Metabolism And Immune Tolerance

Historically the study of the immune system and metabolism have been two very separate fields. In recent years, a growing literature has emerged illustrating how the multiple processes of cellular metabolism are intricately linked to several aspects of immune function and development. This Research Topic covers recent progress in the field now known as “Immunometabolism” and the role of metabolism in immune tolerance. Immune tolerance is operationally defined as a state where a host’s immune system is balanced such that although self-reactive lymphocytes are present, they are kept in check by immune regulation. Perturbations to this homeostasis may result in self-reactive lymphocytes gaining the upper hand and mediating auto-immune disease. Maintenance of immune tolerance involves a large cast of different cell types including effector T cells, regulatory T cells, B cells, stromal cells, dendritic cells and macrophages. Intracellular pathways and individual enzymes of metabolism have been shown to be harnessed by cells of both the adaptive and innate immune system to allow particular immune functions to be achieved. Examples include metabolic enzymes serving ‘moonlighting’ functions in mRNA translation, gene splicing, and kinase activation. Other examples include the requirement for de novo fatty acid synthesis for differentiation into Th17 effectors and CD8 memory T cells or products of the TCA cycle promoting pro-inflammatory cytokine production. Likewise, the availability of extracellular metabolic substrates has a large impact on the maintenance of local immune tolerance. For example, there are different requirements for glucose, glutamine and fatty acids for effector versus regulatory T cell development. Also tolerogenic dendritic cells mediate lowering of extracellular essential amino acids by their enhanced catabolism, promoting the induction of regulatory T cells. The purpose of this Research Topic is to provide an update on the current understanding of the multiple roles for metabolism in regulating the immune system.

Historically the study of the immune system and metabolism have been two very separate fields. In recent years, a growing literature has emerged illustrating how the multiple processes of cellular metabolism are intricately linked to several aspects of immune function and development. This Research Topic covers recent progress in the field now known as "Immunometabolism" and the role of metabolism in immune tolerance. Immune tolerance is operationally defined as a state where a host's immune system is balanced such that although self-reactive lymphocytes are present, they are kept in check by immune regulation. Perturbations to this homeostasis may result in self-reactive lymphocytes gaining the upper hand and mediating auto-immune disease. Maintenance of immune tolerance involves a large cast of different cell types including effector T cells, regulatory T cells, B cells, stromal cells, dendritic cells and macrophages. Intracellular pathways and individual enzymes of metabolism have been shown to be harnessed by cells of both the adaptive and innate immune system to allow particular immune functions to be achieved. Examples include metabolic enzymes serving 'moonlighting' functions in mRNA translation, gene splicing, and kinase activation. Other examples include the requirement for de novo fatty acid synthesis for differentiation into Th17 effectors and CD8 memory T cells or products of the TCA cycle promoting pro-inflammatory cytokine production. Likewise, the availability of extracellular metabolic substrates has a large impact on the maintenance of local immune tolerance. For example, there are different requirements for glucose, glutamine and fatty acids for effector versus regulatory T cell development. Also tolerogenic dendritic cells mediate lowering of extracellular essential amino acids by their enhanced catabolism, promoting the induction of regulatory T cells. The purpose of this Research Topic is to provide an update on the current understanding of the multiple roles for metabolism in regulating the immune system.

Obesity and its co-morbidities, including atherosclerosis, insulin resistance and diabetes, are a world-wide epidemic. Inflammatory immune responses in metabolic tissues have emerged as a universal feature of these metabolic disorders. While initial work highlighted the contribution of macrophages to tissue inflammation and insulin resistance, recent studies demonstrate that cells of the adaptive immune compartment, including T and B lymphocytes and dendritic cells also participate in obesity-induced pathogenesis of these conditions. However, the molecular and cellular pathways by which the innate and adaptive branches of immunity control tissue and systemic metabolism remain poorly understood. To engage in growth and activation, cells need to increase their biomass and replicate their genome. This process presents a substantial bioenergetic challenge: growing and activated cells must increase ATP production and acquire or synthesize raw materials, including lipids, proteins and nucleic acids. To do so, they actively reprogram their intracellular metabolism from catabolic mitochondrial oxidative phosphorylation to glycolysis and other anabolic pathways. This metabolic reprogramming is under the control of specific signal transduction pathways whose underlying molecular mechanisms and relevance to physiology and disease are subject of considerable current interest and under intense study. Recent reports have elucidated the physiological role of metabolic reprogramming in macrophage and T cell activation and differentiation, B- and dendritic cell biology, as well as in the crosstalk of immune cells with endothelial and stem cells. It is also becoming increasingly evident that alterations of metabolic pathways play a major role in the pathogenesis of chronic inflammatory disorders. Due to the scientific distance between immunologists and experts in metabolism (e.g., clinicians and biochemists), however, there has been limited cross-talk between these communities. This collection of articles aims at promoting such cross-talk and accelerating discoveries in the emerging field of immunometabolism.

