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A major process of rediscovery has taken place in the field of Cellular Immunology over the past 12 years—subsets of T lymphocytes exist that are specifically dedicated to regulation or as it should be more appropriately termed suppression of all aspects of immune responses. It was only after Prof. Sakaguchi identified the CD25 antigen in 1995 as a marker for a major population of T cells that had suppressor functions both in vitro and in vivo that the resurgence in the regulatory T cell area could begin. The regulatory T cells field has grown dramatically over the past decade. It is now impossible to read a journal that does not contain numerous papers whose titles deal with regulatory T cells. More importantly, it is also difficult to submit a new research grant proposal in any area of immunologic research that does not include a section on analysis on the contribution of regulatory T cells to the subject matter under study. Regulatory T cells can be best thought of today as'teenagers'ready to take on all the challenges of complex immune responses. In ten years, the field will certainly be more mature, and manipulation of regulatory T cell function by cellular biotherapy, antibodies and small molecules will be routine function of the clinical immunologist. - From Preface by Prof. Ethan Shevach, National Institute of Health, USA It has been for long debated whether suppressor/regulatory T cells did actually even exist. Today, this question is no longer accurate and the subject of regulatory T cells is the object of a constantly growing interest in immunologists and clinicians. There is no doubt that the history of Tregs will make a new big leap ahead. - From Chapter One by Prof. Shimon Sakaguchi, Kyoto University, Japan

This book is about the escape strategies used by cancer cells to avoid the immune response of the host. The main characters of this story are the “Antigen Presenting Molecules” and the “T Lymphocytes”. The former are known as the Major Histocompatibility Complex (MHC): the H-2 and the HLA molecules. The latter are a subgroup of white cells travelling all over our body which are capable to distinguish between “self and non self”. Readers will know from the inside about the history of the HLA genetic system and will discover how T lymphocytes recognize and destroy cancer cells. One of the key important questions is: Why tumors arise, develop and metastasize? This book tries to answer this question and will explain how cancer cells become invisible to killer T lymphocytes. The loss of the HLA molecules is a major player in this tumor escape mechanism. Cancer immunotherapy is aimed at stimulating T lymphocytes to destroy tumor cells. However, the clinical response rate is not as high as expected. The molecular mechanisms responsible for MHC/HLA antigen loss play a crucial role in this resistance to immunotherapy. This immune escape mechanism will be discussed in different types of tumors: lung, prostate, bladder and breast…ect. as well as melanoma and lymphoma. This book will be useful to Oncologists, Pathologists and Immunologist that will enter this fascinating area of research. It will be also interesting for biologist, doctoral students and medical residents interested in “Tumor Immunology”.

T cells play a vital role mediating adaptive immunity, a specific acquired resistance to an infectious agent produced by the introduction of an antigen. There are a variety of T cell types with different functions. They are called T cells, because they are derived from the thymus gland. This volume discusses how T cells are regulated through the operation of signaling mechanisms. Topics covered include positive and negative selection, early events in T cell receptor engagement, and various T cell subsets.

The book starts with an introduction to and history of myeloid-derived suppressor cells (MDSCs), followed by a description of their differentiation, their role in the tumour microenvironment and their therapeutic targeting. It closes with an outlook on future developments. In cancer patients, myelopoiesis is perturbed and instead of generating immunogenic myeloid cells (such as dendritic cells, inflammatory macrophages and granulocytes), there is an increase in highly immature MDSCs. These cells are distributed systemically, resulting in general immunosuppression. They also infiltrate tumours, promoting their progression and metastasis by inhibiting the natural anti-tumour immune response. As these cells also interact with classical anti-neoplastic treatments, they have become major therapeutic targets in the pharmaceutical industry and in oncology research.

The thymus is an evolutionarily ancient primary lymphoid organ common to all vertebrates in which T cell development takes place. Failing thymus function is associated with immunodeficiency and/or autoimmunity. In this volume, leading experts provide a comprehensive overview of recent advances in thymopoiesis research. The chapters cover the development of the thymic epithelial microenvironment, address the formation of a diverse and self-tolerant repertoire of T cell receptors as the basis for cellular immunity, discuss the mechanisms by which progenitor cells colonize the thymus and detail the molecular basis for T lineage decisions. The reviews illustrate the important role of the multifaceted process of thymopoiesis for adaptive immunity.

