Showing papers in "Nature Reviews Immunology in 2002"
TL;DR: The physical properties that define exosomes as a specific population of secreted vesicles are described, their biological effects, particularly on the immune system, are summarized, and the potential roles that secretedvesicles could have as intercellular messengers are discussed.
Abstract: Exosomes are small membrane vesicles of endocytic origin that are secreted by most cells in culture. Interest in exosomes has intensified after their recent description in antigen-presenting cells and the observation that they can stimulate immune responses in vivo. In the past few years, several groups have reported the secretion of exosomes by various cell types, and have discussed their potential biological functions. Here, we describe the physical properties that define exosomes as a specific population of secreted vesicles, we summarize their biological effects, particularly on the immune system, and we discuss the potential roles that secreted vesicles could have as intercellular messengers.
4,380 citations
TL;DR: The role of NF-κB proteins as potential therapeutic targets in clinical applications and their role in the immune system and inflammatory diseases are discussed.
Abstract: The nuclear factor-kappaB (NF-kappaB)/REL family of transcription factors has a central role in coordinating the expression of a wide variety of genes that control immune responses. There has been intense scientific activity in the NF-kappaB field owing to the involvement of these factors in the activation and regulation of key molecules that are associated with diseases ranging from inflammation to cancer. In this review, we focus on our current understanding of NF-kappaB regulation and its role in the immune system and inflammatory diseases. We also discuss the role of NF-kappaB proteins as potential therapeutic targets in clinical applications.
3,603 citations
TL;DR: The dynamics of the DC network in response to microbial invasion is studied, because many DC subtypes arise from separate developmental pathways, and their development and function are modulated by exogenous factors.
Abstract: Dendritic cells (DCs) collect and process antigens for presentation to T cells, but there are many variations on this basic theme. DCs differ in the regulatory signals they transmit, directing T cells to different types of immune response or to tolerance. Although many DC subtypes arise from separate developmental pathways, their development and function are modulated by exogenous factors. Therefore, we must study the dynamics of the DC network in response to microbial invasion. Despite the difficulty of comparing the DC systems of humans and mice, recent work has revealed much common ground.
2,394 citations
TL;DR: The enhancement of suppressor-cell function might prove useful for the treatment of immune-mediated diseases, whereas the downregulation of these cells might be beneficial for the enhancement of the immunogenicity of vaccines that are specific for tumour antigens.
Abstract: Several mechanisms control discrimination between self and non-self, including the thymic deletion of autoreactive T cells and the induction of anergy in the periphery. In addition to these passive mechanisms, evidence has accumulated for the active suppression of autoreactivity by a population of regulatory or suppressor T cells that co-express CD4 and CD25 (the interleukin-2 receptor alpha-chain). CD4+ CD25+ T cells are powerful inhibitors of T-cell activation both in vivo and in vitro. The enhancement of suppressor-cell function might prove useful for the treatment of immune-mediated diseases, whereas the downregulation of these cells might be beneficial for the enhancement of the immunogenicity of vaccines that are specific for tumour antigens.
2,246 citations
TL;DR: The current understanding of the new members of the B7 and CD28 families is summarized, their therapeutic potential is discussed, and other immunoregulatory pathways remain to be described.
Abstract: The B7-1/B7-2-CD28/CTLA-4 pathway is crucial in regulating T-cell activation and tolerance New B7 and CD28 molecules have recently been discovered and new pathways have been delineated that seem to be important for regulating the responses of previously activated T cells Several B7 homologues are expressed on cells other than professional antigen-presenting cells, indicating new mechanisms for regulating T-cell responses in peripheral tissues Some B7 homologues have unknown receptors, indicating that other immunoregulatory pathways remain to be described Here, we summarize our current understanding of the new members of the B7 and CD28 families, and discuss their therapeutic potential
1,707 citations
TL;DR: The signals required for commitment to this programme of development and the factors that might influence its progression are discussed and models of the pathways of effector and memory T-cell differentiation are discussed.
Abstract: Recent work shows that after stimulation with antigen, CD4+ and CD8+ T cells embark on a programme of proliferation that is closely linked with the acquisition of effector functions and leads ultimately to memory-cell formation. Here, we discuss the signals required for commitment to this programme of development and the factors that might influence its progression. Models of the pathways of effector and memory T-cell differentiation are discussed, and we highlight the implications of this new understanding for the optimization of vaccine strategies.
