Showing papers in "Nature Reviews Immunology in 2014"
TL;DR: In this paper, the authors summarize the signalling and epigenetic mechanisms that regulate type I IFN-induced STAT activation and ISG transcription and translation and conclude that these regulatory mechanisms determine the biological outcomes of type I ILN responses and whether pathogens are cleared effectively or chronic infection or autoimmune disease ensues.
Abstract: Type I interferons (IFNs) activate intracellular antimicrobial programmes and influence the development of innate and adaptive immune responses. Canonical type I IFN signalling activates the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway, leading to transcription of IFN-stimulated genes (ISGs). Host, pathogen and environmental factors regulate the responses of cells to this signalling pathway and thus calibrate host defences while limiting tissue damage and preventing autoimmunity. Here, we summarize the signalling and epigenetic mechanisms that regulate type I IFN-induced STAT activation and ISG transcription and translation. These regulatory mechanisms determine the biological outcomes of type I IFN responses and whether pathogens are cleared effectively or chronic infection or autoimmune disease ensues.
2,273 citations
TL;DR: This Review provides a comprehensive overview of how IECs maintain host–commensal microbial relationships and immune cell homeostasis in the intestine.
Abstract: The abundance of innate and adaptive immune cells that reside together with trillions of beneficial commensal microorganisms in the mammalian gastrointestinal tract requires barrier and regulatory mechanisms that conserve host-microbial interactions and tissue homeostasis. This homeostasis depends on the diverse functions of intestinal epithelial cells (IECs), which include the physical segregation of commensal bacteria and the integration of microbial signals. Hence, IECs are crucial mediators of intestinal homeostasis that enable the establishment of an immunological environment permissive to colonization by commensal bacteria. In this Review, we provide a comprehensive overview of how IECs maintain host-commensal microbial relationships and immune cell homeostasis in the intestine.
2,046 citations
TL;DR: The role of cytokines produced by innate and adaptive immune cells, as well as their relevance to the future therapy of IBD are discussed.
Abstract: Erroneous communication between the innate and adaptive immune systems through cytokines results in exaggerated or attenuated immune response. It is not known whether the pathologic immune response in inflammatory bowel disease has its origin in a dysbalance of pro- and anti-inflammatory cytokine release or whether it is secondary in subsequence of a defective intestinal barrier or the destructive power of aggressive microbiota in the gut lumen.
1,938 citations
TL;DR: Given the tremendous therapeutic potential of extracellular vesicles, this Review focuses on their role in modulating immune responses, as well as their potential therapeutic applications.
Abstract: Extracellular vesicles, including exosomes, are small membrane vesicles derived from multivesicular bodies or from the plasma membrane. Most, if not all, cell types release extracellular vesicles, which then enter the bodily fluids. These vesicles contain a subset of proteins, lipids and nucleic acids that are derived from the parent cell. It is thought that extracellular vesicles have important roles in intercellular communication, both locally and systemically, as they transfer their contents, including proteins, lipids and RNAs, between cells. Extracellular vesicles are involved in numerous physiological processes, and vesicles from both non-immune and immune cells have important roles in immune regulation. Moreover, extracellular vesicle-based therapeutics are being developed and clinically tested for the treatment of inflammatory diseases, autoimmune disorders and cancer. Given the tremendous therapeutic potential of extracellular vesicles, this Review focuses on their role in modulating immune responses, as well as their potential therapeutic applications.
1,634 citations
TL;DR: The evidence that has dramatically changed the authors' understanding of monocyte and macrophage development, and the maintenance of these cells in the steady state is discussed.
Abstract: Monocytes and macrophages have crucial and distinct roles in tissue homeostasis and immunity, but they also contribute to a broad spectrum of pathologies and are thus attractive therapeutic targets. Potential intervention strategies that aim to manipulate these cells will require an in-depth understanding of their origins and the mechanisms that ensure their homeostasis. Recent evidence shows that monocytes do not substantially contribute to most tissue macrophage populations in the steady state or during certain types of inflammation. Rather, most tissue macrophage populations in mice are derived from embryonic precursors, are seeded before birth and can maintain themselves in adults by self-renewal. In this Review, we discuss the evidence that has dramatically changed our understanding of monocyte and macrophage development, and the maintenance of these cells in the steady state.