This book will focus on the differentiation and regulation of subsets of CD4+ T cells. It will also cover other aspects of research on these cells, which has made great advances in recent years, such as subsets'plasticity and their role in healthy and disease conditions. The book provides researchers and graduate students with a cutting-edge and comprehensive overview of essential research on CD4+ T cells.

This book summarizes the state-of-the art in the development of T cell-based in vitro assays, which offer useful tools for hazard identification, risk assessment and improvement of diagnostics. It will be of interest to scientists, the chemical and pharmaceutical industry, and regulators involved in the replacement of animal testing methods.The identification of hazardous chemicals and drugs is essential to ensuring human health. The ban on animal testing for the cosmetics industry since 2009 and international efforts to reduce and replace animal testing in research and immunotoxicology call for alternative in vitro methods. The most specific immune response to chemicals and drugs that cause allergic contact dermatitis, respiratory disease and adverse drug reactions is the highly antigen-specific T lymphocyte response. Therefore the use of T cells as tools for identifying contact allergens and drugs that may cause health problems is of great interest.

Our motivation for putting together this book was the need for a single source reference that could be used as an introduction to cell-mediated cytotoxicity for newcomers to this field, such as students and fellows beginning work in our laboratories. At present no such book is available, and we felt that it would be useful as a teaching tool and as a way of conveying our enthusiasm about recent progress in the cytotoxicity field to our colleagues in allied areas. It was with some hesitation that we approached our colleagues with the proposal for this book, and we were pleased to find them very supportive of the idea and willing to participate. We thought it important to broaden the scope of the book to include historical, molecular, cell biological, and clinical aspects of cell-mediated cytotoxicity. To our knowledge this is the first book on cell-mediated cytotoxicity with such a broad scope. Historically, studies on cellular cytotoxicity were part of cellular immunology from its origin. One development of tremendous import was the advent of the 51 Cr assay, which allowed this arm of the immune response to be measured easily and quantitatively. Thus, a readout of this effector pathway is available within a few hours; other immune effector functions can take days or even longer to assay, and the assays are often less quantitative.

And even I can remember A day when historians left blanks in their writings, I mean for things they didn't know. -Ezra Pound, Canto XIII • The prefaces to the previous volumes of this series have all expressed in various ways the actual motivation behind these collective efforts. There was agreement in most instances that we are facing some kind of publication explosion, and that the present type of compact and personalized reviews may be of help, from both a conceptual and a purely informational standpoint. The aims of the series were, and still are, to focus attention on the rapidly changing fields within the realm of immunology, and to present in each chapter the summation of results generated by an investigator or group of Investigators, either as an analysis of their own work or as a correlation of such work with the general field in question. The present volume does not differ in its construction from its predecessors, although it does concentrate on a single target, the T lymphocyte and its biology. The selection of subjects as well as contributors has been the sole responsi­ bility of this editor; however, the actual format and length of the individual contributions was left to the discretion and inspiration of the different authors. Even the styles, ranging from the concise statement to the meticulously detailed review, attest to the freedom of format.

Regulatory T cells (sometimes known as suppressor T cells) are a specialized subpopulation of T cells that act to suppress activation of the immune system and thereby maintain immune system homeostasis and tolerance to self-antigens. This book presents topical research in the study of regulatory T cells, including the role of regulatory T cells in the treatment of multiple sclerosis and hepatocellular carcinoma; genetic engineering of antigen-specific regulatory T cells; regulatory T cells in arthritis, allergic disorders and immunomodulation; and the roles of immunoregulatory cells and the mechanisms of immune response.