Tolerogenic dendritic cells (TolDCs) are actively involved in the elimination of autoreactive T cells in the thymus and quench T cell responses to self-antigens in the periphery under steady state. Normal dendritic cell (DC) maturation is influenced by both the inflammatory milieu and foreign antigens, and is required to generate an immunogenic response. These immunogenic DCs then interact with T and B cells to assist in antibody production. An imbalance between TolDCs and immunogenic DCs may instigate the development of autoimmunity and therefore, TolDCs have emerged as an expedient therapeutic target to manage autoimmunity. Although there is enough scientific evidence available depicting the development and functional utility of TolDCs in preclinical models of autoimmunity, in the absence of a more thorough understanding of TolDC biology their clinical use remains limited. This research work explores the immunomodulatory functions of TolDCs and the discovery of new possible therapeutic targets for the treatment of autoimmunity and provide three major insights. First, the protocol that we established in this thesis will help investigators to evaluate the capacity of new agents to promote the induction of TolDCs and to facilitate the effort to broaden the scope of TolDC therapeutics. Second, our data reveal that DCs are one of the principal cellular mediators of the immunomodulatory responses to the synthetic triterpenoid, CDDO-DFPA, and to related small molecules in the triterpenoid family for which we have shown efficacy in the preclinical model of multiple sclerosis. Third, we report that Nrf2 regulates DC tolerance by modulating their cytokine profile and cellular metabolism. Lastly our data show the therapeutic relevance of targeting Nrf2 signaling in the context of autoimmune disease. These data include analyses of Nrf2 function in preclinical models of multiple sclerosis (MS) and aplastic anemia (AA), and analyses of clinical specimens from patients with aplastic anemia, and together they help to further establish the therapeutic utility of TolDCs in managing clinical manifestations of these diseases. Overall, this is the first systematic research report revealing the Nrf2-dependent mechanisms of DC metabolic reprograming to generate tolerance and highlight their potential therapeutic utility in the treatment of autoimmunity.

This book discusses the relationship between cellular immunity and tryptophan metabolism, as well as its products, serotonin and melatonin, in the development of several diseases and reappraises the common signal transduction pathways of the neurodegenerative diseases, carcinogenesis, immune tolerance, inflammation, hypersensitivity reactions, neuropsychiatric disorders, in addition to bacterial tryptophan biosynthesis and novel antimicrobials. Tryptophan Metabolism: Implications for Biological Processes, Health and Disease presents fundamental information on tryptophan related metabolic pathways and metabolites, implications of these products for specific biological processes, diseases and conditions. This book focuses on effects of tryptophan metabolites on human health and will appeal to researchers, clinicians and students within this field.

Microbes, Microbial Metabolism and Mucosal Immunity: An Overview presents a concise and well-vetted treatise on the study of microbiome and microbial metabolites. This volume is up-to-date with the most recent developments from the last decade. It encompasses the interaction of immunity and microbes — and their metabolites — from different mucosal organs including gastrointestinal system, lung, oral cavity, eye. Along with the efficiency of the immune system in inhibiting the growth and proliferation of microbes, the volume discusses how the mediators of the immune system can be targeted to develop therapies. This book presents the latest methods, gives broad and systematic coverage of most mucosal systems and diseases, and takes a fresh perspective that looks at the functional aspects of change in the microbiome. The study of microbiome and microbial metabolites and their roles in host mucosal immunology is a rapidly developing area of research. One major way in which the microbiome influences the host is through altered metabolism. Metabolites, readily available to the host, engender significant consequences. Microbial metabolites have been shown to impact the disease processes in both proximal and distal organs, including the brain in several neurocognitive disorders. Offers a concise solution for the study of microbiome, microbial metabolism, and mucosal immunology Presents contemporary studies that incorporate the latest research methods Gives a broad and systematic accounting of most mucosal systems and diseases Looks at the functional aspects of changes to the microbiome as well as specific changes to microbiota Affords entry-level and advanced readers with the theory and knowledge needed for further research

We acknowledge the initiation and support of this Research Topic by the International Union of Immunological Societies (IUIS). We hereby state publicly that the IUIS has had no editorial input in articles included in this Research Topic, thus ensuring that all aspects of this Research Topic are evaluated objectively, unbiased by any specific policy or opinion of the IUIS.

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Among the topics reviewed are T and B cell tolerance, clonal deletion, suppressor cells, mechanisms of immune privileged sites and experimental models of tumor immunity. Oral tolerance, ultraviolet radiation and photosensitized effects on immunity, allograft management, T cell vaccination and regulation of immunity with T cell epitopes are discussed from the point of view of possible therapeutic application.

Genetic alterations in cancer, in addition to being the fundamental drivers of tumorigenesis, can give rise to a variety of metabolic adaptations that allow cancer cells to survive and proliferate in diverse tumor microenvironments. This metabolic flexibility is different from normal cellular metabolic processes and leads to heterogeneity in cancer metabolism within the same cancer type or even within the same tumor. In this book, we delve into the complexity and diversity of cancer metabolism, and highlight how understanding the heterogeneity of cancer metabolism is fundamental to the development of effective metabolism-based therapeutic strategies. Deciphering how cancer cells utilize various nutrient resources will enable clinicians and researchers to pair specific chemotherapeutic agents with patients who are most likely to respond with positive outcomes, allowing for more cost-effective and personalized cancer therapeutic strategies.