Annual Review of Immunology - Volume 22, 2004

Dendritic cells (DCs) are highly efficient antigen-presenting cells (APCs) that collect antigen in body tissues and transport them to draining lymph nodes. Antigenic peptides are loaded onto major histocompatibility complex (MHC) molecules for presentation to naïve T cells, resulting in the induction of cellular and humoral immune responses. DCs take up antigen through phagocytosis, pinocytosis, and endocytosis via different groups of receptor families, such as Fc receptors for antigen-antibody complexes, C-type lectin receptors (CLRs) for glycoproteins, and pattern recognition receptors, such as Toll-like receptors (TLRs), for microbial antigens. Uptake of antigen by CLRs leads to presentation of antigens on MHC class I and II molecules. DCs are well equipped to distinguish between self- and nonself-antigens by the variable expression of cell-surface receptors such as CLRs and TLRs. In the steady state, DCs are not immunologically quiescent but use their antigen-handling capacities to maintain peripheral tolerance. DCs are continuously sampling and presenting self- and harmless environmental proteins to silence immune activation. Uptake of self-components in the intestine and airways are good examples of sites where continuous presentation of self- and foreign antigens occurs without immune activation. In contrast, efficient antigen-specific immune activation occurs upon encounter of DCs with nonself-pathogens. Recognition of pathogens by DCs triggers specific receptors such as TLRs that result in DC maturation and subsequently immune activation. Here we discuss the concept that cross talk between TLRs and CLRs, differentially expressed by subsets of DCs, accounts for the different pathways to peripheral tolerance, such as deletion and suppression, and immune activation.

The generation of B-lymphocytes from hematopoietic stem cells is controlled by multiple transcription factors regulating distinct developmental aspects. Ikaros and PU.1 act in parallel pathways to control the development of lymphoid progenitors in part by regulating the expression of essential signaling receptors (Flt3, c-Kit, and IL-7Rα). The generation of the earliest B cell progenitors depends on E2A and EBF, which coordinately activate the B cell gene expression program and immunoglobulin heavy-chain gene rearrangements at the onset of B-lymphopoiesis. Pax5 restricts the developmental options of lymphoid progenitors to the B cell lineage by repressing the transcription of lineage-inappropriate genes and simultaneously activating the expression of B-lymphoid signaling molecules. LEF1 and Sox4 contribute to the survival and proliferation of pro-B cells in response to extracellular signals. Finally, IRF4 and IRF8 together control the termination of pre-B cell receptor signaling and thus promote differentiation to small pre-B cells undergoing light-chain gene rearrangements.

Ubiquitin (Ub)-protein conjugation represents a novel means of posttranscriptional modification in a proteolysis-dependent or -independent manner. E3 Ub ligases play a key role in governing the cascade of Ub transfer reactions by recognizing and catalyzing Ub conjugation to specific protein substrates. The E3s, which can be generally classified into HECT-type and RING-type families, are involved in the regulation of many aspects of the immune system, including the development, activation, and differentiation of lymphocytes, T cell–tolerance induction, antigen presentation, immune evasion, and virus budding. E3-promoted ubiquitination affects a wide array of biological processes, such as receptor downmodulation, signal transduction, protein processing or translocation, protein-protein interaction, and gene transcription, in addition to proteasome-mediated degradation. Deficiency or mutation of some of the E3s like Cbl, Cbl-b, or Itch, causes abnormal immune responses such as autoimmunity, malignancy, and inflammation. This review discusses our current understanding of E3 Ub ligases in both innate and adaptive immunity. Such knowledge may facilitate the development of novel therapeutic approaches for immunological diseases.