1,641 citations
TL;DR: Apoptosis, which is a programmed and physiological form of cell death, is known to shape the immune system by regulating populations of effector lymphocytes, but the binding and ingestion of dying cells by monocytes/macrophages and dendritic cells can also influence immune responses markedly by enhancing or suppressing inflammation.
Abstract: Apoptosis, which is a programmed and physiological form of cell death, is known to shape the immune system by regulating populations of effector lymphocytes. However, the binding and ingestion of dying cells by monocytes/macrophages and dendritic cells can also influence immune responses markedly by enhancing or suppressing inflammation. Therefore, dead cells, which are a reflection of an organism's immediate past, can control its immunological future.
1,563 citations
TL;DR: In this paper, the authors summarize the latest insights into mechanisms that govern the lineage choices that are made during T(H)-cell responses to foreign pathogens, including cytokines being key regulators.
Abstract: After encountering antigen, helper T (T(H)) cells undergo differentiation to effector cells, which can secrete high levels of interferon-gamma, interleukin-4 (IL-4), IL-10 and other immunomodulators. How T(H) cells acquire, and remember, new patterns of gene expression is an area of intensive investigation. The process is remarkably plastic, with cytokines being key regulators. Extrinsic signals seem to be integrated into cell-intrinsic programming, in what is becoming an intriguing story of regulated development. We summarize the latest insights into mechanisms that govern the lineage choices that are made during T(H)-cell responses to foreign pathogens.
1,540 citations
TL;DR: The interplay between the IFN system and four medically important and challenging viruses — influenza, hepatitis C, herpes simplex and vaccinia — is discussed to highlight the diversity of viral strategies.
Abstract: The action of interferons (IFNs) on virus-infected cells and surrounding tissues elicits an antiviral state that is characterized by the expression and antiviral activity of IFN-stimulated genes. In turn, viruses encode mechanisms to counteract the host response and support efficient viral replication, thereby minimizing the therapeutic antiviral power of IFNs. In this review, we discuss the interplay between the IFN system and four medically important and challenging viruses -- influenza, hepatitis C, herpes simplex and vaccinia -- to highlight the diversity of viral strategies. Understanding the complex network of cellular antiviral processes and virus-host interactions should aid in identifying new and common targets for the therapeutic intervention of virus infection. This effort must take advantage of the recent developments in functional genomics, bioinformatics and other emerging technologies.
1,256 citations
TL;DR: Critically recent findings on cytotoxic granule-mediated cell death are evaluated to assess the functional significance of postulated cell-death pathways in appropriate pathophysiological contexts, including virus infection and susceptibility to experimental or spontaneous tumorigenesis.
Abstract: Perforin/granzyme-induced apoptosis is the main pathway used by cytotoxic lymphocytes to eliminate virus-infected or transformed cells. Studies in gene-disrupted mice indicate that perforin is vital for cytotoxic effector function; it has an indispensable, but undefined, role in granzyme-mediated apoptosis. Despite its vital importance, the molecular and cellular functions of perforin and the basis of perforin and granzyme synergy remain poorly understood. The purpose of this review is to evaluate critically recent findings on cytotoxic granule-mediated cell death and to assess the functional significance of postulated cell-death pathways in appropriate pathophysiological contexts, including virus infection and susceptibility to experimental or spontaneous tumorigenesis.
1,195 citations
TL;DR: No convincing evidence of uterine maternal T-cell recognition of placental trophoblast cells has been found, but instead, there might be maternal allorecognition mediated by uterine natural killer cells that recognize unusual fetal trophOBlast MHC ligands.
Abstract: The fetus is considered to be an allograft that, paradoxically, survives pregnancy despite the laws of classical transplantation immunology. There is no direct contact of the mother with the embryo, only with the extraembryonic placenta as it implants in the uterus. No convincing evidence of uterine maternal T-cell recognition of placental trophoblast cells has been found, but instead, there might be maternal allorecognition mediated by uterine natural killer cells that recognize unusual fetal trophoblast MHC ligands.
TL;DR: Established models of T-helper-2-cell dominance in BALB/c mice infected with Leishmania major — involving the early production of interleukin-4 by a small subset of LeishMania-specific CD4+ T cells — have been refined by accumulating evidence that this response is not sufficient and, under some circumstances, not required to promote susceptibility.
