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  • Sixty Years of Discovery
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2018-10-31
    David Baltimore

    Each of us is a story. Mine is a story of doing science for 60 years, and I am honored to be asked to tell it. Even though this autobiography was written for the Annual Review of Immunology, I have chosen to describe my whole career in science because the segment that was immunology is so intertwined with all else I was doing. This article is an elongation and modification of a talk I gave at my 80th birthday celebration at Caltech on March 23, 2018.

    更新日期:2019-11-18
  • Neuro–Immune Cell Units: A New Paradigm in Physiology
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2018-10-31
    Cristina Godinho-Silva, Filipa Cardoso, Henrique Veiga-Fernandes

    The interplay between the immune and nervous systems has been acknowledged in the past, but only more recent studies have started to unravel the cellular and molecular players of such interactions. Mounting evidence indicates that environmental signals are sensed by discrete neuro–immune cell units (NICUs), which represent defined anatomical locations in which immune and neuronal cells colocalize and functionally interact to steer tissue physiology and protection. These units have now been described in multiple tissues throughout the body, including lymphoid organs, adipose tissue, and mucosal barriers. As such, NICUs are emerging as important orchestrators of multiple physiological processes, including hematopoiesis, organogenesis, inflammation, tissue repair, and thermogenesis. In this review we focus on the impact of NICUs in tissue physiology and how this fast-evolving field is driving a paradigm shift in our understanding of immunoregulation and organismal physiology.

    更新日期:2019-11-18
  • Tuft Cells—Systemically Dispersed Sensory Epithelia Integrating Immune and Neural Circuitry
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2018-10-31
    Claire E. O'Leary, Christoph Schneider, Richard M. Locksley

    Tuft cells—rare solitary chemosensory cells in mucosal epithelia—are undergoing intense scientific scrutiny fueled by recent discovery of unsuspected connections to type 2 immunity. These cells constitute a conduit by which ligands from the external space are sensed via taste-like signaling pathways to generate outputs unique among epithelial cells: the cytokine IL-25, eicosanoids associated with allergic immunity, and the neurotransmitter acetylcholine. The classic type II taste cell transcription factor POU2F3 is lineage defining, suggesting a conceptualization of these cells as widely distributed environmental sensors with effector functions interfacing type 2 immunity and neural circuits. Increasingly refined single-cell analytics have revealed diversity among tuft cells that extends from nasal epithelia and type II taste cells to ex-Aire-expressing medullary thymic cells and small-intestine cells that mediate tissue remodeling in response to colonizing helminths and protists.

    更新日期:2019-11-18
  • Neuroinflammation During RNA Viral Infections
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2019-04-26
    Robyn S. Klein, Charise Garber, Kristen E. Funk, Hamid Salimi, Allison Soung, Marlene Kanmogne, Sindhu Manivasagam, Shannon Agner, Matthew Cain

    Neurotropic RNA viruses continue to emerge and are increasingly linked to diseases of the central nervous system (CNS) despite viral clearance. Indeed, the overall mortality of viral encephalitis in immunocompetent individuals is low, suggesting efficient mechanisms of virologic control within the CNS. Both immune and neural cells participate in this process, which requires extensive innate immune signaling between resident and infiltrating cells, including microglia and monocytes, that regulate the effector functions of antiviral T and B cells as they gain access to CNS compartments. While these interactions promote viral clearance via mainly neuroprotective mechanisms, they may also promote neuropathology and, in some cases, induce persistent alterations in CNS physiology and function that manifest as neurologic and psychiatric diseases. This review discusses mechanisms of RNA virus clearance and neurotoxicity during viral encephalitis with a focus on the cytokines essential for immune and neural cell inflammatory responses and interactions. Understanding neuroimmune communications in the setting of viral infections is essential for the development of treatments that augment neuroprotective processes while limiting ongoing immunopathological processes that cause ongoing CNS disease.

    更新日期:2019-11-18
  • Antigen Receptor Function in the Context of the Nanoscale Organization of the B Cell Membrane
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2019-04-26
    Michael R. Gold, Michael G. Reth

    The B cell antigen receptor (BCR) plays a central role in the self/nonself selection of B lymphocytes and in their activation by cognate antigen during the clonal selection process. It was long thought that most cell surface receptors, including the BCR, were freely diffusing and randomly distributed. Since the advent of superresolution techniques, it has become clear that the plasma membrane is compartmentalized and highly organized at the nanometer scale. Hence, a complete understanding of the precise conformation and activation mechanism of the BCR must take into account the organization of the B cell plasma membrane. We review here the recent literature on the nanoscale organization of the lymphocyte membrane and discuss how this new information influences our view of the conformational changes that the BCR undergoes during activation.

    更新日期:2019-11-18
  • The Platelet Napoleon Complex—Small Cells, but Big Immune Regulatory Functions
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2018-11-28
    Craig N. Morrell, Daphne N. Pariser, Zachary T. Hilt, Denisse Vega Ocasio

    Platelets have dual physiologic roles as both cellular mediators of thrombosis and immune modulatory cells. Historically, the thrombotic function of platelets has received significant research and clinical attention, but emerging research indicates that the immune regulatory roles of platelets may be just as important. We now know that in addition to their role in the acute thrombotic event at the time of myocardial infarction, platelets initiate and accelerate inflammatory processes that are part of the pathogenesis of atherosclerosis and myocardial infarction expansion. Furthermore, it is increasingly apparent from recent studies that platelets impact the pathogenesis of many vascular inflammatory processes such as autoimmune diseases, sepsis, viral infections, and growth and metastasis of many types of tumors. Therefore, we must consider platelets as immune cells that affect all phases of immune responses.

    更新日期:2019-11-18
  • Emerging Cellular Therapies for Cancer
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2018-12-10
    Sonia Guedan, Marco Ruella, Carl H. June

    Genetically engineered T cells are powerful new medicines, offering hope for curative responses in patients with cancer. Chimeric antigen receptor (CAR) T cells were recently approved by the US Food and Drug Administration and are poised to enter the practice of medicine for leukemia and lymphoma, demonstrating that engineered immune cells can serve as a powerful new class of cancer therapeutics. The emergence of synthetic biology approaches for cellular engineering provides a broadly expanded set of tools for programming immune cells for enhanced function. Advances in T cell engineering, genetic editing, the selection of optimal lymphocytes, and cell manufacturing have the potential to broaden T cell–based therapies and foster new applications beyond oncology, in infectious diseases, organ transplantation, and autoimmunity.

    更新日期:2019-11-18
  • Cancer Neoantigens
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2018-12-14
    Ton N. Schumacher, Wouter Scheper, Pia Kvistborg

    Malignant transformation of cells depends on accumulation of DNA damage. Over the past years we have learned that the T cell–based immune system frequently responds to the neoantigens that arise as a consequence of this DNA damage. Furthermore, recognition of neoantigens appears an important driver of the clinical activity of both T cell checkpoint blockade and adoptive T cell therapy as cancer immunotherapies. Here we review the evidence for the relevance of cancer neoantigens in tumor control and the biological properties of these antigens. We discuss recent technological advances utilized to identify neoantigens, and the T cells that recognize them, in individual patients. Finally, we discuss strategies that can be employed to exploit cancer neoantigens in clinical interventions.

    更新日期:2019-11-18
  • Origin, Organization, Dynamics, and Function of Actin and Actomyosin Networks at the T Cell Immunological Synapse
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2018-12-21
    John A. Hammer, Jia C. Wang, Mezida Saeed, Antonio T. Pedrosa

    The engagement of a T cell with an antigen-presenting cell (APC) or activating surface results in the formation within the T cell of several distinct actin and actomyosin networks. These networks reside largely within a narrow zone immediately under the T cell's plasma membrane at its site of contact with the APC or activating surface, i.e., at the immunological synapse. Here we review the origin, organization, dynamics, and function of these synapse-associated actin and actomyosin networks. Importantly, recent insights into the nature of these actin-based cytoskeletal structures were made possible in several cases by advances in light microscopy.

