Immunogenicity depends on two key factors: antigenicity and adjuvanticity. The presence of exogenous or mutated antigens explains why infected cells and malignant cells can initiate an adaptive immune response provided that the cells also emit adjuvant signals as a consequence of cellular stress and death. Several infectious pathogens have devised strategies to control cell death and limit the emission of danger signals from dying cells, thereby avoiding immune recognition. Similarly, cancer cells often escape immunosurveillance owing to defects in the molecular machinery that underlies the release of endogenous adjuvants. Here, we review current knowledge on the mechanisms that underlie the activation of immune responses against dying cells and their pathophysiological relevance.
Two decades of clinical experience with immunomodulatory treatments for multiple sclerosis point to distinct immunological pathways that drive disease relapses and progression. In light of this, we discuss our current understanding of multiple sclerosis immunopathology, evaluate long-standing hypotheses regarding the role of the immune system in the disease and delineate key questions that are still unanswered. Recent and anticipated advances in the field of immunology, and the increasing recognition of inflammation as an important component of neurodegeneration, are shaping our conceptualization of disease pathophysiology, and we explore the potential implications for improved healthcare provision to patients in the future.
gamma delta T cells are a unique and conserved population of lymphocytes that have been the subject of a recent explosion of interest owing to their essential contributions to many types of immune response and immunopathology. But what does the integration of recent and long-established studies really tell us about these cells and their place in immunology? The time is ripe to consider the evidence for their unique and crucial functions. We conclude that whereas B cells and alpha beta T cells are commonly thought to contribute primarily to the antigen-specific effector and memory phases of immunity, gamma delta T cells are distinct in that they combine conventional adaptive features (inherent in their T cell receptors and pleiotropic effector functions) with rapid, innate-like responses that can place them in the initiation phase of immune reactions. This underpins a revised perspective on lymphocyte biology and the regulation of imnnunogenicity.
Regular exercise reduces the risk of chronic metabolic and cardiorespiratory diseases, in part because exercise exerts anti-inflammatory effects. However, these effects are also likely to be responsible for the suppressed immunity that makes elite athletes more susceptible to infections. The anti-inflammatory effects of regular exercise may be mediated via both a reduction in visceral fat mass (with a subsequent decreased release of adipokines) and the induction of an anti-inflammatory environment with each bout of exercise. In this Review, we focus on the known mechanisms by which exercise-both acute and chronic-exerts its anti-inflammatory effects, and we discuss the implications of these effects for the prevention and treatment of disease.
Antibody production is an important feature of the vertebrate immune system. Antibodies neutralize and clear pathogens, thereby protecting against infectious diseases. Such humoral immunity has great longevity, often persisting for the host's lifetime. Long-lived humoral immunity depends on help provided by CD4(+) T cells, namely T follicular helper (T-FH) cells, which support the differentiation of antigen-specific B cells into memory and plasma cells. T-FH cells are stringently regulated, as aberrant T-FH cell activity is involved in immunopathologies such as autoimmunity, immunodeficiencies and lymphomas. The elucidation of the mechanisms that regulate T-FH cell differentiation, function and fate should highlight targets for novel therapeutics.
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.
Regulatory T (T-Reg) cells are crucial for the prevention of fatal autoimmunity in mice and humans. Forkhead box P3 (FOXP3)(+) T-Reg cells are produced in the thymus and are also generated from conventional CD4(+) T cells in peripheral sites. It has been suggested that FOXP3(+) T-Reg cells might become unstable under certain inflammatory conditions and might adopt a phenotype that is more characteristic of effector CD4(+) T cells. These suggestions have caused considerable debate in the field and have important implications for the therapeutic use of T-Reg cells. In this article, Nature Reviews Immunology asks several experts for their views on the plasticity and stability of T-Reg cells.
With the promise of T cell-based therapy for cancer finally becoming reality, this Review focuses on the less-studied gamma delta T cell lineage and its diverse responses to tumours gamma delta T cells have well-established protective roles in cancer, largely on the basis of their potent cytotoxicity and interferon-gamma production. Besides this, recent studies have revealed a series of tumour-promoting functions that are linked to interleukin-17-producing gamma delta T cells. Here, we integrate the current knowledge from both human and mouse studies to highlight the potential of gamma delta T cell modulation to improve cancer immunotherapy.
gamma delta T cells have several innate cell-like features that allow their early activation following recognition of conserved stress-induced ligands. Here we review recent observations revealing the ability of gamma delta T cells to rapidly produce cytokines that regulate pathogen clearance, inflammation and tissue homeostasis in response to tissue stress. These studies provide insights into how they acquire these properties, through both developmental programming in the thymus and functional polarization in the periphery. Innate features of gamma delta T cells underlie their non-redundant role in several physiopathological contexts and are therefore being exploited in the design of new immunotherapeutic approaches.
CD4(+) T helper (T(H)) cells have crucial roles in orchestrating adaptive immune responses. T(H)2 cells control immunity to extracellular parasites and all forms of allergic inflammatory responses. Although we understand the initiation of the T(H)2-type response in tissue culture in great detail, much less is known about T(H)2 cell induction in vivo. Here we discuss the involvement of allergen- and parasite product-mediated activation of epithelial cells, basophils and dendritic cells and the functions of the cytokines interleukin-4 (IL-4), IL-25, IL-33 and thymic stromal lymphopoietin in the initiation and amplification of T(H)2-type immune responses in vivo.