1,450 citations
TL;DR: This Opinion article suggests that the mononuclear phagocyte system can be classified primarily by their ontogeny and secondarily by their location, function and phenotype, which permits a more robust classification during both steady-state and inflammatory conditions.
Abstract: The mononuclear phagocyte system (MPS) has historically been categorized into monocytes, dendritic cells and macrophages on the basis of functional and phenotypical characteristics. However, considering that these characteristics are often overlapping, the distinction between and classification of these cell types has been challenging. In this Opinion article, we propose a unified nomenclature for the MPS. We suggest that these cells can be classified primarily by their ontogeny and secondarily by their location, function and phenotype. We believe that this system permits a more robust classification during both steady-state and inflammatory conditions, with the benefit of spanning different tissues and across species.
1,404 citations
TL;DR: This Review focuses on the recent advances that have been made regarding the transcriptional control of TH 17 cell plasticity and stability, as well as the effector functions of TH17 cells, and highlights the mechanisms of IL-17 signalling in mesenchymal and barrier epithelial tissues.
Abstract: Following the discovery of T helper 17 (TH17) cells, the past decade has witnessed a major revision of the TH subset paradigm and substantial progress has been made in deciphering the molecular mechanisms of T cell lineage commitment and function. In this Review, we focus on the recent advances that have been made regarding the transcriptional control of TH17 cell plasticity and stability, as well as the effector functions of TH17 cells, and we highlight the mechanisms of IL-17 signalling in mesenchymal and barrier epithelial tissues. We also discuss the emerging clinical data showing that IL-17-specific and IL-23-specific antibody treatments are remarkably effective for treating many immune-mediated inflammatory diseases.
1,174 citations
TL;DR: The anatomical and physiological distinctions that are observed in the small and large intestines are detailed, and it is suggested how these may account for the diversity in the immune apparatus that is seen throughout the intestine.
Abstract: The intestine represents the largest compartment of the immune system. It is continually exposed to antigens and immunomodulatory agents from the diet and the commensal microbiota, and it is the port of entry for many clinically important pathogens. Intestinal immune processes are also increasingly implicated in controlling disease development elsewhere in the body. In this Review, we detail the anatomical and physiological distinctions that are observed in the small and large intestines, and we suggest how these may account for the diversity in the immune apparatus that is seen throughout the intestine. We describe how the distribution of innate, adaptive and innate-like immune cells varies in different segments of the intestine and discuss the environmental factors that may influence this. Finally, we consider the implications of regional immune specialization for inflammatory disease in the intestine.
1,094 citations
TL;DR: It is discussed 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.
Abstract: 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.
1,069 citations
TL;DR: How the activation of innate immune signalling pathways — in particular, the NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome — by aberrant host proteins may be a common step in the development of diverse neurodegenerative disorders is discussed.
Abstract: The triggering of innate immune mechanisms is emerging as a crucial component of major neurodegenerative diseases. Microglia and other cell types in the brain can be activated in response to misfolded proteins or aberrantly localized nucleic acids. This diverts microglia from their physiological and beneficial functions, and leads to their sustained release of pro-inflammatory mediators. In this Review, we discuss how the activation of innate immune signalling pathways - in particular, the NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome - by aberrant host proteins may be a common step in the development of diverse neurodegenerative disorders. During chronic activation of microglia, the sustained exposure of neurons to pro-inflammatory mediators can cause neuronal dysfunction and contribute to cell death. As chronic neuroinflammation is observed at relatively early stages of neurodegenerative disease, targeting the mechanisms that drive this process may be useful for diagnostic and therapeutic purposes.
1,030 citations
TL;DR: The unique tissue location and function of alveolarmacrophages distinguish them from other macrophage populations and suggest that it is important to classify macrophages according to the site that they occupy.
