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The role of the cytokine, macrophage migration inhibitory factor (MIF), in the immune response and in the immunopathogenesis of different inflammatory, autoimmune, and infectious disorders is now well established. The aim of this handbook is to provide an authoritative volume covering all aspects of MIF, from basic molecular biology to structure-function relationships, pathophysiology, genetics, and drug development.

Key Points Endogenous and pharmacological glucocorticoids exert robust effects on inflammatory and immune processes. Glucocorticoids receptors are expressed by nearly all cells in the body, yet the effects of glucocorticoids vary by cell type. The production of endogenous glucocorticoids is regulated by the hypothalamic–pituitary–adrenal axis. Glucocorticoids are rapidly induced in response to inflammation and other stressors, but they also follow secretion patterns that are associated with circadian and ultradian rhythms. Glucocorticoids bind cytosolic glucocorticoids receptors, which are ligand-dependent transcription factors. Ligand-bound glucocorticoid receptors regulate gene transcription through three mechanisms: direct binding to DNA via glucocorticoid response elements; protein–protein interactions with other transcription factors; and composite binding to DNA and other transcription factors. Glucocorticoids inhibit inflammation by dampening signal transduction downstream of pattern recognition receptors (PRRs), cytokine receptors and Fcɛ receptors. Glucocorticoids promote the resolution of the inflammatory response through programming effects on macrophages. Glucocorticoids regulate adaptive immunity by inhibiting lymphocyte activation and promoting lymphocyte apoptosis. At high concentrations, glucocorticoids also inhibit the production of B cells and T cells. Glucocorticoid exposure at low doses and/or before challenge can enhance inflammatory responses. Glucocorticoid receptor signalling spares or enhances many pathways that are involved in innate immunity, while suppressing those that are involved in adaptive immunity. We propose that low concentrations of endogenous glucocorticoids sensitize the innate immune system by upregulating PRRs, cytokine receptors and complement factors, thus allowing for rapid responses to danger signals. High concentrations of glucocorticoids, by contrast, suppress signals that are mediated by PRRs and cytokine receptors, thereby preventing excessive and/or prolonged immune responses. In this Review, the authors discuss the effects of glucocorticoids on both innate and adaptive immunity. They explain the mechanistic basis of glucocorticoid-mediated immunosuppression and highlight the less well-appreciated roles of glucocorticoids in enhancing immune responses. Endogenous glucocorticoids are crucial to various physiological processes, including metabolism, development and inflammation. Since 1948, synthetic glucocorticoids have been used to treat various immune-related disorders. The mechanisms that underlie the immunosuppressive properties of these hormones have been intensely scrutinized, and it is widely appreciated that glucocorticoids have pleiotropic effects on the immune system. However, a clear picture of the cellular and molecular basis of glucocorticoid action has remained elusive. In this Review, we distil several decades of intense (and often conflicting) research that defines the interface between the endocrine stress response and the immune system.

Regulatory T (Treg ) cells suppress inflammation and regulate immune system activity. In patients with systemic or organ-specific autoimmune diseases or those receiving transplanted organs, Treg cells are compromised. Approaches to strengthen Treg cell function, either by expanding them ex vivo and reinfusing them or by increasing the number or capacity of existing Treg cells, have entered clinical trials. Unlike the situation in autoimmunity, in patients with cancer, Treg cells limit the antitumour immune response and promote angiogenesis and tumour growth. Their immunosuppressive function may, in part, explain the failure of many immunotherapies in cancer. Strategies to reduce the function and/or number of Treg cells specifically in tumour sites are being investigated to promote antitumour immunity and regression. Here, we describe the current progress in modulating Treg cells in autoimmune disorders, transplantation and cancer.

Tumor-associated macrophages (TAMs) play an important role in the immune response to cancer, but the mechanisms by which the tumor microenvironment controls TAMs and T cell immunity are not completely understood. Here we report that kynurenine produced by glioblastoma cells activates aryl hydrocarbon receptor (AHR) in TAMs to modulate their function and T cell immunity. AHR promotes CCR2 expression, driving TAM recruitment in response to CCL2. AHR also drives the expression of KLF4 and suppresses NF-κB activation in TAMs. Finally, AHR drives the expression of the ectonucleotidase CD39 in TAMs, which promotes CD8+ T cell dysfunction by producing adenosine in cooperation with CD73. In humans, the expression of AHR and CD39 was highest in grade 4 glioma, and high AHR expression was associated with poor prognosis. In summary, AHR and CD39 expressed in TAMs participate in the regulation of the immune response in glioblastoma and constitute potential targets for immunotherapy.Using animal models and clinical samples, the authors report that glioblastoma metabolites activate the transcription factor aryl hydrocarbon receptor in tumor-associated macrophages to modulate their function and T cell immunity, promoting tumor growth.