    更新日期:2019-11-18
  • The Antibody Response to Plasmodium falciparum: Cues for Vaccine Design and the Discovery of Receptor-Based Antibodies
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2018-12-19
    Joshua Tan, Luca Piccoli, Antonio Lanzavecchia

    Plasmodium falciparum remains a serious public health problem and a continuous challenge for the immune system due to the complexity and diversity of the pathogen. Recent advances from several laboratories in the characterization of the antibody response to the parasite have led to the identification of critical targets for protection and revealed a new mechanism of diversification based on the insertion of host receptors into immunoglobulin genes, leading to the production of receptor-based antibodies. These advances have opened new possibilities for vaccine design and passive antibody therapies to provide sterilizing immunity and control blood-stage parasites.

    更新日期:2019-11-18
  • Self-Awareness: Nucleic Acid–Driven Inflammation and the Type I Interferonopathies
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2019-01-11
    Carolina Uggenti, Alice Lepelley, Yanick J. Crow

    Recognition of foreign nucleic acids is the primary mechanism by which a type I interferon–mediated antiviral response is triggered. Given that human cells are replete with DNA and RNA, this evolutionary strategy poses an inherent biological challenge, i.e., the fundamental requirement to reliably differentiate self–nucleic acids from nonself nucleic acids. We suggest that the group of Mendelian inborn errors of immunity referred to as the type I interferonopathies relate to a breakdown of self/nonself discrimination, with the associated mutant genotypes involving molecules playing direct or indirect roles in nucleic acid signaling. This perspective begs the question as to the sources of self-derived nucleic acids that drive an inappropriate immune response. Resolving this question will provide fundamental insights into immune tolerance, antiviral signaling, and complex autoinflammatory disease states. Here we develop these ideas, discussing type I interferonopathies within the broader framework of nucleic acid–driven inflammation.

    更新日期:2019-11-18
  • The Myeloid Cell Compartment—Cell by Cell
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2019-01-16
    Kevin Bassler, Jonas Schulte-Schrepping, Stefanie Warnat-Herresthal, Anna C. Aschenbrenner, Joachim L. Schultze

    Myeloid cells are a major cellular compartment of the immune system comprising monocytes, dendritic cells, tissue macrophages, and granulocytes. Models of cellular ontogeny, activation, differentiation, and tissue-specific functions of myeloid cells have been revisited during the last years with surprising results; for example, most tissue macrophages are yolk sac derived, monocytes and macrophages follow a multidimensional model of activation, and tissue signals have a significant impact on the functionality of all these cells. While these exciting results have brought these cells back to center stage, their enormous plasticity and heterogeneity, during both homeostasis and disease, are far from understood. At the same time, the ongoing revolution in single-cell genomics, with single-cell RNA sequencing (scRNA-seq) leading the way, promises to change this. Prevailing models of hematopoiesis with distinct intermediates are challenged by scRNA-seq data suggesting more continuous developmental trajectories in the myeloid cell compartment. Cell subset structures previously defined by protein marker expression need to be revised based on unbiased analyses of scRNA-seq data. Particularly in inflammatory conditions, myeloid cells exhibit substantially vaster heterogeneity than previously anticipated, and work performed within large international projects, such as the Human Cell Atlas, has already revealed novel tissue macrophage subsets. Based on these exciting developments, we propose the next steps to a full understanding of the myeloid cell compartment in health and diseases.

    更新日期:2019-11-18
  • Fine-Tuning Cytokine Signals
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2019-01-16
    Jian-Xin Lin, Warren J. Leonard

    Cytokines are secreted or otherwise released polypeptide factors that exert autocrine and/or paracrine actions, with most cytokines acting in the immune and/or hematopoietic system. They are typically pleiotropic, controlling development, cell growth, survival, and/or differentiation. Correspondingly, cytokines are clinically important, and augmenting or attenuating cytokine signals can have deleterious or therapeutic effects. Besides physiological fine-tuning of cytokine signals, altering the nature or potency of the signal can be important in pathophysiological responses and can also provide novel therapeutic approaches. Here, we give an overview of cytokines, their signaling and actions, and the physiological mechanisms and pharmacologic strategies to fine-tune their actions. In particular, the differential utilization of STAT proteins by a single cytokine or by different cytokines and STAT dimerization versus tetramerization are physiological mechanisms of fine-tuning, whereas anticytokine and anticytokine receptor antibodies and cytokines with altered activities, including cytokine superagonists, partial agonists, and antagonists, represent new ways of fine-tuning cytokine signals.

    更新日期:2019-11-18
  • Purine Release, Metabolism, and Signaling in the Inflammatory Response
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2016-05-27
    Joel Linden, Friedrich Koch-Nolte, Gerhard Dahl

    ATP, NAD+, and nucleic acids are abundant purines that, in addition to having critical intracellular functions, have evolved extracellular roles as danger signals released in response to cell lysis, apoptosis, degranulation, or membrane pore formation. In general ATP and NAD+ have excitatory and adenosine has anti-inflammatory effects on immune cells. This review focuses on recent advances in our understanding of purine release mechanisms, ectoenzymes that metabolize purines (CD38, CD39, CD73, ENPP1, and ENPP2/autotaxin), and signaling by key P2 purinergic receptors (P2X7, P2Y2, and P2Y12). In addition to metabolizing ATP or NAD+, some purinergic ectoenzymes metabolize other inflammatory modulators, notably lysophosphatidic acid and cyclic GMP-AMP (cGAMP). Also discussed are extracellular signaling effects of NAD+ mediated by ADP-ribosylation, and epigenetic effects of intracellular adenosine mediated by modification of S-adenosylmethionine-dependent DNA methylation.

    更新日期:2019-11-18
  • Double-Stranded RNA Sensors and Modulators in Innate Immunity
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2019-01-23
    Sun Hur

    Detection of double-stranded RNAs (dsRNAs) is a central mechanism of innate immune defense in many organisms. We here discuss several families of dsRNA-binding proteins involved in mammalian antiviral innate immunity. These include RIG-I-like receptors, protein kinase R, oligoadenylate synthases, adenosine deaminases acting on RNA, RNA interference systems, and other proteins containing dsRNA-binding domains and helicase domains. Studies suggest that their functions are highly interdependent and that their interdependence could offer keys to understanding the complex regulatory mechanisms for cellular dsRNA homeostasis and antiviral immunity. This review aims to highlight their interconnectivity, as well as their commonalities and differences in their dsRNA recognition mechanisms.

    更新日期:2019-11-18
  • The Microbiome and Food Allergy
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2019-04-26
    Onyinye I. Iweala, Cathryn R. Nagler

    The gut-associated lymphoid tissue (GALT) faces a considerable challenge. It encounters antigens derived from an estimated 1014 commensal microbes and greater than 30 kg of food proteins yearly. It must distinguish these harmless antigens from potential pathogens and mount the appropriate host immune response. Local and systemic hyporesponsiveness to dietary antigens, classically referred to as oral tolerance, comprises a distinct complement of adaptive cellular and humoral immune responses. It is increasingly evident that a functional epithelial barrier engaged in intimate interplay with innate immune cells and the resident microbiota is critical to establishing and maintaining oral tolerance. Moreover, innate immune cells serve as a bridge between the microbiota, epithelium, and the adaptive immune system, parlaying tonic microbial stimulation into signals critical for mucosal homeostasis. Dysregulation of gut homeostasis and the subsequent disruption of tolerance therefore have clinically significant consequences for the development of food allergy.