Abstract: Alveolar macrophages exist in a unique microenvironment and, despite historical evidence showing that they are in close contact with the respiratory epithelium, have until recently been investigated in isolation. The microenvironment of the airway lumen has a considerable influence on many aspects of alveolar macrophage phenotype, function and turnover. As the lungs adapt to environmental challenges, so too do alveolar macrophages adapt to accommodate the ever-changing needs of the tissue. In this Review, we discuss the unique characteristics of alveolar macrophages, the mechanisms that drive their adaptation and the direct and indirect influences of epithelial cells on them. We also highlight how airway luminal macrophages function as sentinels of a healthy state and how they do not respond in a pro-inflammatory manner to antigens that do not disrupt lung structure. The unique tissue location and function of alveolar macrophages distinguish them from other macrophage populations and suggest that it is important to classify macrophages according to the site that they occupy.
TL;DR: This Review focuses on recent advances in liver fibrosis research as a paradigm for wound healing in solid organs and the role of the immune system in regulating and balancing this response.
Abstract: Fibrosis is a highly conserved and co-ordinated protective response to tissue injury. The interaction of multiple pathways, molecules and systems determines whether fibrosis is self-limiting and homeostatic, or whether it is uncontrolled and excessive. Immune cells have been identified as key players in this fibrotic cascade, with the capacity to exert either injury-inducing or repair-promoting effects. A multi-organ approach was recently suggested to identify the core and regulatory pathways in fibrosis, with the aim of integrating the wealth of information emerging from basic fibrosis research. In this Review, we focus on recent advances in liver fibrosis research as a paradigm for wound healing in solid organs and the role of the immune system in regulating and balancing this response.
TL;DR: The current understanding of the complex process of apoptotic cell clearance in physiology and pathology is reviewed, and how this knowledge could be harnessed for new therapeutic strategies are discussed.
Abstract: Prompt removal of apoptotic cells by phagocytes is important for maintaining tissue homeostasis. The molecular and cellular events that underpin apoptotic cell recognition and uptake, and the subsequent biological responses are increasingly better defined. The detection and disposal of apoptotic cells generally promote an anti-inflammatory response at the tissue level, as well as immunological tolerance. Consequently, defects in apoptotic cell clearance have been linked with a variety of inflammatory diseases and autoimmunity. Conversely, under certain conditions such as killing tumour cells by specific cell death inducers, the recognition of apoptotic tumour cells can promote an immunogenic response and anti-tumour immunity. Here, we review the current understanding of the complex process of apoptotic cell clearance in physiology and pathology, and discuss how this knowledge could be harnessed for new therapeutic strategies.
TL;DR: Whether the outcome of innate sensor stimulation promotes antiviral resistance or disease tolerance, and proposed rational treatment strategies for the acute respiratory disease that is caused by influenza virus infection are considered.
Abstract: Influenza viruses are a major pathogen of both humans and animals. Recent studies using gene-knockout mice have led to an in-depth understanding of the innate sensors that detect influenza virus infection in a variety of cell types. Signalling downstream of these sensors induces distinct sets of effector mechanisms that block virus replication and promote viral clearance by inducing innate and adaptive immune responses. In this Review, we discuss the various ways in which the innate immune system uses pattern recognition receptors to detect and respond to influenza virus infection. We consider whether the outcome of innate sensor stimulation promotes antiviral resistance or disease tolerance, and propose rational treatment strategies for the acute respiratory disease that is caused by influenza virus infection.
TL;DR: The current knowledge of mast cell secretory granules is discussed, which shows that mast cell granule proteases account for many of the protective and detrimental effects of mast cells in various inflammatory settings.
Abstract: Mast cells are important effector cells of the immune system and recent studies show that they have immunomodulatory roles in diverse processes in both health and disease. Mast cells are distinguished by their high content of electron-dense secretory granules, which are filled with large amounts of preformed and pre-activated immunomodulatory compounds. When appropriately activated, mast cells undergo degranulation, a process by which these preformed granule compounds are rapidly released into the surroundings. In many cases, the effects that mast cells have on an immune response are closely associated with the biological actions of the granule compounds that they release, as exemplified by the recent studies showing that mast cell granule proteases account for many of the protective and detrimental effects of mast cells in various inflammatory settings. In this Review, we discuss the current knowledge of mast cell secretory granules.