Abstract: Established models of T-helper-2-cell dominance in BALB/c mice infected with Leishmania major -- involving the early production of interleukin-4 by a small subset of Leishmania-specific CD4+ T cells -- have been refined by accumulating evidence that this response is not sufficient and, under some circumstances, not required to promote susceptibility. In addition, more recent studies in L. major-resistant mice have revealed complexities in the mechanisms responsible for acquired immunity, which necessitate the redesign of vaccines against Leishmania and other pathogens that require sustained cell-mediated immune responses.
TL;DR: There is increasing evidence that smokers have a lower incidence of some inflammatory and neurodegenerative diseases and nicotine, one of the main constituents of cigarette smoke, suppresses the immune system but might have therapeutic potential as a neuroprotective and anti-inflammatory agent.
Abstract: Although the health risks of tobacco smoking are well documented, there is increasing evidence that smokers have a lower incidence of some inflammatory and neurodegenerative diseases. Many of the adverse and beneficial effects of smoking might result from the ability of cigarette smoke to suppress the immune system. Nicotine, which is one of the main constituents of cigarette smoke, suppresses the immune system but might have therapeutic potential as a neuroprotective and anti-inflammatory agent.
TL;DR: Advances in the understanding of the immunology of schistosomiasis are summarized, with the bulk of the review reflecting the experimental focus on Schistosoma mansoni infection in mice.
Abstract: Schistosomes are parasitic worms that are a prime example of a complex multicellular pathogen that flourishes in the human host despite the development of a pronounced immune response. Understanding how the immune system deals with such pathogens is a daunting challenge. The past decade has seen the use of a wide range of new approaches to determine the nature and function of the immune response to schistosomes. Here, we attempt to summarize advances in our understanding of the immunology of schistosomiasis, with the bulk of the review reflecting the experimental focus on Schistosoma mansoni infection in mice.
TL;DR: The immunological properties of HSPs enable them to be used in new immunotherapies of cancers and infections and make them uniquely suited to an important role in organismal survival by their participation in innate and adaptive immune responses.
Abstract: Heat-shock proteins (HSPs) are the most abundant and ubiquitous soluble intracellular proteins. In single-cell organisms, invertebrates and vertebrates, they perform a multitude of housekeeping functions that are essential for cellular survival. In higher vertebrates, their ability to interact with a wide range of proteins and peptides--a property that is shared by major histocompatibility complex molecules--has made the HSPs uniquely suited to an important role in organismal survival by their participation in innate and adaptive immune responses. The immunological properties of HSPs enable them to be used in new immunotherapies of cancers and infections.
TL;DR: The use of mathematical modelling to interpret experimental results has made a significant contribution to the understanding of human immunodeficiency virus 1 and other viruses, such as hepatitis B virus and hepatitis C virus, that cause chronic infection.
Abstract: During the past 6 years, there have been substantial advances in our understanding of human immunodeficiency virus 1 and other viruses, such as hepatitis B virus and hepatitis C virus, that cause chronic infection. The use of mathematical modelling to interpret experimental results has made a significant contribution to this field. Mathematical modelling is also improving our understanding of T-cell dynamics and the quantitative events that underlie the immune response to pathogens.
TL;DR: This dissection of the pathogenic mechanisms of coeliac disease has uncovered principles that are relevant to other chronic inflammatory diseases.
Abstract: The disease mechanisms of complex inflammatory disorders are difficult to define because of extensive interactions between genetic and environmental factors. Coeliac disease is a typical complex inflammatory disorder, but this disease is unusual in that crucial genetic and environmental factors have been identified. This knowledge has allowed functional studies of the predisposing HLA molecules, the identification of antigenic epitopes and detailed studies of disease-relevant T cells in coeliac disease. This dissection of the pathogenic mechanisms of coeliac disease has uncovered principles that are relevant to other chronic inflammatory diseases.
TL;DR: An understanding of the mechanisms that are used by CTLs to destroy targets and a knowledge of pathogen immune-evasion strategies will provide vital information for the design of new therapies.
Abstract: Cytotoxic T lymphocytes (CTLs) provide potent defences against virus infection and intracellular pathogens. However, CTLs have a dark side--their lytic machinery can be directed against self-tissues in autoimmune disorders, transplanted cells during graft rejection and host tissues to cause graft-versus-host disease, which is one of the most serious diseases related to CTL function. Although this duplicitous behaviour might seem contradictory, both beneficial and detrimental effects are the result of the same effector proteins. So, an understanding of the mechanisms that are used by CTLs to destroy targets and a knowledge of pathogen immune-evasion strategies will provide vital information for the design of new therapies.