    更新日期:2019-11-18
  • Disease Tolerance as an Inherent Component of Immunity
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2019-01-23
    Rui Martins, Ana Rita Carlos, Faouzi Braza, Jessica A. Thompson, Patricia Bastos-Amador, Susana Ramos, Miguel P. Soares

    Pathogenic organisms exert a negative impact on host health, revealed by the clinical signs of infectious diseases. Immunity limits the severity of infectious diseases through resistance mechanisms that sense and target pathogens for containment, killing, or expulsion. These resistance mechanisms are viewed as the prevailing function of immunity. Under pathophysiologic conditions, however, immunity arises in response to infections that carry health and fitness costs to the host. Therefore, additional defense mechanisms are required to limit these costs, before immunity becomes operational as well as thereafter to avoid immunopathology. These are tissue damage control mechanisms that adjust the metabolic output of host tissues to different forms of stress and damage associated with infection. Disease tolerance is the term used to define this defense strategy, which does not exert a direct impact on pathogens but is essential to limit the health and fitness costs of infection. Under this argument, we propose that disease tolerance is an inherent component of immunity.

    更新日期:2019-11-18
  • Nonclassical Monocytes in Health and Disease
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2019-04-26
    Prakash Babu Narasimhan, Paola Marcovecchio, Anouk A.J. Hamers, Catherine C. Hedrick

    Monocytes are innate blood cells that maintain vascular homeostasis and are early responders to pathogens in acute infections. There are three well-characterized classes of monocytes: classical (CD14+CD16− in humans and Ly6Chi in mice), intermediate (CD14+CD16+ in humans and Ly6C+Treml4+ in mice), and nonclassical (CD14−CD16+ in humans and Ly6Clo in mice). Classical monocytes are critical for the initial inflammatory response. Classical monocytes can differentiate into macrophages in tissue and can contribute to chronic disease. Nonclassical monocytes have been widely viewed as anti-inflammatory, as they maintain vascular homeostasis. They are a first line of defense in recognition and clearance of pathogens. However, their roles in chronic disease are less clear. They have been shown to be protective as well as positively associated with disease burden. This review focuses on the state of the monocyte biology field and the functions of monocytes, particularly nonclassical monocytes, in health and disease.

    更新日期:2019-11-18
  • CD8 T Cell Exhaustion During Chronic Viral Infection and Cancer
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2015-04-16
    Laura M. McLane, Mohamed S. Abdel-Hakeem, E. John Wherry

    Exhausted CD8 T (Tex) cells are a distinct cell lineage that arise during chronic infections and cancers in animal models and humans. Tex cells are characterized by progressive loss of effector functions, high and sustained inhibitory receptor expression, metabolic dysregulation, poor memory recall and homeostatic self-renewal, and distinct transcriptional and epigenetic programs. The ability to reinvigorate Tex cells through inhibitory receptor blockade, such as αPD-1, highlights the therapeutic potential of targeting this population. Emerging insights into the mechanisms of exhaustion are informing immunotherapies for cancer and chronic infections. However, like other immune cells, Tex cells are heterogeneous and include progenitor and terminal subsets with unique characteristics and responses to checkpoint blockade. Here, we review our current understanding of Tex cell biology, including the developmental paths, transcriptional and epigenetic features, and cell intrinsic and extrinsic factors contributing to exhaustion and how this knowledge may inform therapeutic targeting of Tex cells in chronic infections, autoimmunity, and cancer.

    更新日期:2019-11-18
  • New Molecular Insights into Immune Cell Development
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2019-04-26
    Ana Cumano, Claire Berthault, Cyrille Ramond, Maxime Petit, Rachel Golub, Antonio Bandeira, Pablo Pereira

    During development innate lymphoid cells and specialized lymphocyte subsets colonize peripheral tissues, where they contribute to organogenesis and later constitute the first line of protection while maintaining tissue homeostasis. A few of these subsets are produced only during embryonic development and remain in the tissues throughout life. They are generated through a unique developmental program initiated in lympho-myeloid-primed progenitors, which lose myeloid and B cell potential. They either differentiate into innate lymphoid cells or migrate to the thymus to give rise to embryonic T cell receptor–invariant T cells. At later developmental stages, adaptive T lymphocytes are derived from lympho-myeloid progenitors that colonize the thymus, while lymphoid progenitors become specialized in the production of B cells. This sequence of events highlights the requirement for stratification in the establishment of immune functions that determine efficient seeding of peripheral tissues by a limited number of cells.

    更新日期:2019-11-18
  • Tissue-Resident T Cells and Other Resident Leukocytes
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2019-02-06
    David Masopust, Andrew G. Soerens

    Resident memory T (Trm) cells stably occupy tissues and cannot be sampled in superficial venous blood. Trm cells are heterogeneous but collectively constitute the most abundant memory T cell subset. Trm cells form an integral part of the immune sensing network, monitor for local perturbations in homeostasis throughout the body, participate in protection from infection and cancer, and likely promote autoimmunity, allergy, and inflammatory diseases and impede successful transplantation. Thus Trm cells are major candidates for therapeutic manipulation. Here we review CD8+ and CD4+ Trm ontogeny, maintenance, function, and distribution within lymphoid and nonlymphoid tissues and strategies for their study. We briefly discuss other resident leukocyte populations, including innate lymphoid cells, macrophages, natural killer and natural killer T cells, nonclassical T cells, and memory B cells. Lastly, we highlight major gaps in knowledge and propose ways in which a deeper understanding could result in new methods to prevent or treat diverse human diseases.

    更新日期:2019-11-18
  • Using T Cell Receptor Repertoires to Understand the Principles of Adaptive Immune Recognition
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2019-01-30
    Philip Bradley, Paul G. Thomas

    Adaptive immune recognition is mediated by antigen receptors on B and T cells generated by somatic recombination during lineage development. The high level of diversity resulting from this process posed technical limitations that previously limited the comprehensive analysis of adaptive immune recognition. Advances over the last ten years have produced data and approaches allowing insights into how T cells develop, evolutionary signatures of recombination and selection, and the features of T cell receptors that mediate epitope-specific binding and T cell activation. The size and complexity of these data have necessitated the generation of novel computational and analytical approaches, which are transforming how T cell immunology is conducted. Here we review the development and application of novel biological, theoretical, and computational methods for understanding T cell recognition and discuss the potential for improved models of receptor:antigen interactions.

    更新日期:2019-11-18
  • CRISPR-Based Tools in Immunity
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2019-01-30
    Dimitre R. Simeonov, Alexander Marson

    CRISPR technology has opened a new era of genome interrogation and genome engineering. Discovered in bacteria, where it protects against bacteriophage by cleaving foreign nucleic acid sequences, the CRISPR system has been repurposed as an adaptable tool for genome editing and multiple other applications. CRISPR's ease of use, precision, and versatility have led to its widespread adoption, accelerating biomedical research and discovery in human cells and model organisms. Here we review CRISPR-based tools and discuss how they are being applied to decode the genetic circuits that control immune function in health and disease. Genetic variation in immune cells can affect autoimmune disease risk, infectious disease pathogenesis, and cancer immunotherapies. CRISPR provides unprecedented opportunities for functional mechanistic studies of coding and noncoding genome sequence function in immunity. Finally, we discuss the potential of CRISPR technology to engineer synthetic cellular immunotherapies for a wide range of human diseases.

