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- Volume 31, 2013
Annual Review of Immunology - Volume 31, 2013
Volume 31, 2013
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Years in Cologne
Vol. 31 (2013), pp. 1–29More LessThis review describes the building and scientific activity of the Immunology Department at the Institute for Genetics in Cologne, cofounded by Max Delbrück in post–World War II Germany. The protagonist, a child of Russian emigrants, became interested in antibodies as a postdoc at the Pasteur Institute in Paris and a proponent of the antigen-bridge model of T-B cell collaboration during his early time in Cologne. He was challenged by the gap between cellular immunology and molecular genetics and profited from the advances of the latter as well as postwar economic growth in Germany. The Immunology Department became a place, and little universe in itself, where young scientists from all over the world came together to study cellular and molecular mechanisms of antibody formation. This included work on normal and malignant B cells in the human, particularly the origin of Hodgkin lymphoma, but the main focus was on B cell development and homeostasis, the germinal center reaction, and immunological memory, developing recombinase-assisted and conditional gene targeting in mice as a main technical tool.
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The Biology of Recent Thymic Emigrants
Vol. 31 (2013), pp. 31–50More LessThe generation of the TCRαβ lineage of T cells occurs in the thymus through a series of orchestrated developmental events that result in a carefully selected population of CD4 or CD8 lineage–committed TCR+ thymocytes capable of recognizing foreign antigen in the context of self MHC. T cells first exit the thymus in a phenotypically and functionally immature state and require an approximately 3-week period of post-thymic maturation before transitioning into the mature T cell compartment. A greater understanding of recent thymic emigrant biology has come with the development of methods to exclusively identify and isolate this population for further characterization. I now review current knowledge about the phenotype and function of this key but understudied population of peripheral T cells.
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Immunogenic Cell Death in Cancer Therapy
Vol. 31 (2013), pp. 51–72More LessDepending on the initiating stimulus, cancer cell death can be immunogenic or nonimmunogenic. Immunogenic cell death (ICD) involves changes in the composition of the cell surface as well as the release of soluble mediators, occurring in a defined temporal sequence. Such signals operate on a series of receptors expressed by dendritic cells to stimulate the presentation of tumor antigens to T cells. We postulate that ICD constitutes a prominent pathway for the activation of the immune system against cancer, which in turn determines the long-term success of anticancer therapies. Hence, suboptimal regimens (failing to induce ICD), selective alterations in cancer cells (preventing the emission of immunogenic signals during ICD), or defects in immune effectors (abolishing the perception of ICD by the immune system) can all contribute to therapeutic failure. We surmise that ICD and its subversion by pathogens also play major roles in antiviral immune responses.
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Recognition of Bacteria by Inflammasomes
Vol. 31 (2013), pp. 73–106More LessInflammasomes are cytosolic multiprotein complexes that assemble in response to a variety of infectious and noxious insults. Inflammasomes play a critical role in the initiation of innate immune responses, primarily by serving as platforms for the activation of inflammatory caspase proteases. One such caspase, CASPASE-1 (CASP1), initiates innate immune responses by cleaving pro-IL-1β and pro-IL-18, leading to their activation and release. CASP1 and another inflammatory caspase termed CASP11 can also initiate a rapid and inflammatory form of cell death termed pyroptosis. Several distinct inflammasomes have been described, each of which contains a unique sensor protein of the NLR (nucleotide-binding domain, leucine-rich repeat–containing) superfamily or the PYHIN (PYRIN and HIN-200 domain–containing) superfamily. Here we describe the surprisingly diverse mechanisms by which NLR/PYHIN proteins sense bacteria and initiate innate immune responses. We conclude that inflammasomes represent a highly adaptable scaffold ideally suited for detecting and initiating rapid innate responses to diverse and rapidly evolving bacteria.
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The Immunology of Fibrosis
Vol. 31 (2013), pp. 107–135More LessFibrosis is the production of excessive amounts of connective tissue, i.e., scar formation, in the course of reactive and reparative processes. Fibrosis develops as a consequence of various underlying diseases and presents a major diagnostically and therapeutically unsolved problem. In this review, we postulate that fibrosis is always a sequela of inflammatory processes and that the many different causes of fibrosis all channel into the same final stereotypical pathways. During the inflammatory phase, both innate and adaptive immune mechanisms are operative. This concept is exemplified by fibrotic diseases that develop as a consequence of tissue damage, primary inflammatory diseases, fibrotic alterations induced by foreign body implants, “spontaneous” fibrosis, and tumor-associated fibrotic changes.