TL;DR: The recent advances in understanding of the roles of Siglecs in the regulation of immune cell function in infectious diseases, inflammation, neurodegeneration, autoimmune diseases and cancer are described.
Abstract: All mammalian cells display a diverse array of glycan structures that differ from those that are found on microbial pathogens Siglecs are a family of sialic acid-binding immunoglobulin-like receptors that participate in the discrimination between self and non-self, and that regulate the function of cells in the innate and adaptive immune systems through the recognition of their glycan ligands In this Review, we describe the recent advances in our understanding of the roles of Siglecs in the regulation of immune cell function in infectious diseases, inflammation, neurodegeneration, autoimmune diseases and cancer
TL;DR: Studies focused on human memory T cells that reveal key properties of these cells, including subset heterogeneity and diverse tissue residence in multiple mucosal and lymphoid tissue sites are discussed.
Abstract: Memory T cells constitute the most abundant lymphocyte population in the body for the majority of a person's lifetime; however, our understanding of memory T cell generation, function and maintenance mainly derives from mouse studies, which cannot recapitulate the exposure to multiple pathogens that occurs over many decades in humans. In this Review, we discuss studies focused on human memory T cells that reveal key properties of these cells, including subset heterogeneity and diverse tissue residence in multiple mucosal and lymphoid tissue sites. We also review how the function and the adaptability of human memory T cells depend on spatial and temporal compartmentalization.
TL;DR: The current understanding of the contribution of central immune mechanisms to pathological pain is discussed, and how the heterogeneous immune functions of different cells in the CNS could be harnessed to develop new therapeutics for pain control is discussed.
Abstract: Reciprocal signalling between immunocompetent cells in the central nervous system (CNS) has emerged as a key phenomenon underpinning pathological and chronic pain mechanisms Neuronal excitability can be powerfully enhanced both by classical neurotransmitters derived from neurons, and by immune mediators released from CNS-resident microglia and astrocytes, and from infiltrating cells such as T cells In this Review, we discuss the current understanding of the contribution of central immune mechanisms to pathological pain, and how the heterogeneous immune functions of different cells in the CNS could be harnessed to develop new therapeutics for pain control Given the prevalence of chronic pain and the incomplete efficacy of current drugs — which focus on suppressing aberrant neuronal activity — new strategies to manipulate neuroimmune pain transmission hold considerable promise
TL;DR: Recent findings that highlight the complex regulatory networks that control skin immunity are discussed, and new paradigms for the mechanisms that regulate skin immune responses in host defence and in chronic inflammation are provided.
Abstract: Immune responses in the skin are important for host defence against pathogenic microorganisms However, dysregulated immune reactions can cause chronic inflammatory skin diseases Extensive crosstalk between the different cellular and microbial components of the skin regulates local immune responses to ensure efficient host defence, to maintain and restore homeostasis, and to prevent chronic disease In this Review, we discuss recent findings that highlight the complex regulatory networks that control skin immunity, and we provide new paradigms for the mechanisms that regulate skin immune responses in host defence and in chronic inflammation
TL;DR: The molecular basis for the recognition of pathogen-associated molecular patterns, the nature of the protein complexes that mediate signalling, and the way in which signals are regulated and integrated at the level of allosteric assembly, post-translational modification and subcellular trafficking of the components of the signalling complexes are discussed.
Abstract: Signal transduction by the Toll-like receptors (TLRs) is central to host defence against many pathogenic microorganisms and also underlies a large burden of human disease. Thus, the mechanisms and regulation of signalling by TLRs are of considerable interest. In this Review, we discuss the molecular basis for the recognition of pathogen-associated molecular patterns, the nature of the protein complexes that mediate signalling, and the way in which signals are regulated and integrated at the level of allosteric assembly, post-translational modification and subcellular trafficking of the components of the signalling complexes. These fundamental molecular mechanisms determine whether the signalling output leads to a protective immune response or to serious pathologies such as sepsis. A detailed understanding of these processes at the molecular level provides a rational framework for the development of new drugs that can specifically target pathological rather than protective signalling in inflammatory and autoimmune disease.