    更新日期:2019-11-18
  • Gut Microbiota Regulation of T Cells During Inflammation and Autoimmunity
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2019-04-26
    Eric M. Brown, Douglas J. Kenny, Ramnik J. Xavier

    The intestinal microbiota plays a crucial role in influencing the development of host immunity, and in turn the immune system also acts to regulate the microbiota through intestinal barrier maintenance and immune exclusion. Normally, these interactions are homeostatic, tightly controlled, and organized by both innate and adaptive immune responses. However, a combination of environmental exposures and genetic defects can result in a break in tolerance and intestinal homeostasis. The outcomes of these interactions at the mucosal interface have broad, systemic effects on host immunity and the development of chronic inflammatory or autoimmune disease. The underlying mechanisms and pathways the microbiota can utilize to regulate these diseases are just starting to emerge. Here, we discuss the recent evidence in this area describing the impact of microbiota-immune interactions during inflammation and autoimmunity, with a focus on barrier function and CD4+ T cell regulation.

    更新日期:2019-11-18
  • Development and maturation of secondary lymphoid tissues.
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 1999-06-08
    Y X Fu,D D Chaplin

    The secondary lymphoid tissues are located at strategic sites where foreign antigens can be efficiently brought together with immune system regulatory and effector cells. The organized structure of the secondary lymphoid tissues is thought to enhance the sensitivity of antigen recognition and to support proper regulation of the activation and maturation of the antigen-responsive lymphoid cells. Although a substantial amount is known about the cellular elements that compose the lymphoid and nonlymphoid components of the secondary lymphoid tissues, information concerning the signals that control the development of the tissues and that maintain the organized tissue microenvironment remain undefined. Studies over the past few years have identified lymphotoxin as a critical signaling molecule not only for the organogenesis of secondary lymphoid tissues but for the maintenance of aspects of their microarchitecture as well. Additional signaling molecules that contribute to the formation of normal lymphoid tissue structure are being identified at an accelerating pace. Analyses of mouse strains with congenital defects in different aspects of secondary lymphoid tissue development are beginning to clarify the role of these tissues in immune responses and host defense. This review focuses on studies defining recently identified crucial signals for the biogenesis of secondary lymphoid organs and for the maintenance of their proper microarchitecture. It also discusses new insights into how the structure of these tissues supports effective immune responses.

    更新日期:2019-11-01
  • Activating receptors and coreceptors involved in human natural killer cell-mediated cytolysis.
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2001-03-13
    A Moretta,C Bottino,M Vitale,D Pende,C Cantoni,M C Mingari,R Biassoni,L Moretta

    Natural killer cells can discriminate between normal cells and cells that do not express adequate amounts of major histocompatibility complex (MHC) class I molecules. The discovery, both in mouse and in human, of MHC-specific inhibitory receptors clarified the molecular basis of this important NK cell function. However, the triggering receptors responsible for positive NK cell stimulation remained elusive until recently. Some of these receptors have now been identified in humans, thus shedding some light on the molecular mechanisms involved in NK cell activation during the process of natural cytotoxicity. Three novel, NK-specific, triggering surface molecules (NKp46, NKp30, and NKp44) have been identified. They represent the first members of a novel emerging group of receptors collectively termed natural cytotoxicity receptors (NCR). Monoclonal antibodies (mAbs) to NCR block to differing extents the NK-mediated lysis of various tumors. Moreover, lysis of certain tumors can be virtually abrogated by the simultaneous masking of the three NCRs. There is a coordinated surface expression of the three NCRs, their surface density varying in different individuals and also in the NK cells isolated from a given individual. A direct correlation exists between the surface density of NCR and the ability of NK cells to kill various tumors. NKp46 is the only NCR involved in human NK-mediated killing of murine target cells. Accordingly, a homologue of NKp46 has been detected in mouse. Molecular cloning of NCR revealed novel members of the Ig superfamily displaying a low degree of similarity to each other and to known human molecules. NCRs are coupled to different signal transducing adaptor proteins, including CD3 zeta, Fc epsilon RI gamma, and KARAP/DAP12. Another triggering NK receptor is NKG2D. It appears to play either a complementary or a synergistic role with NCRs. Thus, the triggering of NK cells in the process of tumor cell lysis may often depend on the concerted action of NCR and NKG2D. In some instances, however, it may uniquely depend upon the activity of NCR or NKG2D only. Strict NKG2D-dependency can be appreciated using clones that, in spite of their NCR(dull) phenotype, efficiently lyse certain epithelial tumors or leukemic cell lines. Other triggering surface molecules including 2B4 and the novel NKp80 appear to function as coreceptors rather than as true receptors. Indeed, they can induce natural cytotoxicity only when co-engaged with a triggering receptor. While an altered expression or function of NCR or NKG2D is being explored as a possible cause of immunological disorders, 2B4 dysfunction has already been associated with a severe form of immunodeficiency. Indeed, in patients with the X-linked lymphoproliferative disease, the inability to control Epstein-Barr virus infections may be consequent to a major dysfunction of 2B4 that exerts inhibitory instead of activating functions.

    更新日期:2019-11-01
  • The Innate Lymphoid Cell Precursor.
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2016-05-12
    Isabel E Ishizuka,Michael G Constantinides,Herman Gudjonson,Albert Bendelac

    The discovery of tissue-resident innate lymphoid cell populations effecting different forms of type 1, 2, and 3 immunity; tissue repair; and immune regulation has transformed our understanding of mucosal immunity and allergy. The emerging complexity of these populations along with compounding issues of redundancy and plasticity raise intriguing questions about their precise lineage relationship. Here we review advances in mapping the emergence of these lineages from early lymphoid precursors. We discuss the identification of a common innate lymphoid cell precursor characterized by transient expression of the transcription factor PLZF, and the lineage relationships of innate lymphoid cells with conventional natural killer cells and lymphoid tissue inducer cells. We also review the rapidly growing understanding of the network of transcription factors that direct the development of these lineages.

    更新日期:2019-11-01
  • Obsessive-Compulsive Behavior Isn't Necessarily a Bad Thing.
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2019-10-09
    Philippa Marrack

    It is difficult to believe that in about 1960 practically nothing was known about the thymus and some of its products, T cells bearing αβ receptors for antigen. Thus I was lucky to join the field of T cell biology almost at its beginning, when knowledge about the cells was just getting off the ground and there was so much to discover. This article describes findings about these cells made by others and myself that led us all from ignorance, via complete confusion, to our current state of knowledge. I believe I was fortunate to practice science in very supportive institutions and with very collaborative colleagues in two countries that both encourage independent research by independent scientists, while simultaneously ignoring or somehow being able to avoid some of the difficulties of being a woman in what was, at the time, a male-dominated profession. Expected final online publication date for the Annual Review of Immunology, Volume 38 is April 26, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

    更新日期:2019-11-01
  • Transcriptional Control of Dendritic Cell Development.
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2016-01-07
    Theresa L Murphy,Gary E Grajales-Reyes,Xiaodi Wu,Roxane Tussiwand,Carlos G Briseño,Arifumi Iwata,Nicole M Kretzer,Vivek Durai,Kenneth M Murphy

    The dendritic cells (DCs) of the immune system function in innate and adaptive responses by directing activity of various effector cells rather than serving as effectors themselves. DCs and closely related myeloid lineages share expression of many surface receptors, presenting a challenge in distinguishing their unique in vivo functions. Recent work has taken advantage of unique transcriptional programs to identify and manipulate murine DCs in vivo. This work has assigned several nonredundant in vivo functions to distinct DC lineages, consisting of plasmacytoid DCs and several subsets of classical DCs that promote different immune effector modules in response to pathogens. In parallel, a correspondence between human and murine DC subsets has emerged, underlying structural similarities for the DC lineages between these species. Recent work has begun to unravel the transcriptional circuitry that controls the development and diversification of DCs from common progenitors in the bone marrow.