TL;DR: How the peroxisome proliferator-activated receptors, a subset of the nuclear-hormone-receptor superfamily, have important regulatory roles in innate and adaptive immunity is described.
Abstract: Lipids and lipid metabolism have well-documented regulatory effects on inflammatory processes. Recent work has highlighted the role of the peroxisome proliferator-activated receptors (PPARs)--a subset of the nuclear-hormone-receptor superfamily that are activated by various lipid species--in regulating inflammatory responses. Here, we describe how the PPARs, through their interactions with transcription factors and other cell-signalling systems, have important regulatory roles in innate and adaptive immunity.
TL;DR: Recent advances in genomics and proteomics, combined with the facilitated generation and analysis of transgenic and gene-knockout animals, have revealed new complexities in classical biological systems, including the B-cell compartment.
Abstract: Recent advances in genomics and proteomics, combined with the facilitated generation and analysis of transgenic and gene-knockout animals, have revealed new complexities in classical biological systems, including the B-cell compartment. Studies on an 'old', but poorly characterized, B-cell subset--the naive, marginal-zone (MZ) B-cell subset--over the past two years have spawned an avalanche of data that encompass the generation and function of these cells. Now that the initial 'infatuation' is over, it is time to reconsider these data and generate some conclusions that can be incorporated into a working model of the B-cell system.
TL;DR: This review focuses on this emerging area of inflammation research and describes the mediators and mechanisms that are currently stealing the headlines.
Abstract: The pro-inflammatory signalling pathways and cellular mechanisms that initiate the inflammatory response have become increasingly well characterized. However, little is known about the mediators and mechanisms that switch off inflammation. Recent data indicate that the resolution of inflammation is an active process controlled by endogenous mediators that suppress pro-inflammatory gene expression and cell trafficking, as well as induce inflammatory-cell apoptosis and phagocytosis, which are crucial determinants of successful resolution. This review focuses on this emerging area of inflammation research and describes the mediators and mechanisms that are currently stealing the headlines.
TL;DR: This review will focus primarily on epitope spreading at the T-cell level, which is crucial to understanding the pathogenesis of these diseases and to the ultimate goal of designing antigen-specific treatments.
Abstract: Evidence continues to accumulate supporting the hypothesis that tissue damage during an immune response can lead to the priming of self-reactive T and/or B lymphocytes, regardless of the specificity of the initial insult. This review will focus primarily on epitope spreading at the T-cell level. Understanding the cellular and molecular basis of epitope spreading in various chronic immune-mediated human diseases and their animal models is crucial to understanding the pathogenesis of these diseases and to the ultimate goal of designing antigen-specific treatments.
TL;DR: In vitro studies provide a better understanding of how TGF-β regulates T-cell homeostasis, through multiple mechanisms involving numerous cell types, and advances in cell-specific targeting of T GF-β signalling in vivo clearer.
Abstract: Strict control of T-cell homeostasis is required to permit normal immune responses and prevent undesirable self-targeted responses. Transforming growth factor-beta (TGF-beta) has been shown to have an essential role in that regulation. Owing to its broad expression, and inhibitory effects on multiple cell types of the immune system, TGF-beta regulation is complex. Through advances in cell-specific targeting of TGF-beta signalling in vivo, the role of TGF-beta in T-cell regulation has become clearer. Recent in vitro studies provide a better understanding of how TGF-beta regulates T-cell homeostasis, through multiple mechanisms involving numerous cell types.
TL;DR: New studies are beginning to shed light on the development, selection, homeostasis and possible function(s) of Vα14i T cells, which are 'non-conformists' compared with the main T-cell populations, which might lead to the development of techniques for the controlled manipulation of the Vα 14i T- cell response, which could one day form the basis of immune therapies.
Abstract: Many characteristics distinguish CD1d-reactive natural killer T (NKT) cells that express the invariant Vα14–Jα18 T-cell receptor (known here as Vα14i T cells) from conventional T cells. Because of their apparent self-reactivity, their expression of natural-killer receptors and their capacity to secrete large quantities of cytokines rapidly — including interferon-γ and interleukin-4 — it has been proposed that Vα14i T cells might be important for the initiation and regulation of immune responses. New studies are beginning to shed light on the development, selection, homeostasis and possible function(s) of Vα14i T cells, which are 'non-conformists' compared with the main T-cell populations. These studies might lead to the development of techniques for the controlled manipulation of the Vα14i T-cell response, which could one day form the basis of immune therapies.
