Volume Of Immunological Reviews Research Articles

Immunity to viruses

The analysis of the innate and adaptive immune response to viruses has provided fundamental insight into the functioning of the immune system. Early studies on the host response to virus infection were instrumental in establishing the concept of immunological tolerance (1). Similarly, the realization that T lymphocytes are ‘restricted’ in their recognition of antigens by gene products encoded within the major histocompatibility complex (MHC) locus came from the analysis of T-lymphocyte recognition of virus-infected cells (2). Likewise, important initial insights into antigen processing and presentation came from the analysis of viruses and virus-infected cells (3, 4). Until recently, it was convenient to view immunity to infectious agents like viruses as a separate branch of immunology distinct from immunity to tumors, self-molecules (antigens), or allergens. As demonstrated in many of the articles in this volume of Immunological Reviews, the mechanisms underlying the induction and regulation of the innate and adaptive immune response to viruses represent the same processes controlling immunity to tumor antigens, allergens, and self-constituents. Thus, the results summarized in these review articles and the implications of these findings are applicable not only to those of us who study immunity to viruses but also to the immunology community at large. In selecting the topics for review in this volume of Immunological Reviews, we were first and foremost limited by space. Consequently, many important contributors to the field of viral immunology (indeed several topics) are not represented in this volume. Our selection of topics and authors was biased towards emerging areas, such as the application of systems biology approaches to viral pathogenesis and immunity, the contribution of inflammatory and stress responses to the induction of Innate and adaptive immune responses, and the impact of the microbiome on immunity to virus infection. We also considered it relevant to include reviews focused on well defined areas where recent findings have resulted in potential paradigm shifts in our understanding of topics such as B-lymphocyte or T-lymphocyte responses to virus infection. This volume of Immunological Reviews is also somewhat weighted towards analyses of the immune response to respiratory viruses. With the recent episodic infections with the severe acute respiratory syndrome (SARS)-like coronavirus and the outbreak of human infections with the avian influenza A H7N9 virus, respiratory viruses such as these organisms are recognized as major human pathogens with the potential for pandemic spread. Therefore, this class of viruses is a focus of immunological research. The reviews in this volume can be grouped according to the following scheme: (i) molecules and cells regulating the induction of the innate and adaptive response, (ii) expression of immune effector activity, (iii) regulation of the antiviral immune response, and (iv) systems analysis of the host response to infection and vaccination (Fig. 1). Fig. 1 Immunity to viruses

Cell:cell interactions in the immune system

Video podcast available Go to www.immunologicalreviews.com to watch an interview with Guest Editor Facundo Batista. The cells of the immune system are continually on the move! Naive T cells in a human collectively crawl over 10 000 miles a day in search of antigens (1). Each dendritic cell (DC) touches 5000 T cells an hour to scan repertoires over a million deep (2, 3). The adaptive immune system functions through a vast network of provisional cell–cell interactions that are continuously changing. When this frenetic scanning finds a fit between T-cell antigen receptor (TCR) and DC antigen, the interaction can be prolonged with a pronounced deceleration of the T cell and finally a long-lived interaction that has been described as an immunological synapse (2, 4). In vitro studies on the immunological synapse suggest a profound supramolecular organization that serves focused trans-synaptic and juxtracrine information transfer between cells (5–8). Immunological synapses are not restricted to T cells but are also formed by natural killer (NK) cells, B cells, granulocytes, and phagocytes using related immunotyrosine-based activation motif-containing receptors (9, 10). These interactions are profoundly influenced by the three-dimensional (3D) tissue environment (11). This volume of Immunological Reviews takes a broader look at the cell–cell interactions in the immune system from the molecular organization of antigen receptors during surveillance to the organization of stromal cell networks in lymph nodes, bone marrow, and the lung (Fig. 1). The organization of the plasma membrane is a fundamental issue in biology that sets the stage for cell–cell interaction and communication. The classical fluid mosaic model suggested membrane proteins diffusing in a lipid sea with potential for interactions with cytoplasmic and extra-cytoplasmic binding partners that account for regulation and processes like adhesion and receptor capping. Observations on lipid phases in model systems with disordered, liquidordered, and gel phases in order of increasing viscosity suggested that such phases could also exist in biological membranes on some scale (12). Biophysical observations of liquid-ordered domains enriched in various lipid-modified proteins have led to models in which lipids have a role in providing a higher level of organization (13). Most recently, evidence for protein-driven domains, referred to as Immunological Reviews 2013 Vol. 251: 7–12 Printed in Singapore. All rights reserved