    更新日期:2019-11-01
  • Genomics of Immune Diseases and New Therapies.
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2016-01-07
    Michael Lenardo,Bernice Lo,Carrie L Lucas

    Genomic DNA sequencing technologies have been one of the great advances of the 21st century, having decreased in cost by seven orders of magnitude and opening up new fields of investigation throughout research and clinical medicine. Genomics coupled with biochemical investigation has allowed the molecular definition of a growing number of new genetic diseases that reveal new concepts of immune regulation. Also, defining the genetic pathogenesis of these diseases has led to improved diagnosis, prognosis, genetic counseling, and, most importantly, new therapies. We highlight the investigational journey from patient phenotype to treatment using the newly defined XMEN disease, caused by the genetic loss of the MAGT1 magnesium transporter, as an example. This disease illustrates how genomics yields new fundamental immunoregulatory insights as well as how research genomics is integrated into clinical immunology. At the end, we discuss two other recently described diseases, CHAI/LATAIE (CTLA-4 deficiency) and PASLI (PI3K dysregulation), as additional examples of the journey from unknown immunological diseases to new precision medicine treatments using genomics.

    更新日期:2019-11-01
  • Stromal cells in chronic inflammation and tertiary lymphoid organ formation.
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2015-04-12
    Christopher D Buckley,Francesca Barone,Saba Nayar,Cecile Bénézech,Jorge Caamaño

    Inflammation is an unstable state. It either resolves or persists. Why inflammation persists and the factors that define tissue tropism remain obscure. Increasing evidence suggests that tissue-resident stromal cells not only provide positional memory but also actively regulate the differential accumulation of inflammatory cells within inflamed tissues. Furthermore, at many sites of chronic inflammation, structures that mimic secondary lymphoid tissues are observed, suggesting that chronic inflammation and lymphoid tissue formation share common activation programs. Similarly, blood and lymphatic endothelial cells contribute to tissue homeostasis and disease persistence in chronic inflammation. This review highlights our increasing understanding of the role of stromal cells in inflammation and summarizes the novel immunological role that stromal cells exert in the persistence of inflammatory diseases.

    更新日期:2019-11-01
  • Molecular mechanisms in genetically defined autoinflammatory diseases: disorders of amplified danger signaling.
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2015-02-24
    Adriana Almeida de Jesus,Scott W Canna,Yin Liu,Raphaela Goldbach-Mansky

    Patients with autoinflammatory diseases present with noninfectious fever flares and systemic and/or disease-specific organ inflammation. Their excessive proinflammatory cytokine and chemokine responses can be life threatening and lead to organ damage over time. Studying such patients has revealed genetic defects that have helped unravel key innate immune pathways, including excessive IL-1 signaling, constitutive NF-κB activation, and, more recently, chronic type I IFN signaling. Discoveries of monogenic defects that lead to activation of proinflammatory cytokines have inspired the use of anticytokine-directed treatment approaches that have been life changing for many patients and have led to the approval of IL-1-blocking agents for a number of autoinflammatory conditions. In this review, we describe the genetically characterized autoinflammatory diseases, we summarize our understanding of the molecular pathways that drive clinical phenotypes and that continue to inspire the search for novel treatment targets, and we provide a conceptual framework for classification.

    更新日期:2019-11-01
  • The immunology of Epstein-Barr virus-induced disease.
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2015-02-24
    Graham S Taylor,Heather M Long,Jill M Brooks,Alan B Rickinson,Andrew D Hislop

    Epstein-Barr virus (EBV) is usually acquired silently early in life and carried thereafter as an asymptomatic infection of the B lymphoid system. However, many circumstances disturb the delicate EBV-host balance and cause the virus to display its pathogenic potential. Thus, primary infection in adolescence can manifest as infectious mononucleosis (IM), as a fatal illness that magnifies the immunopathology of IM in boys with the X-linked lymphoproliferative disease trait, and as a chronic active disease leading to life-threatening hemophagocytosis in rare cases of T or natural killer (NK) cell infection. Patients with primary immunodeficiencies affecting the NK and/or T cell systems, as well as immunosuppressed transplant recipients, handle EBV infections poorly, and many are at increased risk of virus-driven B-lymphoproliferative disease. By contrast, a range of other EBV-positive malignancies of lymphoid or epithelial origin arise in individuals with seemingly intact immune systems through mechanisms that remain to be understood.

    更新日期:2019-11-01
  • Malaria immunity in man and mosquito: insights into unsolved mysteries of a deadly infectious disease.
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2014-03-25
    Peter D Crompton,Jacqueline Moebius,Silvia Portugal,Michael Waisberg,Geoffrey Hart,Lindsey S Garver,Louis H Miller,Carolina Barillas-Mury,Susan K Pierce

    Malaria is a mosquito-borne disease caused by parasites of the obligate intracellular Apicomplexa phylum the most deadly of which, Plasmodium falciparum, prevails in Africa. Malaria imposes a huge health burden on the world's most vulnerable populations, claiming the lives of nearly one million children and pregnant women each year. Although there is keen interest in eradicating malaria, we do not yet have the necessary tools to meet this challenge, including an effective malaria vaccine and adequate vector control strategies. Here we review what is known about the mechanisms at play in immune resistance to malaria in both the human and mosquito hosts at each step in the parasite's complex life cycle with a view toward developing the tools that will contribute to the prevention of disease and death and, ultimately, to the goal of malaria eradication. In so doing, we hope to inspire immunologists to participate in defeating this devastating disease.

    更新日期:2019-11-01
  • Biology of CD1- and MR1-restricted T cells.
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2014-02-07
    Mariolina Salio,Jonathan D Silk,E Yvonne Jones,Vincenzo Cerundolo

    Over the past 15 years, investigators have shown that T lymphocytes can recognize not only peptides in the context of MHC class I and class II molecules but also foreign and self-lipids in association with the nonclassical MHC class I-like molecules, CD1 proteins. In this review, we describe the most recent events in the field, with particular emphasis on (a) structural and functional aspects of lipid presentation by CD1 molecules, (b) the development of CD1d-restricted invariant natural killer T (iNKT) cells and transcription factors required for their differentiation, (c) the ability of iNKT cells to modulate innate and adaptive immune responses through their cross talk with lymphoid and myeloid cells, and (d) MR1-restricted and group I (CD1a, CD1b, and CD1c)-restricted T cells.

    更新日期:2019-11-01
  • Microglia development and function.
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2014-01-30
    Debasis Nayak,Theodore L Roth,Dorian B McGavern

    Proper development and function of the mammalian central nervous system (CNS) depend critically on the activity of parenchymal sentinels referred to as microglia. Although microglia were first described as ramified brain-resident phagocytes, research conducted over the past century has expanded considerably upon this narrow view and ascribed many functions to these dynamic CNS inhabitants. Microglia are now considered among the most versatile cells in the body, possessing the capacity to morphologically and functionally adapt to their ever-changing surroundings. Even in a resting state, the processes of microglia are highly dynamic and perpetually scan the CNS. Microglia are in fact vital participants in CNS homeostasis, and dysregulation of these sentinels can give rise to neurological disease. In this review, we discuss the exciting developments in our understanding of microglial biology, from their developmental origin to their participation in CNS homeostasis and pathophysiological states such as neuropsychiatric disorders, neurodegeneration, sterile injury responses, and infectious diseases. We also delve into the world of microglial dynamics recently uncovered using real-time imaging techniques.

    更新日期:2019-11-01
  • Controlling natural killer cell responses: integration of signals for activation and inhibition.
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2013-03-23
    Eric O Long,Hun Sik Kim,Dongfang Liu,Mary E Peterson,Sumati Rajagopalan

    Understanding 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.