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Memory T Cell Subsets, Migration Patterns, and Tissue Residence
Vol. 31 (2013), pp. 137–161More LessTissues such as the skin and mucosae are frequently exposed to microbial pathogens. Infectious agents must be quickly and efficiently controlled by our immune system, but the low frequency of naive T cells specific for any one pathogen means dependence on primary responses initiated in draining lymph nodes, often allowing time for serious infection to develop. These responses imprint effectors with the capacity to home to infected tissues; this process, combined with inflammatory signals, ensures the effective targeting of primary immunity. Upon vaccination or previous pathogen exposure, increased pathogen-specific T cell numbers together with altered migratory patterns of memory T cells can greatly improve immune efficacy, ensuring infections are prevented or at least remain subclinical. Until recently, memory T cell populations were considered to comprise central memory T cells (TCM), which are restricted to the secondary lymphoid tissues and blood, and effector memory T cells (TEM), which broadly migrate between peripheral tissues, the blood, and the spleen. Here we review evidence for these two memory populations, highlight a relatively new player, the tissue-resident memory T cell (TRM), and emphasize the potential differences between the migratory patterns of CD4+ and CD8+ T cells. This new understanding raises important considerations for vaccine design and for the measurement of immune parameters critical to the control of infectious disease, autoimmunity, and cancer.
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Control of Human Viral Infections by Natural Killer Cells
Vol. 31 (2013), pp. 163–194More LessNatural killer (NK) cells are effector cells of the innate immune system and are important in the control of viral infections. Their relevance is reflected by the multiple mechanisms evolved by viruses to evade NK cell–mediated immune responses. Over recent years, our understanding of the interplay between NK cell immunity and viral pathogenesis has improved significantly. Here, we review the role of NK cells in the control of four important viral infections in humans: cytomegalovirus, influenza virus, HIV-1, and hepatitis C virus.
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Functional T Cell Immunodeficiencies (with T Cells Present)
Vol. 31 (2013), pp. 195–225More LessSevere combined immunodeficiency (SCID) comprises a group of disorders that are fatal owing to genetic defects that abrogate T cell development. Numerous related defects have recently been identified that allow T cell development but that compromise T cell function by affecting proximal or distal steps in intracellular signaling. These functional T cell immunodeficiencies are characterized by immune dysregulation and increased risk of malignancies, in addition to infections. The study of patients with these rare conditions, and of corresponding animal models, illustrates the importance of intracellular signaling to maintain T cell homeostasis.
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Controlling Natural Killer Cell Responses: Integration of Signals for Activation and Inhibition
Vol. 31 (2013), pp. 227–258More LessUnderstanding how signals are integrated to control natural killer (NK) cell responsiveness in the absence of antigen-specific receptors has been a challenge, but recent work has revealed some underlying principles that govern NK cell responses. NK cells use an array of innate receptors to sense their environment and respond to alterations caused by infections, cellular stress, and transformation. No single activation receptor dominates; instead, synergistic signals from combinations of receptors are integrated to activate natural cytotoxicity and cytokine production. Inhibitory receptors for major histocompatibility complex class I (MHC-I) have a critical role in controlling NK cell responses and, paradoxically, in maintaining NK cells in a state of responsiveness to subsequent activation events, a process referred to as licensing. MHC-I-specific inhibitory receptors both block activation signals and trigger signals to phosphorylate and inactivate the small adaptor Crk. These different facets of inhibitory signaling are incorporated into a revocable license model for the reversible tuning of NK cell responsiveness.
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Metabolic Regulation of T Lymphocytes
Vol. 31 (2013), pp. 259–283More LessT cell activation leads to dramatic shifts in cell metabolism to protect against pathogens and to orchestrate the action of other immune cells. Quiescent T cells require predominantly ATP-generating processes, whereas proliferating effector T cells require high metabolic flux through growth-promoting pathways. Further, functionally distinct T cell subsets require distinct energetic and biosynthetic pathways to support their specific functional needs. Pathways that control immune cell function and metabolism are intimately linked, and changes in cell metabolism at both the cell and system levels have been shown to enhance or suppress specific T cell functions. As a result of these findings, cell metabolism is now appreciated as a key regulator of T cell function specification and fate. This review discusses the role of cellular metabolism in T cell development, activation, differentiation, and function to highlight the clinical relevance and opportunities for therapeutic interventions that may be used to disrupt immune pathogenesis.
