: Host defence peptides (HDPs) are short, cationic amphipathic peptides with diverse sequences that are produced by various cells and tissues in all complex life forms. HDPs have important roles in the body's response to infection and inflammation. This Review focuses on human HDPs and explores the diverse immunomodulatory effects of HDPs from a systems biology perspective, which highlights the interconnected nature of the effect (or effects) of HDPs on the host. Studies have demonstrated that HDPs are expressed throughout the body and mediate a broad range of activities, which explains their association with various inflammatory diseases and autoimmune disorders. The diverse actions of HDPs, such as their roles in wound healing and in the maintenance of the microbiota, are also explored, in addition to potential therapeutic applications.

632 citations


Journal ArticleDOI
TL;DR: How local purinergic signalling changes over time during tissue responses to injury or disease is reviewed, and the potential of targeting purInergic signalling pathways for the immunotherapeutic treatment of ischaemia, organ transplantation, autoimmunity or cancer is discussed.
Abstract: Cellular stress or apoptosis triggers the release of ATP, ADP and other nucleotides into the extracellular space. Extracellular nucleotides function as autocrine and paracrine signalling molecules by activating cell-surface P2 purinergic receptors that elicit pro-inflammatory immune responses. Over time, extracellular nucleotides are metabolized to adenosine, leading to reduced P2 signalling and increased signalling through anti-inflammatory adenosine (P1 purinergic) receptors. Here, we review how local purinergic signalling changes over time during tissue responses to injury or disease, and we discuss the potential of targeting purinergic signalling pathways for the immunotherapeutic treatment of ischaemia, organ transplantation, autoimmunity or cancer.

Journal ArticleDOI
TL;DR: This Review will give a basic overview of mucus, mucins and goblet cells, and explain how each of these contributes to immune regulation in the intestine.
Abstract: A number of mechanisms ensure that the intestine is protected from pathogens and also against our own intestinal microbiota. The outermost of these is the secreted mucus, which entraps bacteria and prevents their translocation into the tissue. Mucus contains many immunomodulatory molecules and is largely produced by the goblet cells. These cells are highly responsive to the signals they receive from the immune system and are also able to deliver antigens from the lumen to dendritic cells in the lamina propria. In this Review, we will give a basic overview of mucus, mucins and goblet cells, and explain how each of these contributes to immune regulation in the intestine.

Journal ArticleDOI
TL;DR: The importance of the UPR in the development, differentiation, function and survival of immune cells in meeting the needs of an immune response is discussed and current insights into how it is involved in complex chronic inflammatory diseases and, through its role in immune regulation, antitumour responses are reviewed.
Abstract: The unfolded protein response (UPR) is a highly conserved pathway that allows the cell to manage endoplasmic reticulum (ER) stress that is imposed by the secretory demands associated with environmental forces. In this role, the UPR has increasingly been shown to have crucial functions in immunity and inflammation. In this Review, we discuss the importance of the UPR in the development, differentiation, function and survival of immune cells in meeting the needs of an immune response. In addition, we review current insights into how the UPR is involved in complex chronic inflammatory diseases and, through its role in immune regulation, antitumour responses.

Journal ArticleDOI
TL;DR: The mechanisms by which several miRNAs influence immune development and buffer normal haematopoietic output are discussed, first at the level of haematic stem cells, then in innate and adaptive immune cells, and the pathological consequences of dysregulation of these mi RNAs are discussed.
Abstract: MicroRNAs (miRNAs) are crucial post-transcriptional regulators of haematopoietic cell fate decisions. They act by negatively regulating the expression of key immune development genes, thus contributing important logic elements to the regulatory circuitry. Deletion studies have made it increasingly apparent that they confer robustness to immune cell development, especially under conditions of environmental stress such as infectious challenge and ageing. Aberrant expression of certain miRNAs can lead to pathological consequences, such as autoimmunity and haematological cancers. In this Review, we discuss the mechanisms by which several miRNAs influence immune development and buffer normal haematopoietic output, first at the level of haematopoietic stem cells, then in innate and adaptive immune cells. We then discuss the pathological consequences of dysregulation of these miRNAs.