    更新日期:2019-11-01
  • Signaling by the phosphoinositide 3-kinase family in immune cells.
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2013-01-22
    Klaus Okkenhaug

    Phosphoinositide 3-kinases (PI3Ks) control many important aspects of immune cell development, differentiation, and function. Mammals have eight PI3K catalytic subunits that are divided into three classes based on similarities in structure and function. Specific roles for the class I PI3Ks have been broadly investigated and are relatively well understood, as is the function of their corresponding phosphatases. More recently, specific roles for the class II and class III PI3Ks have emerged. Through vertebrate evolution and in parallel with the evolution of adaptive immunity, there has been a dramatic increase not only in the genes for PI3K subunits but also in genes for phosphatases that act on 3-phosphoinositides and in 3-phosphoinositide-binding proteins. Our understanding of the PI3Ks in immunity is guided by fundamental discoveries made in simpler model organisms as well as by appreciating new adaptations of this signaling module in mammals in general and in immune cells in particular.

    更新日期:2019-11-01
  • Microbial translocation across the GI tract.
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2012-01-10
    Jason M Brenchley,Daniel C Douek

    The lumen of the gastrointestinal (GI) tract is home to an enormous quantity of different bacterial species, our microbiota, that thrive in an often symbiotic relationship with the host. Given that the healthy host must regulate contact between the microbiota and its immune system to avoid overwhelming systemic immune activation, humans have evolved several mechanisms to attenuate systemic microbial translocation (MT) and its consequences. However, several diseases are associated with the failure of one or more of these mechanisms, with consequent immune activation and deleterious effects on health. Here, we discuss the mechanisms underlying MT, diseases associated with MT, and therapeutic interventions that aim to decrease it.

    更新日期:2019-11-01
  • Transcriptional and epigenetic control of T helper cell specification: molecular mechanisms underlying commitment and plasticity.
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2012-01-10
    Yuka Kanno,Golnaz Vahedi,Kiyoshi Hirahara,Kentner Singleton,John J O'Shea

    T helper cell differentiation occurs in the context of the extracellular cytokine milieu evoked by diverse microbes and other pathogenic stimuli along with T cell receptor stimulation. The culmination of these signals results in specification of T helper lineages, which occurs through the combinatorial action of multiple transcription factors that establish distinctive transcriptomes. In this manner, inducible, but constitutively active, master regulators work in conjunction with factors such as the signal transducer and activator of transcriptions (STATs) that sense the extracellular environment. The acquisition of a distinctive transcriptome also depends on chromatin modifications that impact key cis elements as well as the changes in global genomic organization. Thus, signal transduction and epigenetics are linked in these processes of differentiation. In this review, recent advances in understanding T helper lineage specification and deciphering the action of transcription factors are summarized with emphasis on comprehensive views of the dynamic T cell epigenome.

    更新日期:2019-11-01
  • Systems biology in immunology: a computational modeling perspective.
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2011-01-12
    Ronald N Germain,Martin Meier-Schellersheim,Aleksandra Nita-Lazar,Iain D C Fraser

    Systems biology is an emerging discipline that combines high-content, multiplexed measurements with informatic and computational modeling methods to better understand biological function at various scales. Here we present a detailed review of the methods used to create computational models and to conduct simulations of immune function. We provide descriptions of the key data-gathering techniques employed to generate the quantitative and qualitative data required for such modeling and simulation and summarize the progress to date in applying these tools and techniques to questions of immunological interest, including infectious disease. We include comments on what insights modeling can provide that complement information obtained from the more familiar experimental discovery methods used by most investigators and the reasons why quantitative methods are needed to eventually produce a better understanding of immune system operation in health and disease.

    更新日期:2019-11-01
  • HLA/KIR restraint of HIV: surviving the fittest.
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2011-01-12
    Arman A Bashirova,Rasmi Thomas,Mary Carrington

    Multiple epidemiological studies have demonstrated associations between the human leukocyte antigen (HLA) loci and human immunodeficiency virus (HIV) disease, and more recently the killer cell immunoglobulin-like (KIR) locus has been implicated in differential responses to the virus. Genome-wide association studies have convincingly shown that the HLA class I locus is the most significant host genetic contributor to the variation in HIV control, underscoring a central role for CD8 T cells in resistance to the virus. However, both genetic and functional data indicate that part of the HLA effect on HIV is due to interactions between KIR and HLA genes, also implicating natural killer cells in defense against viral infection and viral expansion prior to initiation of an adaptive response. We review the HLA and KIR associations with HIV disease and the progress that has been made in understanding the mechanisms that explain these associations.

    更新日期:2019-11-01
  • Innate antifungal immunity: the key role of phagocytes.
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2010-10-13
    Gordon D Brown

    Fungal diseases have emerged as significant causes of morbidity and mortality, particularly in immune-compromised individuals, prompting greater interest in understanding the mechanisms of host resistance to these pathogens. Consequently, the past few decades have seen a tremendous increase in our knowledge of the innate and adaptive components underlying the protective (and nonprotective) mechanisms of antifungal immunity. What has emerged from these studies is that phagocytic cells are essential for protection and that defects in these cells compromise the host's ability to resist fungal infection. This review covers the functions of phagocytes in innate antifungal immunity, along with selected examples of the strategies that are used by fungal pathogens to subvert these defenses.

    更新日期:2019-11-01
  • Differentiation of effector CD4 T cell populations (*).
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2010-03-03
    Jinfang Zhu,Hidehiro Yamane,William E Paul

    CD4 T cells play critical roles in mediating adaptive immunity to a variety of pathogens. They are also involved in autoimmunity, asthma, and allergic responses as well as in tumor immunity. During TCR activation in a particular cytokine milieu, naive CD4 T cells may differentiate into one of several lineages of T helper (Th) cells, including Th1, Th2, Th17, and iTreg, as defined by their pattern of cytokine production and function. In this review, we summarize the discovery, functions, and relationships among Th cells; the cytokine and signaling requirements for their development; the networks of transcription factors involved in their differentiation; the epigenetic regulation of their key cytokines and transcription factors; and human diseases involving defective CD4 T cell differentiation.

    更新日期:2019-11-01
  • Alternative activation of macrophages: an immunologic functional perspective.
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2008-12-25
    Fernando O Martinez,Laura Helming,Siamon Gordon

    Macrophages are innate immune cells with well-established roles in the primary response to pathogens, but also in tissue homeostasis, coordination of the adaptive immune response, inflammation, resolution, and repair. These cells recognize danger signals through receptors capable of inducing specialized activation programs. The classically known macrophage activation is induced by IFN-gamma, which triggers a harsh proinflammatory response that is required to kill intracellular pathogens. Macrophages also undergo alternative activation by IL-4 and IL-13, which trigger a different phenotype that is important for the immune response to parasites. Here we review the cellular sources of these cytokines, receptor signaling pathways, and induced markers and gene signatures. We draw attention to discrepancies found between mouse and human models of alternative activation. The evidence for in vivo alternative activation of macrophages is also analyzed, with nematode infection as prototypic disease. Finally, we revisit the concept of macrophage activation in the context of the immune response.

    更新日期:2019-11-01
  • Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease (*).
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2009-03-24
    Seth L Masters,Anna Simon,Ivona Aksentijevich,Daniel L Kastner

    The autoinflammatory diseases are characterized by seemingly unprovoked episodes of inflammation, without high-titer autoantibodies or antigen-specific T cells. The concept was proposed ten years ago with the identification of the genes underlying hereditary periodic fever syndromes. This nosology has taken root because of the dramatic advances in our knowledge of the genetic basis of both mendelian and complex autoinflammatory diseases, and with the recognition that these illnesses derive from genetic variants of the innate immune system. Herein we propose an updated classification scheme based on the molecular insights garnered over the past decade, supplanting a clinical classification that has served well but is opaque to the genetic, immunologic, and therapeutic interrelationships now before us. We define six categories of autoinflammatory disease: IL-1beta activation disorders (inflammasomopathies), NF-kappaB activation syndromes, protein misfolding disorders, complement regulatory diseases, disturbances in cytokine signaling, and macrophage activation syndromes. A system based on molecular pathophysiology will bring greater clarity to our discourse while catalyzing new hypotheses both at the bench and at the bedside.