Advances in Immunology, a long-established and highly respected publication, presents current developments as well as comprehensive reviews in immunology. Articles address the wide range of topics that comprise immunology, including molecular and cellular activation mechanisms, phylogeny and molecular evolution, and clinical modalities. Edited and authored by the foremost scientists in the field, each volume provides up-to-date information and directions for the future. This volume focuses on regulatory T-cells. - Contributions from leading authorities and industry experts - Informs and updates on all the latest developments in the field

The proper physiological functioning of most eukaryotic cells requires their assembly into multi-cellular tissues that form organized organ systems. Cells of the immune system develop in bone marrow and lymphoid organs, but as the cells mature they leave these organs and circulate as single cells. Antigen receptors (TCRs) of T cells search for membrane MHC proteins that are bound to peptides derived from infectious pathogens or cellular transformations. The detection of such speci?c peptide–MHC antigens initiates T cell activation, adhesion, and immune-effectors functions. Studies of normal and transformed T cell lines and of T cells from transgenic mice led to comprehensive understanding of the mole- lar basis of antigen-receptor recognition and signaling. In spite of these remarkable genetic and biochemical advances, other key physiological mechanisms that par- cipate in sensing and decoding the immune context to induce the appropriate cellular immune responses remain unresolved. TCRrecognition is tightly regulated to trigger sensitive but balanced T cell responses that result in the effective elimination of the pathogens while minimizing collateral damage to the host. The sensitivity of TCR recognition has to be properly tempered to prevent unintended activation by self-peptide–MHC complexes that cause autoimmune diseases. It is likely that once the TCR is engaged by a peptide– MHC and TCR signaling begins, additional regulatory mechanisms, involving other receptors, would increase the?delity of the response.

This book explains how the immune system functions, namely, how individual cells of the immune system make the decision to respond or not to respond to foreign microbes and molecules, and how the critical molecules function to trigger the cellular reactions in an all-or-none (quantal) manner. To date, there has not been a complete description of the immune system and its cells and molecules, primarily because most of the information has accumulated only in the last 40 years and our understanding has been expanding rapidly only in the last 20 years. It is now clear that the cells have evolved a way to “count” the number of foreign antigenic molecular “hits”, and they only react when a critical number of events have accumulated. Subsequently, control over the reaction is transferred to a systemic lymphocytotrophic hormone system that determines the tempo, magnitude and duration of the immune reaction.This book explains in detail how the immune system, cells and molecules work for the first time. With this understanding as a basis, the pathogenesis of autoimmunity can now be understood as a mutational usurpation of the genes encoding molecules that participate in a sensitive feedback regulatory control of the immune reaction. By comparison, malignant transformation is understood as a mutational usurpation of the genes encoding the molecules that control the quantal decision to proliferate, so that normal ligand/receptor cell growth control is circumvented.

T cells belong to a group of white blood cells called lymphocytes and play a large role in the immune response. An increased understanding of T cell immunity will provide new insights into the etiology of human autoimmune disease such as diabetes. This volume reviews the latest developments and discusses the evolution of T cell immunity, thymic requirements, and how to prevent T cell-dependent autoimmunity. - Discusses new discoveries, approaches, and ideas in T cell immunity - Contributions from leading scholars and industry experts - Reference guide for researchers involved in molecular biology and related fields

The IL-17 cytokines represent a novel family of cytokines, which defines a new effector T cell, the Th17 cell, and extend the Th1-Th2 paradigm. Th17 cells in part co-express at least IL-17A and IL-17F, IL-21 and IL-22. IL-17 A/F are produced by T cells ( and), iNKT cells, and possibly neutrophils, dendritic cells and Paneth cells. The regulation of IL-17 family member's expression, and the identification of effector mechanisms are an area of intense current research. Recognized regulators of IL-17A expression include the nuclear receptor ROR t, proinflammatory cyt- ines such as IL-1, IL-6 with TGF-, IL-21, IL-23 IL-25 in the absence of IFN- and IL-4, which are discussed. Recent data suggest that IL-17A may have a dual fu- tion – pro-inflammatory and anti-inflammatory- suggesting that IL-17A may also contribute to terminate inflammation. Further, a reciprocal regulation of Th17 and regulatory T cells including the role of retinoic acid and TGF- is discussed. The discovery that patients with rheumatoid arthritis, allergic disorders, psor- sis and inflammatory bowel disease express IL-17A generated interest in the medical community and instigated a flurry of experimental research on the potential role of Th17 in inflammatory diseases. Experimental studies confirmed that IL-17A is induced and is critical for the development of allergic lung inflammation, arthritis, bacterial sepsis, experimental allergic encephalomyelitis and myocarditis, as well as other inflammatory con- tions including organ transplantation. The role of IL-17F and IL-22 is still poorly defined and is only slowly emerging.