Journal ArticleDOI
TL;DR: The expanding and interconnected roles of caspases that highlight new aspects of this family of cysteine proteases in innate immunity are discussed.
Abstract: Inflammatory and apoptotic caspases are central players in inflammation and apoptosis, respectively. However, recent studies have revealed that these caspases have functions beyond their established roles. In addition to mediating cleavage of the inflammasome-associated cytokines interleukin-1β (IL-1β) and IL-18, inflammatory caspases modulate distinct forms of programmed cell death and coordinate cell-autonomous immunity and other fundamental cellular processes. Certain apoptotic caspases assemble structurally diverse and dynamic complexes that direct inflammasome and interferon responses to fine-tune inflammation. In this Review, we discuss the expanding and interconnected roles of caspases that highlight new aspects of this family of cysteine proteases in innate immunity.

Journal ArticleDOI
TL;DR: This work focuses primarily on SPMs and their roles in lung infection and inflammation to illustrate the potent actions these mediators play in restoring tissue homeostasis after an infection.
Abstract: Specialized pro-resolving mediators (SPMs) are enzymatically derived from essential fatty acids and have important roles in orchestrating the resolution of tissue inflammation - that is, catabasis. Host responses to tissue infection elicit acute inflammation in an attempt to control invading pathogens. SPMs are lipid mediators that are part of a larger family of pro-resolving molecules, which includes proteins and gases, that together restrain inflammation and resolve the infection. These immunoresolvents are distinct from immunosuppressive molecules as they not only dampen inflammation but also promote host defence. Here, we focus primarily on SPMs and their roles in lung infection and inflammation to illustrate the potent actions these mediators play in restoring tissue homeostasis after an infection.

Journal ArticleDOI
TL;DR: In this Review, many of the numerous distinct mechanisms for the self-regulation and cross-regulation of innate immune receptor signalling are described.
Abstract: In the initiation of innate immune responses against pathogens, pattern-recognition receptors (PRRs) have an essential role in recognizing specific components of microorganisms and triggering responses that eliminate the invading microorganisms. However, inappropriate activation of PRRs can lead to prolonged inflammation and even to autoimmune and inflammatory diseases. Thus, PRR-triggered responses are regulated through the degradation or translocation of the innate receptors themselves and through the involvement of intracellular regulators or amplifiers. In addition, a complex interplay between PRRs and/or other immune pathways finely tunes the outcome of host immune defence responses. In this Review, I describe many of the numerous distinct mechanisms for the self-regulation and cross-regulation of innate immune receptor signalling.

Journal ArticleDOI
TL;DR: The basic concepts derived from studying NK cell memory provide new insights about innate immunity and could lead to novel strategies to improve treatments for infectious diseases and cancer.
Abstract: Immunological memory can be defined as a quantitatively and qualitatively enhanced immune response upon rechallenge. For natural killer (NK) cells, two main types of memory exist. First, similarly to T cells and B cells, NK cells can exert immunological memory after encounters with stimuli such as haptens or viruses, resulting in the generation of antigen-specific memory NK cells. Second, NK cells can remember inflammatory cytokine milieus that imprint long-lasting non-antigen-specific NK cell effector function. The basic concepts derived from studying NK cell memory provide new insights about innate immunity and could lead to novel strategies to improve treatments for infectious diseases and cancer.

Journal ArticleDOI
TL;DR: T cell-intrinsic molecular alterations and metabolic communication in the tumour microenvironment are discussed and identification of the underlying molecular drivers of T cell dysfunction is essential for the continued progress of cancer research and therapy.
Abstract: In this Review, the authors summarize the features and the molecular drivers of T cell dysfunction in cancer and compare these with dysfunctional T cells in chronic viral infection. The metabolic competition in the tumour microenvironment is also discussed. Understanding antitumour T cell responses has important implications for cancer immunotherapy.

Journal ArticleDOI
TL;DR: These cells have pivotal roles in the suppression of immune responses against harmless dietary antigens and commensal microorganisms and provide important insights into disease-relevant host–microorganism interactions.
Abstract: Gut-resident forkhead box P3 (FOXP3)(+)CD4(+) regulatory T cells (Treg cells) are distinct from those in other organs and have gut-specific phenotypes and functions. Whereas Treg cells in other organs have T cell receptors (TCRs) specific for self antigens, intestinal Treg cells have a distinct set of TCRs that are specific for intestinal antigens, and these cells have pivotal roles in the suppression of immune responses against harmless dietary antigens and commensal microorganisms. The differentiation, migration and maintenance of intestinal Treg cells are controlled by specific signals from the local environment. In particular, certain members of the microbiota continuously provide antigens and immunoregulatory small molecules that modulate intestinal Treg cells. Understanding the development and the maintenance of intestinal Treg cells provides important insights into disease-relevant host-microorganism interactions.