Research on the biological function of nuclear factor-kappa B (NF-kappa B), a key mediator of inducible transcription in the immune system, has traditionally focused on its role in the initiation of innate and adaptive immune responses. These studies have largely concentrated on the mechanisms of signalling that lead to NF-kappa B activation and on the positive role of NF-kappa B in both physiological immunity and pathological inflammation. More recently, there has been growing interest in the mechanisms that directly regulate the NF-kappa B transcriptional programmes. As a result, several new NF-kappa B regulatory components have been identified and some of the known components have been assigned new roles. In this Review, we discuss these new insights into the regulation of NF-kappa B.
In addition to their role in binding antigen, antibodies can regulate immune responses through interacting with Fc receptors (FcRs). In recent years, significant progress has been made in understanding the mechanisms that regulate the activity of IgG antibodies in vivo. In this Review, we discuss recent studies addressing the multifaceted roles of FcRs for IgG (Fc gamma Rs) in the immune system and how this knowledge could be translated into novel therapeutic strategies to treat human autoimmune, infectious or malignant diseases.
Transforming growth factor-beta (TGF beta) is an immunosuppressive cytokine produced by tumour cells and immune cells that can polarize many components of the immune system. This Review covers the effects of TGF beta on natural killer (NK) cells, dendritic cells, macrophages, neutrophils, CD8(+) and CD4(+) effector and regulatory T cells, and NKT cells in animal tumour models and in patients with cancer. Collectively, many recent studies favour the hypothesis that blocking TGF beta-induced signalling in the tumour microenvironment enhances antitumour immunity and may be beneficial for cancer therapy. An overview of the current drugs and reagents available for inhibiting TGF beta-induced signalling and their phase in clinical development is also provided.
The T cell protein cytotoxic T lymphocyte antigen 4 (CTLA4) was identified as a crucial negative regulator of the immune system over 15 years ago, but its mechanisms of action are still under debate. It has long been suggested that CTLA4 transmits an inhibitory signal to the cells that express it. However, not all the available data fit with a cell-intrinsic function for CTLA4, and other studies have suggested that CTLA4 functions in a T cell-extrinsic manner. Here, we discuss the data for and against the T cell-intrinsic and -extrinsic functions of CTLA4.
Common cytokine-receptor γ-chain (γ c ) family cytokines have critical roles in the development, proliferation, survival and differentiation of multiple cell lineages of both the innate and adaptive immune system. In this review, we focus on our current understanding of the distinct and overlapping effects of IL-2, IL-7, IL-9, IL-15, and IL-21, as well as the IL-7-related cytokine TSLP (thymic stromal lymphopoietin), on the survival and proliferation of conventional αβ T cells, γδ T cells, and regulatory T cells. This knowledge potentially allows for the therapeutic manipulation of immune responses for the treatment of cancer, autoimmunity, allergic diseases and immunodeficiency, as well as for vaccine development.
Asthma has been considered a T helper 2 (T(H)2) cell-associated inflammatory disease, and T(H)2-type cytokines, such as interleukin-4 (IL-4), IL-5 and IL-13, are thought to drive the disease pathology in patients. Although atopic asthma has a substantial T(H)2 cell component, the disease is notoriously heterogeneous, and recent evidence has suggested that other T cells also contribute to the development of asthma. Here, we discuss the roles of different T cell subsets in the allergic lung, consider how each subset can contribute to the development of allergic pathology and evaluate how we might manipulate these cells for new asthma therapies.
Most tissue-resident macrophages are derived from embryonic precursors but, under certain circumstances, circulating monocytes can differentiate into self-maintaining tissue-resident macrophages that resemble their embryonic counterparts. In this Opinion article, we propose that distinct macrophage precursors have an almost identical potential to develop into resident macrophages but they compete for a restricted number of niches. The tight regulation of the niche ensures that monocytes do not differentiate into macrophages when the niche is full but that these cells can differentiate efficiently into macrophages when the niche is available. Imprinting by the niche would be the dominant factor conferring macrophage identity and self-maintenance capacity, rather than origin as was previously proposed.
Following activation, CD4(+) T cells differentiate into different lineages of helper T (T-H) cells that are characterized by distinct developmental regulation and biological functions. T-H 17 cells have recently been identified as a new lineage of effector T-H cells, and they have been shown to be important in immune responses to infectious agents, as well as in various immune diseases. Over the past two to three years, there has been a rapid progress in our understanding of the differentiation programme of T-H 17 cells. Here, I summarize our current knowledge of the unique gene expression, cytokine-mediated regulation and transcriptional programming of T-H 17 cells, and provide my personal perspectives on the future studies that are required to elucidate this lineage in more detail.
T helper 17 (T(H)17) cells have well-described roles in autoimmune disease. Recent evidence suggests that this effector T cell subset is also involved in tumour immunology and may be a target for cancer therapy. In this Review, we summarize recent findings regarding the nature and relevance of T(H)17 cells in mouse models of cancer and human disease. We describe the interplay between T(H)17 cells and other immune cells in the tumour microenvironment, and we assess both the potential antitumorigenic and pro-tumorigenic activities of T(H)17 cells and their associated cytokines. Understanding the nature of T(H)17 cell responses in the tumour microenvironment will be important for the design of more efficacious cancer immunotherapies.