Insights into immune structure, recognition, and signaling

In this volume of Immunological Reviews, the articles focus on the structural biology of immunoreceptors and what structure is telling us about function. The issue is unabashedly ‘receptor-centric’ and the proteins covered range from antigen receptors, innate receptors, and cytokine receptors, thereby providing an unusually comprehensive snapshot of the current state of the art in molecular immunology. Of all the major fields in biomedical research, including neurobiology, developmental biology, immunology, microbiology, and genetics, just to name a subset, perhaps structure in the broadest sense has had more of an impact on immunology and played more of a major role in guiding the evolution and maturation of the field than any other. Here, I use the term ‘structure’ to encompass not only direct structural approaches, such as x-ray crystallography and nuclear magnetic resonance spectroscopy (NMR), but also imaging, biophysical, molecular, and mechanistic approaches to interrogate aspects of molecular recognition, oligomerization, and signaling. Perhaps the fact that immunobiology is centered on questions of recognition and discrimination and is largely controlled by receptor-ligand systems has led to an unusually high level of sophistication about structure among immunologists. Personally speaking, having delved into structural questions in neurobiology and developmental biology, I can state without equivocation that the structural and molecular savvy of immunologists has led to greater mechanistic clarity underlying central tenets of the field compared to other disciplines. Dating back to the days of elucidating the first antibody structures and the relation between hypervariable regions and antigen recognition, to the transformative clarity of the first major histocompatibility complex (MHC) structures in explaining MHC restriction, to more recent biophysical and structural investigations of T-cell receptor (TCR) recognition of both classical and non-classical MHC, innate immune receptors such as natural killer (NK) and Toll-like receptors, and cytokine receptors, molecular science has illuminated the path for the experimentalists and assumed a large and highly visible role in immunobiology as a whole.

Germinal centers

Germinal centers

The TNF receptor super family in immune regulation

The TNF receptor super family in immune regulation

Inflammatory arthritis ‐ an exciting confluence of human and animal research

Inflammatory arthritis ‐ an exciting confluence of human and animal research

Getting Started in Computational Immunology

The immune system acts across multiple scales involving complex interactions and feedback, from somatic modifications of DNA to the systemic inflammatory reaction. Computational modeling provides a framework to integrate observational data collected from multiple modes of experimentation and insight into the immune response in health and disease. This Message attempts to illustrate how different computational methods have been integrated with experimental observations to study an immunological question from multiple perspectives by focusing on a very particular, though fundamental, component of adaptive immunity: B cells and affinity maturation (Figure 1). B cells bind foreign antigens through their Immunoglobulin (Ig) receptor. Affinity maturation is the process by which B cell receptors that initially bind antigen with low affinity are modified through cycles of somatic mutation and affinity-dependent selection to produce high-affinity memory and plasma cells. How this process can reliably generate orders of magnitude increases in affinity over a period of weeks is one of the many questions where computational modeling has made important contributions (for example, the cyclic re-entry model [1]). Yet, even the seemingly straightforward matter of detecting antigen-driven selection remains controversial, and such fundamental questions as whether increased proliferation or decreased death drives the preferential expansion of higher-affinity B cell mutants remain unanswered. A good biological introduction to the immune system is available on the NIH website [2], while more detailed information can be found in any number of textbooks [3]. An animation by Julian Kirk-Elleker provides a visual introduction to the affinity maturation process (http://web.mac.com/patrickwlee/Antibody-affinity_maturation/Movie.html). The kinds of computational techniques described here have been widely applied in other areas of immunology, including the innate response [4],[5], viral dynamics [6], and immune memory [7]. A classic introduction to computational immunology geared to the more mathematically inclined was written by Perelson and Weisbuch [8]. The rapidly expanding area of immunoinformatics was covered in a recent issue of PLoS Computational Biology [9], and several other applications were explored in a 2007 volume of Immunological Reviews (216) devoted to quantitative modeling of immune responses. Figure 1 A wide range of experimental techniques are used in combination with computational modeling to probe the process of affinity maturation at multiple scales (from DNA to tissue).

Immune privilege: a recurrent theme in immunoregulation?