This book presents the state of the art in cellular and molecular mechanisms regulating the immune response in allergic inflammation. Special attention is given to the central role of regulatory T cells (Treg) in immune regulation and induction of peripheral tolerance, as well as to the relevance of Th17 cells in chronic inflammation. The importance of Treg and Th17 cells is demonstrated in bronchial asthma, atopic eczema, contact dermatitis and delayed-type hypersensitivity. Furthermore, T-cell-mediated regulatory mechanisms in helminthic infections and fungal allergy are discussed. Several chapters are devoted to the therapeutic consequences that these recently discovered T-cell functions may have. Their role as a potential target for specific immunotherapy is evaluated and novel approaches for peripheral tolerance induction and treatment of allergic and asthmatic diseases and inflammation are suggested. Stem cell transplantation as a future therapeutic intervention in regulatory T-cell disorders is also considered. Well edited and up to date, this volume is recommended reading for allergologists, immunologists, dermatologists and any scientist interested in the immunological events regulating allergic inflammation in general and allergic manifestations in different organs.

Systems biology and computational biology have recently become prominent areas of research in the biomedical community, especially in the area of cell biology. Given that much information on genes and their protein products has become available, the big question is how the individual components interact and work together, and how this determines the functioning of cells, organs, and organisms. Long before the popularity of systems biology in biomedicine, however, such approaches have been used successfully in a di?erent area of biology: population ecology. Research in the area of population dynamics - vestigated complex interactions between di?erent populations of organisms, such as the dynamics of competition and predation, food webs, community structure, as well as the epidemiology of infectious diseases. In this?eld, t- oretical biology and mathematical modeling have become an integral part of research. Mathematical models allowed people to obtain interesting and counter-intuitive insights into how complex interactions among di?erent p- ulations can play out. Such mathematical studies not only gave rise to - teresting theoretical ideas, but also provided the basis for the design of new experimental work and de?ned major questions and directions of research. Around 1990, such population dynamic concepts, and the use of mathema- cal/computational approaches, started to be applied to the in vivo dynamics between viruses and the immune system. These interactions have many s- ilarities to ecological, epidemiological, and evolutionary principles. Consider theepidemiologicalspreadofapathogen(suchasthecommoncold)througha population of hosts.

Superantigens constitute a growing family of bacterial and viral proteins that share the capacity of inducing massive activation of the immune system. This volume contains contributions from leaders in the field of classical T cell superantigens and sheds light on relevant B cell superantigens at the molecular and biochemical levels. Moreover, articles in this publication deal with the emerging, intriguing possibility that immunoglobulin superantigens can activate primary effector cells of allergic disorders both in vitro and in vivo, thus acting as superallergens. A detailed account is also given of the biochemical, immunological and clinical characteristics of several endogenous, viral and bacterial superallergens, which are probably relevant in a variety of human diseases. This is the first volume to put together basic and clinical aspects of the classical T cell superantigens, B cell superantigens and superallergens. It will therefore be indispensable reading to basic and clinical immunologists, microbiologists, virologists and specialists in allergic and immune disorders.

At first glance, the nervous and immune systems appear very different. However, both systems have developed mechanisms for memory formation – though of quite different quality and significance for the organism. One striking example is that both systems form and communicate via synapses armed with similar sets of proteins. This collection of reviews, contributed by internationally recognized immunologists and molecular and cellular neurobiologists, puts side by side cellular communication devices and signaling mechanisms in the immune and nervous systems and discusses mechanisms of interaction between the two systems, the significance of which has only recently been fully appreciated.

In an effort to go beyond immune-based therapies, researchers are now considering the implications of apoptosis dysregulation during HIV-induced immunodeficiency. This work provides the first comprehensive compendium of the progress made in understanding the process of cell death related to HIV and the potential breakthroughs in treatment that offer much promise. Combining the work of more than two-dozen top researchers, this seminal volume provides clinicians and researchers with an excellent reference, while also serving as an incubator to stimulate future research. It explains the fundamental biology involved with apoptosis, explains its clinical impact in HIV, and examines the newest therapeutic approaches.