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Mesenchymal Stem Cell: Keystone of the Hematopoietic Stem Cell Niche and a Stepping-Stone for Regenerative Medicine
Vol. 31 (2013), pp. 285–316More LessMesenchymal stem cells (MSCs) are self-renewing precursor cells that can differentiate into bone, fat, cartilage, and stromal cells of the bone marrow. Recent studies suggest that MSCs themselves are critical for forming a niche that maintains hematopoietic stem cells (HSCs). The ease by which human MSC-like and stromal progenitor cells can be isolated from the bone marrow and other tissues has led to the rapid development of clinical investigations exploring their anti-inflammatory properties, tissue preservation capabilities, and regenerative potential. However, the identity of genuine MSCs and their specific contributions to these various beneficial effects have remained enigmatic. In this article, we examine the definition of MSCs and discuss the importance of rigorously characterizing their stem cell activity. We review their role and that of other putative niche constituents in the regulation of bone marrow HSCs. Additionally, how MSCs and their stromal progeny alter immune function is discussed, as well as potential therapeutic implications.
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Interleukin-4- and Interleukin-13-Mediated Alternatively Activated Macrophages: Roles in Homeostasis and Disease
Vol. 31 (2013), pp. 317–343More LessThe macrophage, a versatile cell type prominently involved in host defense and immunity, assumes a distinct state of alternative activation in the context of polarized type 2 immune responses such as allergic inflammation and helminth infection. This alternatively activated phenotype is induced by the canonical type 2 cytokines interleukin (IL)-4 and IL-13, which mediate expression of several characteristic markers along with a dramatic shift in macrophage metabolic pathways that influence surrounding cells and tissues. We discuss recent advances in the understanding of IL-4- and IL-13-mediated alternatively activated macrophages and type 2 immune responses; such advances have led to an expanded appreciation for functions of these cells beyond immunity, including maintenance of physiologic homeostasis and tissue repair.
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Brain-Reactive Antibodies and Disease
B. Diamond, G. Honig, S. Mader, L. Brimberg, and B.T. VolpeVol. 31 (2013), pp. 345–385More LessAutoimmune diseases currently affect 5–7% of the world's population; in most diseases there are circulating autoantibodies. Brain-reactive antibodies are present in approximately 2–3% of the general population but do not usually contribute to brain pathology. These antibodies penetrate brain tissue only early in development or under pathologic conditions. This restriction on their pathogenicity and the lack of correlation between serum titers and brain pathology have, no doubt, contributed to a delayed appreciation of the contribution of autoantibodies in diseases of the central nervous system. Nonetheless, it is increasingly clear that antibodies can cause damage in the brain and likely initiate or aggravate multiple neurologic conditions; brain-reactive antibodies contribute to symptomatology in autoimmune disease, infectious disease, and malignancy.
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Immunology of the Maternal-Fetal Interface
Vol. 31 (2013), pp. 387–411More LessThe immune cells that reside at the interface between the placenta and uterus are thought to play many important roles in pregnancy. Recent work has revealed that the composition and function of these cells are locally controlled by the specialized uterine stroma (the decidua) that surrounds the implanted conceptus. Here, I discuss how key immune cell types (natural killer cells, macrophages, dendritic cells, and T cells) are either enriched or excluded from the decidua, how their function is regulated within the decidua, and how they variously contribute to pregnancy success or failure. The discussion emphasizes the relationship between human and mouse studies. Deeper understanding of the immunology of the maternal-fetal interface promises to yield significant insight into the pathogenesis of many human pregnancy complications, including preeclampsia, intrauterine growth restriction, spontaneous abortion, preterm birth, and congenital infection.
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Regulation of Ligands for the NKG2D Activating Receptor
Vol. 31 (2013), pp. 413–441More LessNKG2D is an activating receptor expressed by all NK cells and subsets of T cells. It serves as a major recognition receptor for detection and elimination of transformed and infected cells and participates in the genesis of several inflammatory diseases. The ligands for NKG2D are self-proteins that are induced by pathways that are active in certain pathophysiological states. NKG2D ligands are regulated transcriptionally, at the level of mRNA and protein stability, and by cleavage from the cell surface. In some cases, ligand induction can be attributed to pathways that are activated specifically in cancer cells or infected cells. We review the numerous pathways that have been implicated in the regulation of NKG2D ligands, discuss the pathologic states in which those pathways are likely to act, and attempt to synthesize the findings into general schemes of NKG2D ligand regulation in NK cell responses to cancer and infection.
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Pathways of Antigen Processing
Vol. 31 (2013), pp. 443–473More LessT cell recognition of antigen-presenting cells depends on their expression of a spectrum of peptides bound to major histocompatibility complex class I (MHC-I) and class II (MHC-II) molecules. Conversion of antigens from pathogens or transformed cells into MHC-I- and MHC-II-bound peptides is critical for mounting protective T cell responses, and similar processing of self proteins is necessary to establish and maintain tolerance. Cells use a variety of mechanisms to acquire protein antigens, from translation in the cytosol to variations on the theme of endocytosis, and to degrade them once acquired. In this review, we highlight the aspects of MHC-I and MHC-II biosynthesis and assembly that have evolved to intersect these pathways and sample the peptides that are produced.