    更新日期:2019-11-01
  • Tissue Tregs.
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2016-05-12
    Marisella Panduro,Christophe Benoist,Diane Mathis

    The immune system is responsible for defending an organism against the myriad of microbial invaders it constantly confronts. It has become increasingly clear that the immune system has a second major function: the maintenance of organismal homeostasis. Foxp3(+)CD4(+) regulatory T cells (Tregs) are important contributors to both of these critical activities, defense being the primary purview of Tregs circulating through lymphoid organs, and homeostasis ensured mainly by their counterparts residing in parenchymal tissues. This review focuses on so-called tissue Tregs. We first survey existing information on the phenotype, function, sustaining factors, and human equivalents of the three best-characterized tissue-Treg populations-those operating in visceral adipose tissue, skeletal muscle, and the colonic lamina propria. We then attempt to distill general principles from this body of work-as concerns the provenance, local adaptation, molecular sustenance, and targets of action of tissue Tregs, in particular.

    更新日期:2019-11-01
  • Integration of T cell receptor-dependent signaling pathways by adapter proteins.
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 1999-06-08
    J L Clements,N J Boerth,J R Lee,G A Koretzky

    The initiation of biochemical signal transduction following ligation of surface receptors with intrinsic cytoplasmic tyrosine kinase activity is common for many cell types. T lymphocytes also require activation of tyrosine kinases following T cell receptor (TCR) ligation for maximal stimulation. However, the TCR has no intrinsic tyrosine kinase activity. Instead, the TCR must rely on cytoplasmic tyrosine kinases that localize to the TCR complex and initiate TCR-mediated signaling events. Although much has been learned regarding how these cytosolic tyrosine kinases are activated and recruited to the TCR complex, relatively little is understood about how these initial events are translated into transcriptional activation of genes that regulate cytokine production, cell proliferation, and cell death. Recently, it has become clear that the class of intracellular molecules known collectively as adapter proteins, molecules with modular domains capable of recruiting additional proteins but that exhibit no intrinsic enzymatic activity, serve to couple proximal biochemical events initiated by TCR ligation with more distal signaling pathways.

    更新日期:2019-11-01
  • Autoantigens as Partners in Initiation and Propagation of Autoimmune Rheumatic Diseases.
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2016-02-26
    Antony Rosen,Livia Casciola-Rosen

    Systemic autoimmune diseases are characterized by specific targeting of a limited group of ubiquitously expressed autoantigens by the immune system. This review examines the mechanisms underlying their selection as immune targets. Initiation of autoimmune responses likely reflects the presentation of antigens with a distinct structure not previously encountered by the immune system, in a proimmune context (injury, malignancy, or infection). Causes of modified structure include somatic mutation and posttranslational modifications (including citrullination and proteolysis). Many autoantigens are components of multimolecular complexes, and some of the other components may provide adjuvant activity. Propagation of autoimmune responses appears to reflect a bidirectional interaction between the immune response and the target tissues in a mutually reinforcing cycle: Immune effector pathways generate additional autoantigen, which feeds further immune response. We propose that this resonance may be a critical principle underlying disease propagation, with specific autoantigens functioning as the hubs around which amplification occurs.

    更新日期:2019-11-01
  • Drosophila: the genetics of innate immune recognition and response.
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2004-03-23
    Catherine A Brennan,Kathryn V Anderson

    Because of the evolutionary conservation of innate mechanisms of host defense, Drosophila has emerged as an ideal animal in which to study the genetic control of immune recognition and responses. The discovery that the Toll pathway is required for defense against fungal infection in Drosophila was pivotal in studies of both mammalian and Drosophila immunity. Subsequent genetic screens in Drosophila to isolate additional mutants unable to induce humoral responses to infection have identified and ordered the function of components of two signaling cascades, the Toll and Imd pathways, that activate responses to infection. Drosophila blood cells also contribute to host defense through phagocytosis and signaling, and may carry out a form of self-nonself recognition that is independent of microbial pattern recognition. Recent work suggests that Drosophila will be a useful model for dissecting virulence mechanisms of several medically important pathogens.

    更新日期:2019-11-01
  • Toll-like receptors.
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2003-01-14
    Kiyoshi Takeda,Tsuneyasu Kaisho,Shizuo Akira

    The innate immune system in drosophila and mammals senses the invasion of microorganisms using the family of Toll receptors, stimulation of which initiates a range of host defense mechanisms. In drosophila antimicrobial responses rely on two signaling pathways: the Toll pathway and the IMD pathway. In mammals there are at least 10 members of the Toll-like receptor (TLR) family that recognize specific components conserved among microorganisms. Activation of the TLRs leads not only to the induction of inflammatory responses but also to the development of antigen-specific adaptive immunity. The TLR-induced inflammatory response is dependent on a common signaling pathway that is mediated by the adaptor molecule MyD88. However, there is evidence for additional pathways that mediate TLR ligand-specific biological responses.

    更新日期:2019-11-01
  • Tyrosine phosphatase PTPN22: multifunctional regulator of immune signaling, development, and disease.
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2013-12-25
    Nunzio Bottini,Erik J Peterson

    Inheritance of a coding variant of the protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene is associated with increased susceptibility to autoimmunity and infection. Efforts to elucidate the mechanisms by which the PTPN22-C1858T variant modulates disease risk revealed that PTPN22 performs a signaling function in multiple biochemical pathways and cell types. Capable of both enzymatic activity and adaptor functions, PTPN22 modulates signaling through antigen and innate immune receptors. PTPN22 plays roles in lymphocyte development and activation, establishment of tolerance, and innate immune cell-mediated host defense and immunoregulation. The disease-associated PTPN22-R620W variant protein is likely involved in multiple stages of the pathogenesis of autoimmunity. Establishment of a tolerant B cell repertoire is disrupted by PTPN22-R620W action during immature B cell selection, and PTPN22-R620W alters mature T cell responsiveness. However, after autoimmune attack has initiated tissue injury, PTPN22-R620W may foster inflammation through modulating the balance of myeloid cell-produced cytokines.

    更新日期:2019-11-01
  • Natural antibody repertoires: development and functional role in inhibiting allergic airway disease.
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2015-01-27
    John F Kearney,Preeyam Patel,Emily K Stefanov,R Glenn King

    In this review we discuss the effects of microbial exposure on the B cell repertoire. Neonatal exposure to conserved bacterial carbohydrates and phospholipids permanently reprograms the natural antibody repertoire directed toward these antigens by clonal expansion, alterations in clonal dominance, and increased serum antibody levels. These epitopes are present not only in bacterial cell walls, but also in common environmental allergens. Neonatal immunization with bacterial polysaccharide vaccines results in attenuated allergic airway responses to fungi-, house dust mite-, and cockroach-associated allergens in mouse models. The similarities between mouse and human natural antibody repertoires suggest that reduced microbial exposure in children may have the opposite effect, providing a potential mechanistic explanation for the hygiene hypothesis. We propose that understanding the effects of childhood infections on the natural antibody repertoire and the mechanisms of antibody-mediated immunoregulation observed in allergy models will lead to the development of prevention/interventional strategies for treatment of allergic asthma.

    更新日期:2019-11-01
  • Adoptive immunotherapy for cancer or viruses.
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2014-01-16
    Marcela V Maus,Joseph A Fraietta,Bruce L Levine,Michael Kalos,Yangbing Zhao,Carl H June

    Adoptive immunotherapy, or the infusion of lymphocytes, is a promising approach for the treatment of cancer and certain chronic viral infections. The application of the principles of synthetic biology to enhance T cell function has resulted in substantial increases in clinical efficacy. The primary challenge to the field is to identify tumor-specific targets to avoid off-tumor, on-target toxicity. Given recent advances in efficacy in numerous pilot trials, the next steps in clinical development will require multicenter trials to establish adoptive immunotherapy as a mainstream technology.