Regulatory T-cells are essential components of the immune system, and several different subsets of regulatory T-cells have been described. Considerable regulatory function has been attributed to the CD4+CD25+ T-cell subset. These cells act by suppressing adaptive and possibly innate immune responses thereby maintaining or restoring the balance between immunity and tolerance. The suppressive effects of CD4+CD25+ regulatory T-cells are cell-contact dependent. Recent developments and viewpoints in the field of CD4+CD25+ regulatory T-cells as well as the potential use of regulatory T-cells in immunotherapy of inflammatory diseases are discussed in this volume. By linking data from experimental models with recent findings from the clinic, this book will be of interest to immunologists and other biomedical researchers as well as clinicians interested in the regulation and manipulation of the immune response during inflammatory disease.

The vertebrate immune system defends the organism against invading pathogens while at the same time being self-tolerant to the body's own constituents thus preserving its integrity. Multiple mechanisms work in concert to ensure self-tolerance. Apart from purging the T cell repertoire from auto-reactive T cells via negative selection in the thymus dominant tolerance exerted by regulatory T cells plays a major role in tolerance imposition and maintenance. Among the various regulatory/suppressive cells hitherto described, CD4+CD25+ regulatory T cells (Treg) and interleukin-10 producing T regulatory 1 (Tr1) cells have been studied in most detail and are the subject of most articles in this issue. Treg, also called'natural'regulatory T cells, will be traced from their intra-thymic origin to the site of their action in peripheral lymphoid organs and tissues. The repertoire of Treg is clearly biased towards recognition of self-antigens, thereby potentially preventing autoimmune diseases such as gastritis and oophoritis. Regulatory T cells, however also control infections, allergies and tolerance to transplanted tissues and this requires their induction in the periphery under conditions which are not yet fully understood. The concept of dominant tolerance, by far not novel, will offer new insights and hopefully tools for the successful treatment of autoimmune diseases, improved cancer immunotherapy and transplant survival. The fulfillment of these high expectations will, however, require their unambiguous identification and a better understanding of their mode of action.

Over the last decade, enormous progress in the understanding of T-cell homing has made it possible to identify the multitude of molecules involved, such as cytokines, chemokines, and adhesion molecules, and to unravel their complex interactions resulting in controlled, non-random T-cell recirculation. These insights are now being explored therapeut

Over the last decade, major advances in our understanding of the immune system and its mechanisms have led to promising new treatment strategies. In Adoptive Immunotherapy: Methods and Protocols, leading experts describe in detail their optimal techniques for producing and characterizing the immunologically active cells and effector molecules now gaining wide use in the clinical treatment of patients. Taking advantage of the latest technologies, the authors present readily reproducible experimental protocols for the study of dendritic cells, T-cells, monoclonal antibodies, and bone marrow transplantation. The emphasis is on preclinicical and clinical applications and on the progress of selected approaches in clinical trials. Additional chapters cover the molecular definition of target antigens, mathematical modeling approaches to immonotherapy, and the utilization of regulatory T-cells. Theoretical overviews and discussion of future directions for the improvement of adoptive immunotherapy complete the volume. The protocols follow the successful Methods in Molecular Medicine series format, each offering step-by-step laboratory instructions, an introduction outlining the principle behind the technique, lists of the necessary equipment and reagents, and tips on troubleshooting and avoiding known pitfalls. Comprehensive and state-of-the-art, Adoptive Immunotherapy: Methods and Protocols offers an authoritative collection of novel techniques to study the adoptive transfer of tailored antigen-specific immune cells and to improve their clinical application.

This first thematic issue, of the Advances in Immunology series, highlights the remarkable new insights into the mechanisms that govern development and function of T cell lineages. Recent developments in the understanding of the genetic and epigenetic mechanisms that regulate development of the two major T cell lineages will have a fundamental impact on a number of research fields -immunology, cell biology, hematology and stem cell research. All of these groups have a vested interest in comprehending issues such as stem cell self renewal, progenitor plasticity, lineage commitment and cellular identity. Immunologists have a special interest in the mechanisms that allow selection of a T cell repertoire whose members integrate genetic information for T cell receptor, co-receptor and specialized immunologic function, since this process lies at the core of adaptive immunity.T Cell Subsets is a timely and invaluable review for immunologists, cell biologists hematologists and stem cell researchers

Recent advances in immunology and molecular biology have resulted in new therapeutic approaches being generated and implemented in cancer clinics. The discovery of new antigens, mechanisms of antigen presentation, and interplay of cells involved in anti-tumor immunity have made the clinical control of some cancers more plausible than previously tho