Understanding the molecular basis of lymphocyte homing to lymphoid organs was originally a problem of concern only to immunologists. With the discovery of l-selectin and its ligands, interested scientists have expanded to include glycobiologists, immunopathologists, cancer biologists, and developmental biologists. Going beyond its first discovered role in homing to lymph nodes, the l-selectin system is implicated in such diverse processes as inflammatory leukocyte trafficking in both acute and chronic settings, hematogenous metastasis of carcinoma cells, effector mechanisms for inflammatory demyelination of axons, and implantation of the early mammalian embryo. This review focuses on the ligands for l-selectin that are found on vascular endothelium, leukocytes, carcinoma cells, and at various extravascular sites. The discovery of selectins and their ligands has validated the long-predicted hypothesis that carbohydrate-directed cell adhesion is relevant in eukaryotic systems. Emphasis will be given to the carbohydrate and sulfation modifications of the ligands, which enable recognition by l-selectin.

The rapid “homing” of labeled cells into the lymph nodes presumably had its basis in the special affinity of small lymphocytes for the endothelium of the postcapillary venules.

    Gowans & Knight (1)

Integrin receptors mediate adhesive events that are critical for a specific and effective immune response to foreign pathogens. Integrin-dependent interactions of lymphocytes and antigen-presenting cells (APCs) to endothelium regulate the efficiency and specificity of trafficking into secondary lymphoid organs and peripheral tissue. Within these sites, integrins facilitate cell movement via interactions with the extracellular matrix, and promote and stabilize antigen-specific interactions between T lymphocytes and APCs that are critical for initiating T cell–activation events. In this review, we discuss the role of integrins in T cell–mediated immunity, with a focus on how these receptors participate in lymphocyte recirculation and T cell activation, how antigen stimulation regulates integrin activity, and how integrins define functionally unique subsets of T cells and APCs.

Mammals generate a diverse array of antimicrobial proteins, largely represented by defensins or cathelicidins. The direct in vitro microbicidal activity of antimicrobial proteins has long been considered an important innate immune defense, although the in vivo relevance has only very recently been established for certain defensins and cathelicidins. Mammalian defensins and cathelicidins have also been shown to have multiple receptor-mediated effects on immune cells. Beta-defensins interact with CCR6; murine β-defensin-2 in addition activates TLR4. Cathelicidins act on FPRL1-expressing cells. Furthermore, several defensins have considerable immunoenhancing activity. Thus, it appears that mammalian antimicrobial proteins contribute to both innate and adaptive antimicrobial immunity.

The gastrointestinal tract is the central organ for uptake of fluids and nutrients, and at the same time it forms the main protective barrier between the sterile environment of the body and the outside world. In mammals, the intestine has further evolved to harbor a vast load of commensal bacteria that have important functions for the host. Discrimination by the host defense system of nonself from self can prevent invasion of pathogens, but equivalent responses to dietary or colonizing bacteria can lead to devastating consequences for the organism. This dilemma imposed by the gut environment has probably contributed significantly to the evolutionary drive that has led to sophisticated mechanisms and diversification of the immune system to allow for protection while maintaining the integrity of the mucosal barrier. The immense expansion and specialization of the immune system is particularly mirrored in the phylogeny, ontogeny, organization, and regulation of the adaptive intraepithelial lymphocytes, or IEL, which are key players in the unique intestinal defense mechanisms that have evolved in mammals.

The twenty-first century is beginning with a sharp turn in the field of cancer therapy. Molecular targeted therapies against specific oncogenic events are now possible. The BCR-ABL story represents a notable example of how research from the fields of cytogenetics, retroviral oncology, protein phosphorylation, and small molecule chemical inhibitors can lead to the development of a successful molecular targeted therapy. Imatinib mesylate (Gleevec, STI571, or CP57148B) is a direct inhibitor of ABL (ABL1), ARG (ABL2), KIT, and PDGFR tyrosine kinases. This drug has had a major impact on the treatment of chronic myelogenous leukemia (CML) as well as other blood neoplasias and solid tumors with etiologies based on activation of these tyrosine kinases. Analysis of CML patients resistant to BCR-ABL suppression by Imatinib mesylate coupled with the crystallographic structure of ABL complexed to this inhibitor have shown how structural mutations in ABL can circumvent an otherwise potent anticancer drug. The successes and limitations of Imatinib mesylate hold general lessons for the development of alternative molecular targeted therapies in oncology.