TL;DR: The fruit fly Drosophila melanogaster has been used to understand how the immune response is regulated and coordinated at the level of the whole organism, and recent studies that have explored the effects of organism-wide regulation of theimmune response and, conversely, the effects on organism physiology are highlighted.
Abstract: Since the discovery of antimicrobial peptide responses 40 years ago, the fruit fly Drosophila melanogaster has proven to be a powerful model for the study of innate immunity. Early work focused on innate immune mechanisms of microbial recognition and subsequent nuclear factor-κB signal transduction. More recently, D. melanogaster has been used to understand how the immune response is regulated and coordinated at the level of the whole organism. For example, researchers have used this model in studies investigating interactions between the microbiota and the immune system at barrier epithelial surfaces that ensure proper nutritional and immune homeostasis both locally and systemically. In addition, studies in D. melanogaster have been pivotal in uncovering how the immune response is regulated by both endocrine and metabolic signalling systems, and how the immune response modifies these systems as part of a homeostatic circuit. In this Review, we briefly summarize microbial recognition and antiviral immunity in D. melanogaster, and we highlight recent studies that have explored the effects of organism-wide regulation of the immune response and, conversely, the effects of the immune response on organism physiology.
TL;DR: Recent findings have expanded the scope of the cellular compartments monitored by NOD1 and NOD2 and have elucidated the signalling pathways that are triggered downstream of NOD activation, indicating that a balanced level of N OD signalling is crucial for the maintenance of immune homeostasis.
Abstract: Entry of bacteria into host cells is an important virulence mechanism. Through peptidoglycan recognition, the nucleotide-binding oligomerization domain (NOD) proteins NOD1 and NOD2 enable detection of intracellular bacteria and promote their clearance through initiation of a pro-inflammatory transcriptional programme and other host defence pathways, including autophagy. Recent findings have expanded the scope of the cellular compartments monitored by NOD1 and NOD2 and have elucidated the signalling pathways that are triggered downstream of NOD activation. In vivo, NOD1 and NOD2 have complex roles, both during bacterial infection and at homeostasis. The association of alleles that encode constitutively active or constitutively inactive forms of NOD2 with different diseases highlights this complexity and indicates that a balanced level of NOD signalling is crucial for the maintenance of immune homeostasis.
TL;DR: Investigations in both experimental model systems and patient cohorts are discussed to provide a perspective on the formation and functions of ectopic lymphoid-like structures in human pathology, with particular reference to the clinical implications and the potential for therapeutic targeting.
Abstract: Ectopic lymphoid-like structures often develop at sites of inflammation where they influence the course of infection, autoimmune disease, cancer and transplant rejection. These lymphoid aggregates range from tight clusters of B cells and T cells to highly organized structures that comprise functional germinal centres. Although the mechanisms governing ectopic lymphoid neogenesis in human pathology remain poorly defined, the presence of ectopic lymphoid-like structures within inflamed tissues has been linked to both protective and deleterious outcomes in patients. In this Review, we discuss investigations in both experimental model systems and patient cohorts to provide a perspective on the formation and functions of ectopic lymphoid-like structures in human pathology, with particular reference to the clinical implications and the potential for therapeutic targeting.
TL;DR: How the uptake, processing and presentation of antigens by DCs and macrophages is influenced by FcγR recognition of immunoglobulins and immune complexes in the steady state and during inflammation is discussed.
Abstract: Dendritic cells (DCs) and macrophages use various receptors to recognize foreign antigens and to receive feedback control from adaptive immune cells. Although it was long believed that all immunoglobulin Fc receptors are universally expressed by phagocytes, recent findings indicate that only monocyte-derived DCs and macrophages express high levels of activating Fc receptors for IgG (FcγRs), whereas conventional and plasmacytoid DCs express the inhibitory FcγR. In this Review, we discuss how the uptake, processing and presentation of antigens by DCs and macrophages is influenced by FcγR recognition of immunoglobulins and immune complexes in the steady state and during inflammation.
TL;DR: What is currently known about the makeup of fungal communities in the body and the features of the immune system that are particularly important for interacting with fungi at these sites are discussed.