Journal ArticleDOI
TL;DR: This Review provides non-experts with a broad and practical overview of the many recent developments in computational flow cytometry.
Abstract: Recent advances in flow cytometry allow scientists to measure an increasing number of parameters per cell, generating huge and high-dimensional datasets. To analyse, visualize and interpret these data, newly available computational techniques should be adopted, evaluated and improved upon by the immunological community. Computational flow cytometry is emerging as an important new field at the intersection of immunology and computational biology; it allows new biological knowledge to be extracted from high-throughput single-cell data. This Review provides non-experts with a broad and practical overview of the many recent developments in computational flow cytometry.

Journal ArticleDOI
TL;DR: Recent studies are discussed that provide insight into the multifaceted role of CD4+ T cells in the regulation of memory CD8+ T cell differentiation.
Abstract: Following infection, T cells differentiate into a heterogeneous population of effector T cells that can mediate pathogen clearance. A subset of these effector T cells possesses the ability to survive long term and mature into memory T cells that can provide long-term immunity. Understanding the signals that regulate the development of memory T cells is crucial to efforts to design vaccines capable of eliciting T cell-based immunity. CD4(+) T cells are essential in the formation of protective memory CD8(+) T cells following infection or immunization. However, until recently, the mechanisms by which CD4(+) T cells act to support memory CD8(+) T cell development following infection were unclear. Here, we discuss recent studies that provide insight into the multifaceted role of CD4(+) T cells in the regulation of memory CD8(+) T cell differentiation.

Journal ArticleDOI
TL;DR: This work examines the molecular mechanisms that regulate CD4+ T cell plasticity by examining the extracellular cues that initiate and drive cells towards varying phenotypes, and the cytosolic signalling cascades that decipher these cues and transmit them into the cell and to the nucleus.
Abstract: CD4(+) T cells differentiate and acquire distinct functions to combat specific pathogens but can also adapt their functions in response to changing circumstances. Although this phenotypic plasticity can be potentially deleterious, driving immune pathology, it also provides important benefits that have led to its evolutionary preservation. Here, we review CD4(+) T cell plasticity by examining the molecular mechanisms that regulate it - from the extracellular cues that initiate and drive cells towards varying phenotypes, to the cytosolic signalling cascades that decipher these cues and transmit them into the cell and to the nucleus, where these signals imprint specific gene expression programmes. By understanding how this functional flexibility is achieved, we may open doors to new therapeutic approaches that harness this property of T cells.

Journal ArticleDOI
TL;DR: This Review summarizes the tremendous progress that has been made in understanding how this sophisticated immune sensory system discriminates self from non-self nucleic acids in order to reliably detect pathogenic viruses.
Abstract: Innate immunity against pathogens relies on an array of immune receptors to detect molecular patterns that are characteristic of the pathogens, including receptors that are specialized in the detection of foreign nucleic acids. In vertebrates, nucleic acid sensing is the dominant antiviral defence pathway. Stimulation of nucleic acid receptors results in antiviral immune responses with the production of type I interferon (IFN), as well as the expression of IFN-stimulated genes, which encode molecules such as cell-autonomous antiviral effector proteins. This Review summarizes the tremendous progress that has been made in understanding how this sophisticated immune sensory system discriminates self from non-self nucleic acids in order to reliably detect pathogenic viruses.

Journal ArticleDOI
TL;DR: This work discusses the diagnosis and treatment of IgE-mediated food allergy in the context of the immune mechanisms associated with healthy tolerance to common foods, the inflammatory response underlying most food allergies, and immunotherapy-induced desensitization.
Abstract: Food allergy is a pathological, potentially deadly, immune reaction triggered by normally innocuous food protein antigens The prevalence of food allergies is rising and the standard of care is not optimal, consisting of food-allergen avoidance and treatment of allergen-induced systemic reactions with adrenaline Thus, accurate diagnosis, prevention and treatment are pressing needs, research into which has been catalysed by technological advances that are enabling a mechanistic understanding of food allergy at the cellular and molecular levels We discuss the diagnosis and treatment of IgE-mediated food allergy in the context of the immune mechanisms associated with healthy tolerance to common foods, the inflammatory response underlying most food allergies, and immunotherapy-induced desensitization We highlight promising research advances, therapeutic innovations and the challenges that remain