The word ‘privilege’ implies a special status. The concept of immune privilege was coined in the mid-20th century to describe observations that immunogenic tissues and tumors placed at certain anatomical locations survived longer than anticipated or were accepted indefinitely. The implication was that these anatomical sites were in someway specialized because otherwise potent antigenic stimuli failed to elicit effective immune responses. Historically, passive mechanisms, notably physical and physiologic barriers that maintained local segregation between tissues and immune cells and antibodies, were thought to offer the most likely explanations for localized immune privilege. However, the recognition that multiple mechanisms exist to suppress and subvert adaptive immunity and promote tolerance raises the prospect that active suppressive mechanisms help to maintain immune privilege. This volume of Immunological Reviews was inspired by the original concept of immune privilege and by recent rapid progress in identifying immunoregulatory processes that suppress immunity and promote immune tolerance. Our goal in this issue is to assess contemporary thinking on classical immune privilege and to determine if the concept of immune privilege might have wider implications and value for understanding immunoregulation in general. To this end, we solicited reviews from experts working on traditional immuneprivileged tissues and on immunoregulatory processes. The classical definition of immune privilege and the consequences of active immunoregulation overlap in the sense that these processes prevent elaboration of effective immunity following challengeswith otherwise potent antigenic stimuli. In each case, antigenic challenge provokes weak and ineffective responses,

The road ended up at stem cells.

For me the search for hematopoietic stem cells (HSC) actually started with the discovery by Till, McCulloch, and colleagues (1-3) that bone marrow contained single cells that could give rise to myeloerythroid colonies in the spleen, and sometimes these colonies contained cells that made more spleen colonies as well as radioprotected and reconstituted lethally irradiated mice (3). But in retrospect, it should have started with the remarkable observation of Ray Owen in 1945 that bovine fraternal twins sharing a single placenta and blood circulation retained production of blood cells genetically defined to be from both throughout their life (4). It could be argued that this was the experiment that began both modern experimental hematology as well as modern cellular immunology. The Till, McCulloch, Wu, Becker, and Simonovitch experiments were elegant demonstrations that single, genetically marked cells existed (random DNA breaks and translocations induced by sublethal irradiation of the donor bone marrow) that could both self-renew and differentiate (2, 5). But these experiments did not put the pure cells in the hands of scientists, and so most of their functions for the next 25 years were implied rather than directly analyzed. Just as genetics is the complement to biochemistry (when one considers genes and gene products), cell marking is the complement to cell purification in the fields of developmental and cellular biology. The first attempts at such cellular purification came from the 'school' of Till & McCulloch (6, 7), and independently the school of Van Bekkum in the Netherlands (8). But what was lacking in those experiments and at that time were both a comprehensive approach that would take into account the clonal activity of stem cells in both self-renewal and differentiation to all blood cell outcomes, and the tools with which one could separate what turned out to be an extremely rare population in the bone marrow. And, it wasn't known until much later that most day 8-10 spleen colonies were the progeny of progenitors, not stem cells (9). Two inventions facilitated the technology of purification of HSC: the advent of monoclonal antibody technology by Kohler & Milstein (10), and the development of the multiparameter fluorescence activated cell sorter by the Herzenberg group (11). My laboratory had established assays for the clonal precursors of T cells and B cells, and we had been using the Till-McCulloch spleen colony clonal assays since the mid-1960s. In the late 1970s and early 1980s we began in earnest the search for mouse early hematopoietic progenitors, including HSCs (12-16). The purification of HSCs proved to be much like the purification of an enzyme, or a cell surface receptor, or a gene. Successive enrichments finally led to the isolation of a population, which could no longer be subdivided and which contained precursors that read out in all clonal assays as well as in radioprotection of lethally irradiated hosts (17). Our first experiments transplanting single HSC in 1991 and 1992, led to the definitive demonstration that these were indeed HSCs (18-20). But these experiments and the ideas that led to them were developed in the context of immunology and experimental hematology as they were emerging in the 1950s and 60 s. This volume of Immunological Reviews is a rich testimony to the kinds of ideas and experiments that, at least in retrospect, turned out to be critical. Many roads were taken, but only one ended up at stem cells.

Immunology of hematopoietic stem cell transplantation: a brief review of its history.

The history of clinical marrow transplantation since 1968 is reviewed with an emphasis on immunological and immunogenetic aspects. The events leading to the creation of an international network of volunteer donor registries and the implementation of unrelated allogeneic marrow transplantation as a routine procedure are discussed. Current major issues which need to be resolved are addressed in order to set the stage for the topics covered in this volume of Immunological Reviews.