Abstract: The body is host to a wide variety of microbial communities from which the immune system protects us and that are important for the normal development of the immune system and for the maintenance of healthy tissues and physiological processes. Investigators have mostly focused on the bacterial members of these communities, but fungi are increasingly being recognized to have a role in defining these communities and to interact with immune cells. In this Review, we discuss what is currently known about the makeup of fungal communities in the body and the features of the immune system that are particularly important for interacting with fungi at these sites.
TL;DR: This Review focuses on recent advances that have succeeded in discriminating DCs from macrophages in the skin, based on ontogeny and global gene-expression profiles, and discusses how this has enabled researchers to revisit the origin, diversity and T cell-stimulatory properties of these cells.
Abstract: Recent studies of ontogeny and gene expression have enabled the discrimination of dendritic cell and macrophage subsets in mouse skin and the identification of their human counterparts, which has led to a growing appreciation of the functional specialization of these subsets.
TL;DR: Whether any of these cell populations can prime naive CD4+ T cells and, if not, question the effects that they do have on the development of immune responses.
Abstract: Dendritic cells, macrophages and B cells are regarded as the classical antigen-presenting cells of the immune system. However, in recent years, there has been a rapid increase in the number of cell types that are suggested to present antigens on MHC class II molecules to CD4(+) T cells. In this Review, we describe the key characteristics that define an antigen-presenting cell by examining the functions of dendritic cells. We then examine the functions of the haematopoietic cells and non-haematopoietic cells that can express MHC class II molecules and that have been suggested to represent 'atypical' antigen-presenting cells. We consider whether any of these cell populations can prime naive CD4(+) T cells and, if not, question the effects that they do have on the development of immune responses.
TL;DR: It is highlighted how differing local milieu might drive context-specific TReg cell function and restoration of immune homeostasis, and how dysregulation of these processes can precipitate disease.
Abstract: Regulatory T (TReg) cells constitute an essential counterbalance to adaptive immune responses. Failure to maintain appropriate TReg cell numbers or function leads to autoimmune, malignant and immunodeficient conditions. Dynamic homeostatic processes preserve the number of forkhead box P3-expressing (FOXP3(+)) TReg cells within a healthy range, with high rates of cell division being offset by apoptosis under steady-state conditions. Recent studies have shown that TReg cells become specialized for different environmental contexts, tailoring their functions and homeostatic properties to a wide range of tissues and immune conditions. In this Review, we describe new insights into the molecular controls that maintain the steady-state homeostasis of TReg cells and the cues that drive TReg cell adaptation to inflammation and/or different locations. We highlight how differing local milieu might drive context-specific TReg cell function and restoration of immune homeostasis, and how dysregulation of these processes can precipitate disease.
TL;DR: Clinicians should not only prescribe immunosuppressive treatments to disrupt this circuit, but also implement the neglected therapeutic option of adding compounds that interfere with RCD.
Abstract: In this Opinion article, the authors discuss how the induction of regulated cell death and inflammatory pathways may lead to an auto-amplification loop that causes tissue damage and organ failure. They propose that targeting both processes could be useful for treating a broad range of clinical conditions with an inflammatory basis.
TL;DR: This Review summarizes the Toll-like receptor (TLR)-dependent mechanisms that are responsible for parasite recognition and for the induction of IFNγ production by NK cells, as well as the emerging data about the TLR-independent mechanisms that lead to theIFNγ-mediated elimination of T. gondii.
Abstract: Toxoplasma gondii is a protozoan parasite of global importance In the laboratory setting, T gondii is frequently used as a model pathogen to study mechanisms of T helper 1 (TH1) cell-mediated immunity to intracellular infections However, recent discoveries have shown that innate type 1 immune responses that involve interferon-γ (IFNγ)-producing natural killer (NK) cells and neutrophils, rather than IFNγ-producing T cells, predetermine host resistance to T gondii This Review summarizes the Toll-like receptor (TLR)-dependent mechanisms that are responsible for parasite recognition and for the induction of IFNγ production by NK cells, as well as the emerging data about the TLR-independent mechanisms that lead to the IFNγ-mediated elimination of T gondii