Journal ArticleDOI
TL;DR: The early events associated with infection, the CD4- T cells that mediate protective immunity and the pathological role that CD8+ T cells can have in cutaneous leishmaniasis are discussed.
Abstract: Cutaneous leishmaniasis is a major public health problem and causes a range of diseases from self-healing infections to chronic disfiguring disease. Currently, there is no vaccine for leishmaniasis, and drug therapy is often ineffective. Since the discovery of CD4(+) T helper 1 (TH1) cells and TH2 cells 30 years ago, studies of cutaneous leishmaniasis in mice have answered basic immunological questions concerning the development and maintenance of CD4(+) T cell subsets. However, new strategies for controlling the human disease have not been forthcoming. Nevertheless, advances in our knowledge of the cells that participate in protection against Leishmania infection and the cells that mediate increased pathology have highlighted new approaches for vaccine development and immunotherapy. In this Review, we discuss the early events associated with infection, the CD4(+) T cells that mediate protective immunity and the pathological role that CD8(+) T cells can have in cutaneous leishmaniasis.

Journal ArticleDOI
TL;DR: The emerging understanding of TCR-guided differentiation of TReg cells in the context of their function in health and disease is discussed.
Abstract: Regulatory T cells (TReg cells), a specialized T cell lineage, have a pivotal function in the control of self tolerance and inflammatory responses. Recent studies have revealed a discrete mode of T cell receptor (TCR) signalling that regulates TReg cell differentiation, maintenance and function and that affects gene expression, metabolism, cell adhesion and migration of these cells. Here, we discuss the emerging understanding of TCR-guided differentiation of TReg cells in the context of their function in health and disease.

Journal ArticleDOI
TL;DR: The molecular triggers that promote memory inflation are discussed, the idea that memory inflation could be considered a natural pathway of T cell maturation that could be harnessed in vaccination is considered, and the broader implications of CMV infection and the T cell responses it elicits are discussed.
Abstract: Human cytomegalovirus (HCMV) establishes a latent infection that generally remains asymptomatic in immune-competent hosts for decades but can cause serious illness in immune-compromised individuals. The long-term control of CMV requires considerable effort from the host immune system and has a lasting impact on the profile of the immune system. One hallmark of CMV infection is the maintenance of large populations of CMV-specific memory CD8(+) T cells - a phenomenon termed memory inflation - and emerging data suggest that memory inflation is associated with impaired immunity in the elderly. In this Review, we discuss the molecular triggers that promote memory inflation, the idea that memory inflation could be considered a natural pathway of T cell maturation that could be harnessed in vaccination, and the broader implications of CMV infection and the T cell responses it elicits.

Journal ArticleDOI
TL;DR: In particular, insights from 'search theory' can be used to describe T cell movement across an 'exploitation–exploration trade-off' in the context of activation versus effector function and lymph nodes versus peripheral tissues.
Abstract: T cell migration is essential for T cell responses; it allows for the detection of cognate antigen at the surface of antigen-presenting cells and for interactions with other cells involved in the immune response. Although appearing random, growing evidence suggests that T cell motility patterns are strategic and governed by mechanisms that are optimized for both the activation stage of the cell and for environment-specific cues. In this Opinion article, we discuss how the combined effects of T cell-intrinsic and -extrinsic forces influence T cell motility patterns in the context of highly complex tissues that are filled with other cells involved in parallel motility. In particular, we examine how insights from 'search theory' can be used to describe T cell movement across an 'exploitation-exploration trade-off' in the context of activation versus effector function and lymph nodes versus peripheral tissues.

Journal ArticleDOI
TL;DR: A comprehensive overview of the emerging knowledge about the development, differentiation and function of human NK cell populations, with a particular focus on NK cells in peripheral tissues is provided.
Abstract: Natural killer (NK) cells have long been considered to be a homogenous population of innate lymphocytes with limited phenotypic and functional diversity. However, recent findings have revealed that these cells comprise a large number of distinct populations with diverse characteristics. Some of these characteristics may relate to their developmental origin, and others represent differences in differentiation that are influenced by factors such as tissue localization and imprints by viral infections. In this Review, we provide a comprehensive overview of the emerging knowledge about the development, differentiation and function of human NK cell populations, with a particular focus on NK cells in peripheral tissues.