Over the last 15 years, since the discovery of the T cell receptor gamma and delta genes, rapid progress has been made toward the understanding of the biology of gamma-delta T cells. They differ from conventional alpha-beta T cells not only in T cell receptor composition, but also in their development, tissue distribution, and physiological functions. This volume contains seven chapters contributed by experts on different aspects of gamma-delta T cells, including the natural ligands for gamma-delta T cell receptors, IL-7-dependent regulation of gamma-delta T cell development, cytokine-mediated intercellular communication of gamma-delta T cells with other cell types, and their physiological functions in innate and adaptive immune responses. The comprehensive review articles collected in this volume will be of interest to basic immunologists who wish to update their knowledge on the biology of gamma-delta T cells. The book also provides a unique opportunity for non-immunologists and clinicians to understand how the immune system is specifically equipped to protect the body against pathogens at the environmental interface.

Although immunologists know rather a lot about the manif­ estation of immunological memory, an understanding of the mechanism of memory at cellular and biochemical levels eludes us. Indeed, as we shall see, it is not even clear which of the several models used to explain the working of memory approximates to the truth. It is in order to report on approaches to this problem and on recent experimental advances in the field of memory cells that this volume has been put together. In the past 4-5 years cell surface molecules that may enable us to define memory Band T cells have been identified. It may now be possible to ask how memory cells are generated and to define what signals are required during or after antigenic encounter for a cell to enter the memory cell pool rather than to terminally differentiate into an effector cell. The transition from virgin cell to memory cell is clearly accompanied by several biochemical changes. For B cells, isotype switching and somatic mutations (leading to affinity maturation) are well-defined phenomena, although the molecular mechanisms remain mys­ terious. Both have received attention in many excellent reviews of late and so are not considered in detail in this book. Neither switching nor somatic mutation is a feature of peripheral T-cell maturation; biochemical differences between virgin and mem­ ory T cells may only relate to differing activation requirements and possibly changes in the expression of accessory molecules.

It has been said that the development of vaccines against a variety of infectious diseases is among the greatest triumphs of immunology. Indeed, several pathogens have lost their horror through the availability of effective vaccination measures. Unfortunately, this does not hold true for the pathogens dealt within this volume. Malaria, schistosomiasis, leishmaniasis, leprosy, and tuberculosis together are prevalent in more than 100 countries, and over 400 million persons suffer from these diseases. It is becoming increasingly clear that the failure to control these infections in a satisfactory way is directly related to the complexity oftheir interactions with the immune system. These agents have lived with their hosts for long enough to give both-host and parasite-ample opportunity to develop a highly sophisticated interrelationship. The central role of T lymphocytes both in acquired resistance to and pathogenesis of these microbes is well appreciated. In the beginning it may have been thought that acq uired resistance against infectious agents is nothing but another aspect of the immune response, studied with soluble and particulate antigens. This simple concept has gradually changed, and it has become clear that the viability not only of the immune cells but also of the'antigens'adds another dimension to the game. Several achievements in cellular immunology and molecular biology have now made it possible to better understand at least some mechanisms in this intricate interplay.

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B cells used to be considered as a homogeneous population of cells destined to produce antibodies of increasing affinity and to maintain an immunological memory. In recent years, it has been determined that B cells can be subdivided into different subsets characterized by distinct morphologic, phenotypic, and functional features. Presenting results of research work on the definition of B cell subset populations, this book explains the basic mechanisms that control B cell activation, stimulation and regulation. Articles include studies on both normal and malignant B cells and describe the mechanisms underlying T-B cell interactions during the immune response. The most important advances in the field of immunodeficiency are also reported. This volume will be essential not only for basic and clinical immunologists, but also for hematologists, pathologists and rheumatologists with a special interest in the pathogenesis of lymphoproliferative or autoimmune disorders.

To compile this up-to-date handbook, Dr. Charles Snow of the University of Kentucky Medical Center has assembled works by a premier group of active investigators who meet the needs of todays researchers. The handbookprovides a broad overview of the historical and current research in B- and T-cell biology, and presents the latest developments in this fast-breaking field to all professionals concerned with the humoral immune response of the body.