Development of the acquired immune response is dependent on the signaling of CD40 by its ligand, CD154. These molecules govern both the magnitude and quality of humoral- and cell-mediated immunity. A litany of studies have conclusively documented that blockade of this ligand-receptor pair can prevent, and also intervene in, the progression of antibody- and cell-mediated autoimmune diseases, and can instill long-lived allogeneic and xenogeneic graft tolerance. Many effector mechanisms of inflammation are abolished as a result of CD154 blockade, but we are now beginning to understand that CD154 blockade may, in some instances, engender long-lived, antigen-specific tolerance. In the context of transplantation tolerance, we present a hypothesis that αCD154 blockade is most effective at inducing long-lived allospecific tolerance if anergy and regulation can be elicited prior to the onslaught of inflammation that is induced by grafting (preemptive tolerance). This facet of αCD154-induced tolerance appears to co-opt the normal processes of peripheral tolerance induced by immature DCs and can be exploited to induce long-lived antigen-specific tolerance. The underlying science and the prospects for inducing long-lived antigen-specific tolerance in a model of allograft tolerance through CD154 blockade are presented and discussed.

After a century of controversy, the notion that the immune system regulates cancer development is experiencing a new resurgence. An overwhelming amount of data from animal models—together with compelling data from human patients—indicate that a functional cancer immunosurveillance process indeed exists that acts as an extrinsic tumor suppressor. However, it has also become clear that the immune system can facilitate tumor progression, at least in part, by sculpting the immunogenic phenotype of tumors as they develop. The recognition that immunity plays a dual role in the complex interactions between tumors and the host prompted a refinement of the cancer immunosurveillance hypothesis into one termed “cancer immunoediting.” In this review, we summarize the history of the cancer immunosurveillance controversy and discuss its resolution and evolution into the three Es of cancer immunoediting—elimination, equilibrium, and escape.

The present review focuses on the concept that cellular and humoral immunity to the phylogenetically highly conserved antigen heat shock protein 60 (HSP60) is the initiating mechanism in the earliest stages of atherosclerosis. Subjecting arterial endothelial cells to classical atherosclerosis risk factors leads to the expression of HSP60 that then may serve as a target for pre-existent cross-reactive antimicrobial HSP60 immunity or bona fide autoimmune reactions induced by biochemically altered autologous HSP60. Endothelial cells can also bind microbial or autologous HSP60 via Toll-like receptors, providing another possibility for targetting adaptive or innate immunological effector mechanisms.

Natural killer (NK) cells play important roles in immunological processes, including early defense against viral infections. This review provides an overview of the dynamic in vivo life of NK cells from their development in the bone marrow to their mature peripheral responses and their ultimate demise, with particular emphasis on mouse NK cells and viral infections.

Complement has both beneficial and deleterious roles in the pathogenesis of systemic lupus erythematosus (SLE). On the one hand, patients with SLE present with decreased complement levels and with complement deposition in inflammed tissues, suggestive of a harmful role of complement in the effector phase of disease. On the other hand, homozygous deficiency of any of the classical pathway proteins is strongly associated with the development of SLE. There are two main hypotheses to explain these observations. The first invokes an important role for complement in the physiological waste-disposal mechanisms of dying cells and immune complexes. The second hypothesis is based around the role of complement in determining the activation thresholds of B and T lymphocytes, with the proposal that complement deficiency causes incomplete maintenance of peripheral tolerance. These two hypotheses are not mutually exclusive. In addition, there is evidence for a contribution from other genetic factors in determining the phenotype of disease in the absence of complement.

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.

Autoreactive antibodies are etiologic agents in a number of autoimmune diseases. Like all other antibodies these antibodies are produced in developing B cells by V(D)J recombination in the bone marrow. Three mechanisms regulate autoreactive B cells: deletion, receptor editing, and anergy. Here we review the prevalence of autoantibodies in the initial antibody repertoire, their regulation by receptor editing, and the role of the recombinase proteins (RAG1 and RAG2) in this process.