Innate immune responses are triggered in response to the sensing of pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) by pattern recognition receptors (PRRs). An emerging idea is that inflammasome activation may also occur independently of PRR activation following a disturbance in cellular homeostasis. The authors explore this concept and the implications for chronic inflammatory disease in this Opinion article. The innate immune system uses a distinct set of germline-encoded pattern recognition receptors (PRRs) to initiate downstream inflammatory cascades. This recognition system is in stark contrast to the adaptive immune system, which relies on highly variable, randomly generated antigen receptors. A key limitation of the innate immune system's reliance on fixed PRRs is its inflexibility in responding to rapidly evolving pathogens. Recent advances in our understanding of inflammasome activation suggest that the innate immune system also has sophisticated mechanisms for responding to pathogens for which there is no fixed PRR. This includes the recognition of debris from dying cells, known as danger-associated molecular patterns (DAMPs), which can directly activate PRRs in a similar manner to pathogen-associated molecular patterns (PAMPs). Distinct from this, emerging data for the inflammasome components NLRP3 (NOD-, LRR- and pyrin domain-containing 3) and pyrin suggest that they do not directly detect molecular patterns, but instead act as signal integrators that are capable of detecting perturbations in cytoplasmic homeostasis, for example, as initiated by infection. Monitoring these perturbations, which we term 'homeostasis-altering molecular processes' (HAMPs), provides potent flexibility in the capacity of the innate immune system to detect evolutionarily novel infections; however, HAMP sensing may also underlie the sterile inflammation that drives chronic inflammatory diseases.

Key Points Our understanding of the pathogenesis of systemic lupus erythematosus (SLE) has changed rapidly over the past decade Refinements in our understanding over the past 3 years have led to the potential for precision targeting of therapeutic strategies Advances in epigenetic therapeutic agents and the manipulation of cells ex vivo have the potential to further improve patient care In this Review, Tsokos et al . describe recent advances in our understanding of systemic lupus erythematosus (SLE) that are driving repurposing of existing drugs as well as development of new treatments. Cytokines, tolerance pathways, local tissue mediators, and epigenetic mechanisms all show promise as novel targeted therapies that could lead to individualized care in SLE. The aetiology of systemic lupus erythematosus (SLE) is multifactorial, and includes contributions from the environment, stochastic factors, and genetic susceptibility. Great gains have been made in understanding SLE through the use of genetic variant identification, mouse models, gene expression studies, and epigenetic analyses. Collectively, these studies support the concept that defective clearance of immune complexes and biological waste (such as apoptotic cells), neutrophil extracellular traps, nucleic acid sensing, lymphocyte signalling, and interferon production pathways are all central to loss of tolerance and tissue damage. Increased understanding of the pathogenesis of SLE is driving a renewed interest in targeted therapy, and researchers are now on the verge of developing targeted immunotherapy directed at treating either specific organ system involvement or specific subsets of patients with SLE. Accordingly, this Review places these insights within the context of our current understanding of the pathogenesis of SLE and highlights pathways that are ripe for therapeutic targeting.

Key Points Radiotherapy not only exerts direct cytotoxic effects on tumour cells, but also re-programmes the tumour microenvironment to exert a potent antitumour immune response Tumour-cell proliferation and cell death due to T-cell cytotoxic killing coexist in irradiated tumours, resulting in stable disease that might provide a window of opportunity for immune-modulation Radiotherapy enhances antitumour immunity, but also induces immunosuppressive responses The combination of immunotherapy and radiotherapy presents a multimodal treatment approach that involves stimulating and suppressing various pathways The interaction between radiotherapy and the host immune system has uncovered new mechanisms that can be exploited to improve the efficacy of radiotherapy. In this article, the authors highlight data providing new explanations for the success or failure of radiotherapy, and postulate, using radiation-induced tumour equilibrium (RITE) as an example, how the combination of immune-modulation and radiation could tip the balance of the host immune response to promote cure. Investigations into the interaction between radiotherapy and the host immune system have uncovered new mechanisms that can potentially be exploited to improve the efficacy of radiotherapy. Radiation promotes the release of danger signals and chemokines that recruit inflammatory cells into the tumour microenvironment, including antigen-presenting cells that activate cytotoxic T-cell function. By contrast, radiation can attract immunosuppressive cells into the tumour microenvironment. In rare circumstances, the antitumour effect of radiotherapy has been observed outside of the radiation field, known as the abscopal effect. This phenomenon is proposed to have an immune origin and indicates that local radiotherapy elicits systemic effects. Herein, we highlight data that provide new mechanistic explanations for the success or failure of radiotherapy, and postulate how the combination of immune-modulation and radiation could tip the balance of the host immune response to promote cure. We use the concept of radiation- induced tumour equilibrium (RITE) as a starting point to discuss the mechanistic influence of immune-checkpoint therapies on radiotherapy efficacy.

The cytokine receptor IL-2R is essential for the development of T reg cells; therefore, it has been difficult to separate this from its role in the suppressive function of T reg cells. Rudensky and colleagues use various genetic systems to show that capture of IL-2 by IL-2R is important for suppression of CD8 + T cells but not that of CD4 + T cells. Regulatory T cells (T reg cells), which have abundant expression of the interleukin 2 receptor (IL-2R), are reliant on IL-2 produced by activated T cells. This feature indicates a key role for a simple network based on the consumption of IL-2 by T reg cells in their suppressor function. However, congenital deficiency in IL-2R results in reduced expression of the T reg cell lineage–specification factor Foxp3, which has confounded experimental efforts to understand the role of IL-2R expression and signaling in the suppressor function of T reg cells. Using genetic gain- and loss-of-function approaches, we found that capture of IL-2 was dispensable for the control of CD4 + T cells but was important for limiting the activation of CD8 + T cells, and that IL-2R-dependent activation of the transcription factor STAT5 had an essential role in the suppressor function of T reg cells separable from signaling via the T cell antigen receptor.

It is now accepted that T cell activation by an antigen-presenting cell requires the organization of a supramolecular structure - the immune synapse.This structure, with different types of molecules spatially segregated, is involved in the delivery of quantitative and qualitative signals critical for T cell activation, and therefore in.