TL;DR: It is now becoming clear that lectin receptors not only serve as antigen receptors but also regulate the migration of dendritic cells and their interaction with lymphocytes.
Abstract: Dendritic cells and Langerhans cells are specialized for the recognition of pathogens and have a pivotal role in the control of immunity. As guardians of the immune system, they are present in essentially every organ and tissue, where they operate at the interface of innate and acquired immunity. Recently, several C-type lectin and lectin-like receptors have been characterized that are expressed abundantly on the surface of these professional antigen-presenting cells. It is now becoming clear that lectin receptors not only serve as antigen receptors but also regulate the migration of dendritic cells and their interaction with lymphocytes.
TL;DR: It is argued that γδ T cells perform different functions according to their tissue distribution, antigen-receptor structure and local microenvironment, and how and at what stage of the immune response they become activated.
Abstract: Gammadelta T cells remain an enigma. They are capable of generating more unique antigen receptors than alphabeta T cells and B cells combined, yet their repertoire of antigen receptors is dominated by specific subsets that recognize a limited number of antigens. A variety of sometimes conflicting effector functions have been ascribed to them, yet their biological function(s) remains unclear. On the basis of studies of gammadelta T cells in infectious and autoimmune diseases, we argue that gammadelta T cells perform different functions according to their tissue distribution, antigen-receptor structure and local microenvironment; we also discuss how and at what stage of the immune response they become activated.
TL;DR: The rationale for developing antagonists of chemokine receptors for inflammatory disorders and AIDS, and the accumulating evidence that favours this strategy despite the apparent redundancy in the chemokines system are focused on.
Abstract: Chemokines and their receptors are involved in the pathogenesis of diseases ranging from asthma to AIDS. Chemokine receptors are G-protein-coupled serpentine receptors that present attractive tractable targets for the pharmaceutical industry. It is only ten years since the first chemokine receptor was discovered, and the rapidly expanding number of antagonists holds promise for new medicines to combat diseases that are currently incurable. Here, I focus on the rationale for developing antagonists of chemokine receptors for inflammatory disorders and AIDS, and the accumulating evidence that favours this strategy despite the apparent redundancy in the chemokine system.
TL;DR: Progress in the characterization of intercellular mediators — proteins that are now known as cytokines — has led to the realization that one cytokine, tumour-necrosis factor (TNF; previously known as TNF-α), has an important role in the pathogenesis of rheumatoid arthritis.
Abstract: The aetiology of systemic, autoimmune, chronic inflammatory diseases--such as rheumatoid arthritis--is not known, and their pathogenesis is complex and multifactorial. However, progress in the characterization of intercellular mediators--proteins that are now known as cytokines--has led to the realization that one cytokine, tumour-necrosis factor (TNF; previously known as TNF-alpha), has an important role in the pathogenesis of rheumatoid arthritis. This discovery heralded a new era of targeted and highly effective therapeutics for rheumatoid arthritis and, subsequently, other chronic inflammatory diseases.
TL;DR: C cognate interactions between NK cells and DCs provide a coordinated mechanism that is involved not only in the regulation of innate immunity, but also in the promotion of appropriate downstream adaptive responses for defence against pathogens.
Abstract: Natural killer (NK) cells and dendritic cells (DCs) are two types of specialized cell of the innate immune system, the reciprocal interaction of which results in a potent, activating cross-talk. For example, DCs can prime resting NK cells, which, in turn, after activation, might induce DC maturation. However, NK cells negatively regulate the function of DCs also by killing immature DCs in peripheral tissues. Moreover, a subset of NK cells, after migration to secondary lymphoid tissues, might have a role in the editing of mature DCs based on the selective killing of mature DCs that do not express optimal surface densities of MHC class I molecules. So, cognate interactions between NK cells and DCs provide a coordinated mechanism that is involved not only in the regulation of innate immunity, but also in the promotion of appropriate downstream adaptive responses for defence against pathogens.
TL;DR: The elucidation of the role of BAFF has set the stage for a new approach to the treatment of autoimmune disease.
Abstract: B-cell-activating factor of the tumour-necrosis-factor family (BAFF) enhances B-cell survival--a function that is indispensable for B-cell maturation--and has a role in enhancing immune responses. Moreover, the overexpression of BAFF results in severe autoimmune disorders in mice, and elevated serum levels of BAFF occur in some patients who have autoimmune diseases. The elucidation of the role of BAFF has set the stage for a new approach to the treatment of autoimmune disease.