Cytokines are an integral component of the adaptive and innate immune responses. The signaling pathways triggered by the engagement of cytokines with their specific cell surface receptors have been extensively studied and have provided a profound understanding of the intracellular machinery that translates exposure of cells to cytokine to a coordinated biological response. It has also become clear that cells have evolved sophisticated mechanisms to prevent excessive responses to cytokines. In this review we focus on the suppressors of cytokine signaling (SOCS) family of cytoplasmic proteins that completes a negative feedback loop to attenuate signal transduction from cytokines that act through the janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. SOCS proteins inhibit components of the cytokine signaling cascade via direct binding or by preventing access to the signaling complex. The SOCS proteins also appear to target signal transducers for proteasomal destruction. Analyses of genetically modified mice in which SOCS proteins are overexpressed or deleted have established that this family of negative regulators has indispensable roles in regulating cytokine responses in cells of the immune system as well as other tissues. Emerging evidence also suggests that disruption of SOCS expression or activity is associated with several immune and inflammatory diseases, raising the prospect that manipulation of SOCS activity may provide a novel future therapeutic strategy in the management of immunological disorders.

Naturally occurring CD4⁺ regulatory T cells, the majority of which express CD25, are engaged in dominant control of self-reactive T cells, contributing to the maintenance of immunologic self-tolerance. Their depletion or functional alteration leads to the development of autoimmune disease in otherwise normal animals. The majority, if not all, of such CD25⁺CD4⁺ regulatory T cells are produced by the normal thymus as a functionally distinct and mature subpopulation of T cells. Their repertoire of antigen specificities is as broad as that of naive T cells, and they are capable of recognizing both self and nonself antigens, thus enabling them to control various immune responses. In addition to antigen recognition, signals through various accessory molecules and via cytokines control their activation, expansion, and survival, and tune their suppressive activity. Furthermore, the generation of CD25⁺CD4⁺ regulatory T cells in the immune system is at least in part developmentally and genetically controlled. Genetic defects that primarily affect their development or function can indeed be a primary cause of autoimmune and other inflammatory disorders in humans. Based on recent advances in our understanding of the cellular and molecular basis of this T cell–mediated immune regulation, this review discusses how naturally arising CD25⁺CD4⁺ regulatory T cells contribute to the maintenance of immunologic self-tolerance and negative control of various immune responses, and how they can be exploited to prevent and treat autoimmune disease, allergy, cancer, and chronic infection, or establish donor-specific transplantation tolerance.

Cells of the immune system carry out diverse functions that are controlled by surface receptors for antigen, costimulatory molecules, cytokines, chemokines, and other ligands. A shared feature of signal transduction downstream of most receptors on immune cells, as in nonhematopoietic cell types, is the activation of phosphoinositide 3-kinase (PI3K). The mechanism by which this common signaling event is elicited by distinct receptors and contributes to unique functional outcomes is an intriguing puzzle. Understanding how specificity is achieved in PI3K signaling is of particular significance because altered regulation of this pathway is observed in many disease states, including leukemia and lymphoma. Here we review recent advances in the understanding of PI3K signaling mechanisms in different immune cells and receptor systems. We emphasize the concept that PI3K and its products are components of complex networks of interacting proteins and second messengers, rather than simple links in linear signaling cascades.

Only 5 to 10% of immunocompetent humans are susceptible to tuberculosis, and over 85% of them develop the disease exclusively in the lungs. Human immunodeficiency virus (HIV)-infected humans, in contrast, can develop systemic disease that is more quickly lethal. This is in keeping with other evidence showing that susceptible humans generate some level of Th1 immunity to Mycobacterium tuberculosis (Mtb) infection. Tuberculosis in mice is also exclusively a lung disease that is progressive and lethal, in spite of the generation of Th1-mediated immunity. Thus mouse tuberculosis is a model of tuberculosis in susceptible humans, as is tuberculosis in guinea pigs and rabbits. Inability to resolve infection and prevent disease may not be a consequence of the generation of an inadequate number of Th1 cells but of an intrinsic deficiency in macrophage function that prevents these cells from expressing immunity. If this proves to be true, vaccinating susceptible humans against tuberculosis will be a difficult task.