    更新日期:2019-11-01
  • Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned?
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2001-03-13
    M Feldmann,R N Maini

    Rheumatoid arthritis (RA), a systemic disease, is characterized by a chronic inflammatory reaction in the synovium of joints and is associated with degeneration of cartilage and erosion of juxta-articular bone. Many pro-inflammatory cytokines including TNF alpha, chemokines, and growth factors are expressed in diseased joints. The rationale that TNF alpha played a central role in regulating these molecules, and their pathophysiological potential, was initially provided by the demonstration that anti-TNF alpha antibodies added to in vitro cultures of a representative population of cells derived from diseased joints inhibited the spontaneous production of IL-1 and other pro-inflammatory cytokines. Systemic administration of anti-TNF alpha antibody or sTNFR fusion protein to mouse models of RA was shown to be anti-inflammatory and joint protective. Clinical investigations in which the activity of TNF alpha in RA patients was blocked with intravenously administered infliximab, a chimeric anti-TNF alpha monoclonal antibody (mAB), has provided evidence that TNF regulates IL-6, IL-8, MCP-1, and VEGF production, recruitment of immune and inflammatory cells into joints, angiogenesis, and reduction of blood levels of matrix metalloproteinases-1 and -3. Randomized, placebo-controlled, multi-center clinical trials of human TNF alpha inhibitors have demonstrated their consistent and remarkable efficacy in controlling signs and symptoms, with a favorable safety profile, in approximately two thirds of patients for up to 2 years, and their ability to retard joint damage. Infliximab (a mAB), and etanercept (a sTNF-R-Fc fusion protein) have been approved by regulatory authorities in the United States and Europe for treating RA, and they represent a significant new addition to available therapeutic options.

    更新日期:2019-11-01
  • Regulation and functions of the IL-10 family of cytokines in inflammation and disease.
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2010-12-21
    Wenjun Ouyang,Sascha Rutz,Natasha K Crellin,Patricia A Valdez,Sarah G Hymowitz

    The IL-10 family of cytokines consists of nine members: IL-10, IL-19, IL-20, IL-22, IL-24, IL-26, and the more distantly related IL-28A, IL-28B, and IL-29. Evolutionarily, IL-10 family cytokines emerged before the adaptive immune response. These cytokines elicit diverse host defense mechanisms, especially from epithelial cells, during various infections. IL-10 family cytokines are essential for maintaining the integrity and homeostasis of tissue epithelial layers. Members of this family can promote innate immune responses from tissue epithelia to limit the damage caused by viral and bacterial infections. These cytokines can also facilitate the tissue-healing process in injuries caused by infection or inflammation. Finally, IL-10 itself can repress proinflammatory responses and limit unnecessary tissue disruptions caused by inflammation. Thus, IL-10 family cytokines have indispensable functions in many infectious and inflammatory diseases.

    更新日期:2019-11-01
  • Interleukin-10 and related cytokines and receptors.
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2004-03-23
    Sidney Pestka,Christopher D Krause,Devanand Sarkar,Mark R Walter,Yufang Shi,Paul B Fisher

    The Class 2 alpha-helical cytokines consist of interleukin-10 (IL-10), IL-19, IL-20, IL-22, IL-24 (Mda-7), and IL-26, interferons (IFN-alpha, -beta, -epsilon, -kappa, -omega, -delta, -tau, and -gamma) and interferon-like molecules (limitin, IL-28A, IL-28B, and IL-29). The interaction of these cytokines with their specific receptor molecules initiates a broad and varied array of signals that induce cellular antiviral states, modulate inflammatory responses, inhibit or stimulate cell growth, produce or inhibit apoptosis, and affect many immune mechanisms. The information derived from crystal structures and molecular evolution has led to progress in the analysis of the molecular mechanisms initiating their biological activities. These cytokines have significant roles in a variety of pathophysiological processes as well as in regulation of the immune system. Further investigation of these critical intercellular signaling molecules will provide important information to enable these proteins to be used more extensively in therapy for a variety of diseases.

    更新日期:2019-11-01
  • Chemokines in innate and adaptive host defense: basic chemokinese grammar for immune cells.
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2004-03-23
    Antal Rot,Ulrich H von Andrian

    Chemokines compose a sophisticated communication system used by all our cell types, including immune cells. Chemokine messages are decoded by specific receptors that initiate signal transduction events leading to a multitude of cellular responses, leukocyte chemotaxis and adhesion in particular. Critical determinants of the in vivo activities of chemokines in the immune system include their presentation by endothelial cells and extracellular matrix molecules, as well as their cellular uptake via "silent" chemokine receptors (interceptors) leading either to their transcytosis or to degradation. These regulatory mechanisms of chemokine histotopography, as well as the promiscuous and overlapping receptor specificities of inflammation-induced chemokines, shape innate responses to infections and tissue damage. Conversely, the specific patterns of homeostatic chemokines, where each chemokine is perceived by a single receptor, are charting lymphocyte navigation routes for immune surveillance. This review presents our current understanding of the mechanisms that regulate the cellular perception and pathophysiologic meaning of chemokines.

    更新日期:2019-11-01
  • CD1: antigen presentation and T cell function.
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2004-03-23
    Manfred Brigl,Michael B Brenner

    This review summarizes the major features of CD1 genes and proteins, the patterns of intracellular trafficking of CD1 molecules, and how they sample different intracellular compartments for self- and foreign lipids. We describe how lipid antigens bind to CD1 molecules with their alkyl chains buried in hydrophobic pockets and expose their polar lipid headgroup whose fine structure is recognized by the TCR of CD1-restricted T cells. CD1-restricted T cells carry out effector, helper, and adjuvant-like functions and interact with other cell types including macrophages, dendritic cells, NK cells, T cells, and B cells, thereby contributing to both innate and adaptive immune responses. Insights gained from mice and humans now delineate the extensive range of diseases in which CD1-restricted T cells play important roles and reveal differences in the role of CD1a, CD1b, and CD1c in contrast to CD1d. Invariant TCR alpha chains, self-lipid reactivity, and rapid effector responses empower a subset of CD1d-restricted T cells (NKT cells) to have unique effector functions without counterpart among MHC-restricted T cells. This review describes the function of CD1-restricted T cells in antimicrobial responses, antitumor immunity, and in regulating the balance between tolerance and autoimmunity.

    更新日期:2019-11-01
  • Asthma: mechanisms of disease persistence and progression.
    Annu. Rev. Immunol. (IF 21.429) Pub Date : 2004-03-23
    Lauren Cohn,Jack A Elias,Geoffrey L Chupp

    When asthma is diagnosed, eosinophilic inflammation and airway remodeling are established in the bronchial airways and can no longer be separated as cause and effect because both processes contribute to persistence and progression of disease, despite anti-inflammatory therapy. Th2 cells are continually active in the airways, even when disease is quiescent. IL-13 is the key effector cytokine in asthma and stimulates airway fibrosis through the action of matrix metalloproteinases on TGF-beta and promotes epithelial damage, mucus production, and eosinophilia. The production of IL-13 and other Th2 cytokines by non-T cells augments the inflammatory response. Inflammation is amplified by local responses of the epithelium, smooth muscle, and fibroblasts through the production of chemokines, cytokines, and proteases. Injured cells produce adenosine that enhances IL-13 production. We review human and animal data detailing the cellular and molecular interactions in established allergic asthma that promote persistent disease, amplify inflammation, and, in turn, cause disease progression.

    更新日期:2019-11-01
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