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The Immune Response in Tuberculosis
Vol. 31 (2013), pp. 475–527More LessThere are 9 million cases of active tuberculosis reported annually; however, an estimated one-third of the world's population is infected with Mycobacterium tuberculosis and remains asymptomatic. Of these latent individuals, only 5–10% will develop active tuberculosis disease in their lifetime. CD4+ T cells, as well as the cytokines IL-12, IFN-γ, and TNF, are critical in the control of Mycobacterium tuberculosis infection, but the host factors that determine why some individuals are protected from infection while others go on to develop disease are unclear. Genetic factors of the host and of the pathogen itself may be associated with an increased risk of patients developing active tuberculosis. This review aims to summarize what we know about the immune response in tuberculosis, in human disease, and in a range of experimental models, all of which are essential to advancing our mechanistic knowledge base of the host-pathogen interactions that influence disease outcome.
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The Adaptable Major Histocompatibility Complex (MHC) Fold: Structure and Function of Nonclassical and MHC Class I–Like Molecules
Vol. 31 (2013), pp. 529–561More LessThe MHC fold is found in proteins that have a range of functions in the maintenance of an organism's health, from immune regulation to fat metabolism. Well adapted for antigen presentation, as seen for peptides in the classical MHC molecules and for lipids in CD1 molecules, the MHC fold has also been modified to perform Fc-receptor activity (e.g., FcRn) and for roles in host homeostasis (e.g., with HFE and ZAG). The more divergent MHC-like molecules, such as some of those that interact with the NKG2D receptor, represent the minimal MHC fold, doing away with the α3 domain and β2m while maintaining the α1/α2 platform domain for receptor engagement. Viruses have also co-opted the MHC fold for immune-evasive functions. The variations on the theme of a β-sheet topped by two semiparallel α-helices are discussed in this review, highlighting the fantastic adaptability of this fold for good and for bad.
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The Dendritic Cell Lineage: Ontogeny and Function of Dendritic Cells and Their Subsets in the Steady State and the Inflamed Setting
Vol. 31 (2013), pp. 563–604More LessDendritic cells (DCs) form a remarkable cellular network that shapes adaptive immune responses according to peripheral cues. After four decades of research, we now know that DCs arise from a hematopoietic lineage distinct from other leukocytes, establishing the DC system as a unique hematopoietic branch. Recent work has also established that tissue DCs consist of developmentally and functionally distinct subsets that differentially regulate T lymphocyte function. This review discusses major advances in our understanding of the regulation of DC lineage commitment, differentiation, diversification, and function in situ.
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T Cell–Mediated Host Immune Defenses in the Lung
Kong Chen, and Jay K. KollsVol. 31 (2013), pp. 605–633More LessEvidence has increasingly shown that the lungs are a major site of immune regulation. A robust and highly regulated immune response in the lung protects the host from pathogen infection, whereas an inefficient or deleterious response can lead to various pulmonary diseases. Many cell types, such as epithelial cells, dendritic cells, macrophages, neutrophils, eosinophils, and B and T lymphocytes, contribute to lung immunity. This review focuses on the recent advances in understanding how T lymphocytes mediate pulmonary host defenses against bacterial, viral, and fungal pathogens.
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Previous Volumes
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Volume 41 (2023)
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Volume 40 (2022)
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Volume 39 (2021)
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Volume 38 (2020)
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Volume 37 (2019)
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Volume 36 (2018)
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Volume 35 (2017)
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Volume 34 (2016)
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Volume 33 (2015)
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Volume 32 (2014)
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Volume 31 (2013)
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Volume 30 (2012)
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Volume 29 (2011)
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Volume 28 (2010)
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Volume 27 (2009)
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Volume 26 (2008)
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Volume 25 (2007)
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Volume 24 (2006)
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Volume 23 (2005)
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Volume 22 (2004)
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Volume 21 (2003)
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Volume 20 (2002)
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Volume 19 (2001)
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Volume 18 (2000)
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Volume 17 (1999)
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Volume 16 (1998)
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Volume 15 (1997)
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Volume 14 (1996)
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Volume 13 (1995)
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Volume 12 (1994)
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Volume 11 (1993)
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Volume 10 (1992)
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Volume 9 (1991)
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Volume 8 (1990)
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Volume 7 (1989)
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Volume 6 (1988)
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Volume 5 (1987)
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Volume 4 (1986)
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Volume 3 (1985)
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Volume 2 (1984)
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Volume 1 (1983)
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Volume 0 (1932)