Showing papers in "Nature Immunology in 2001"

Toll-like receptors: critical proteins linking innate and acquired immunity.

Abstract: Recognition of pathogens is mediated by a set of germline-encoded receptors that are referred to as pattern-recognition receptors (PRRs). These receptors recognize conserved molecular patterns (pathogen-associated molecular patterns), which are shared by large groups of microorganisms. Toll-like receptors (TLRs) function as the PRRs in mammals and play an essential role in the recognition of microbial components. The TLRs may also recognize endogenous ligands induced during the inflammatory response. Similar cytoplasmic domains allow TLRs to use the same signaling molecules used by the interleukin 1 receptors (IL-1Rs): these include MyD88, IL-1R--associated protein kinase and tumor necrosis factor receptor--activated factor 6. However, evidence is accumulating that the signaling pathways associated with each TLR are not identical and may, therefore, result in different biological responses.

Nitric oxide and the immune response

Abstract: During the past two decades, nitric oxide (NO) has been recognized as one of the most versatile players in the immune system. It is involved in the pathogenesis and control of infectious diseases, tumors, autoimmune processes and chronic degenerative diseases. Because of its variety of reaction partners (DNA, proteins, low–molecular weight thiols, prosthetic groups, reactive oxygen intermediates), its widespread production (by three different NO synthases (NOS) and the fact that its activity is strongly influenced by its concentration, NO continues to surprise and perplex immunologists. Today, there is no simple, uniform picture of the function of NO in the immune system. Protective and toxic effects of NO are frequently seen in parallel. Its striking inter- and intracellular signaling capacity makes it extremely difficult to predict the effect of NOS inhibitors and NO donors, which still hampers therapeutic applications.

PD-L2 is a second ligand for PD-1 and inhibits T cell activation

Abstract: Programmed death I (PD-I)-deficient mice develop a variety of autoimmune-like diseases, which suggests that this immunoinhibitory receptor plays an important role in tolerance. We identify here PD-1 ligand 2 (PD-L2) as a second ligand for PD-1 and compare the function and expression of PD-L1 and PD-L2. Engagement of PD-1 by PD-L2 dramatically inhibits T cell receptor (TCR)-mediated proliferation and cytokine production by CD4+ T cells. At low antigen concentrations, PD-L2-PD-1 interactions inhibit strong B7-CD28 signals. In contrast, at high antigen concentrations, PD-L2-PD-1 interactions reduce cytokine production but do not inhibit T cell proliferation. PD-L-PD-1 interactions lead to cell cycle arrest in G0/G1 but do not increase cell death. In addition, ligation of PD-1 + TCR leads to rapid phosphorylation of SHP-2, as compared to TCR ligation alone. PD-L expression was up-regulated on antigen-presenting cells by interferon gamma treatment and was also present on some normal tissues and tumor cell lines. Taken together, these studies show overlapping functions of PD-L1 and PD-L2 and indicate a key role for the PD-L-PD-1 pathway in regulatingT cell responses.

Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria.

Abstract: Penetration of the gut mucosa by pathogens expressing invasion genes is believed to occur mainly through specialized epithelial cells, called M cells, that are located in Peyer's patches. However, Salmonella typhimurium that are deficient in invasion genes encoded by Salmonella pathogenicity island 1 (SPI1) are still able to reach the spleen after oral administration. This suggests the existence of an alternative route for bacterial invasion, one that is independent of M cells. We report here a new mechanism for bacterial uptake in the mucosa tissues that is mediated by dendritic cells (DCs). DCs open the tight junctions between epithelial cells, send dendrites outside the epithelium and directly sample bacteria. In addition, because DCs express tight-junction proteins such as occludin, claudin 1 and zonula occludens 1, the integrity of the epithelial barrier is preserved.

Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide.

Abstract: Despite accumulating evidence that regulatory T cells play a crucial role in preventing autoimmunity, the processes underlying their generation during immune repertoire formation are unknown. We show here that interactions with a single self-peptide can induce thymocytes that bear an autoreactive T cell receptor (TCR) to undergo selection to become CD4+CD25+ regulatory T cells. Selection of CD4+CD25+ thymocytes appears to require a TCR with high affinity for a self peptide because thymocytes that bear TCRs with low affinity do not undergo selection into this pathway. Our findings indicate that specificity for self-peptides directs the selection of CD4+CD25+ regulatory thymocytes by a process that is distinct from positive selection and deletion.

Toll-like receptors control activation of adaptive immune responses.

Abstract: Mechanisms that control the activation of antigen-specific immune responses in vivo are poorly understood. It has been suggested that the initiation of adaptive immune responses is controlled by innate immune recognition. Mammalian Toll-like receptors play an essential role in innate immunity by recognizing conserved pathogen-associated molecular patterns and initiating the activation of NF-κB and other signaling pathways through the adapter protein, MyD88. Here we show that MyD88-deficient mice have a profound defect in the activation of antigen-specific T helper type 1 (TH1) but not TH2 immune responses. These results suggest that distinct pathways of the innate immune system control activation of the two effector arms of adaptive immunity.

Chemokines and disease.

Abstract: We examine here several diseases that are associated with inappropriate activation of the chemokine network. Detailed comment has been restricted to pathological states for which there are compelling data either from clinical observations or animal models. These include cardiovascular disease, allergic inflammatory disease, transplantation, neuroinflammation, cancer and HIV-associated disease. Discussion focuses on therapeutic directions in which the rapidly evolving chemokine field appears to be headed.

Lipid mediator class switching during acute inflammation: signals in resolution

Abstract: Leukotrienes (LTs) and prostaglandins (PGs) amplify acute inflammation, whereas lipoxins (LXs) have unique anti-inflammatory actions. Temporal analyses of these eicosanoids in clinical and experimental exudates showed early coordinate appearance of LT and PG with polymorphonuclear neutrophil (PMN) recruitment. This was followed by LX biosynthesis, which was concurrent with spontaneous resolution. Human peripheral blood PMNs exposed to PGE2 (as in exudates) switched eicosanoid biosynthesis from predominantly LTB4 and 5-lipoxygenase (5-LO)-initiated pathways to LXA4, a 15-LO product that "stopped" PMN infiltration. These results indicate that first-phase eicosanoids promote a shift to anti-inflammatory lipids: functionally distinct lipid-mediator profiles switch during acute exudate formation to "reprogram" the exudate PMNs to promote resolution.

Memory CD8+ T cell differentiation: initial antigen encounter triggers a developmental program in naïve cells.

Abstract: The rules that govern memory T cell differentiation are not well understood. This study shows that after antigenic stimulation naive CD8+ T cells become committed to dividing at least seven times and differentiating into effector and memory cells. Once the parental naive CD8+ T cell had been activated, this developmental process could not be interrupted and the daughter cells continued to divide and differentiate in the absence of further antigenic stimulation. These data indicate that initial antigen encounter triggers an instructive developmental program that does not require further antigenic stimulation and does not cease until memory CD8+ T cell formation.

Pulmonary dendritic cells producing IL-10 mediate tolerance induced by respiratory exposure to antigen.

Abstract: Respiratory exposure to allergen induces T cell tolerance and protection against the development of airway hyperreactivity and asthma. However, the specific mechanisms by which tolerance is induced by respiratory allergen are not clear. We report here that pulmonary dendritic cells (DCs) from mice exposed to respiratory antigen transiently produced interleukin 10 (IL-10). These phenotypically mature pulmonary DCs, which were B-7hi as well as producing IL-10, stimulated the development of CD4+ T regulatory 1–like cells that also produced high amounts of IL-10. In addition, adoptive transfer of pulmonary DCs from IL-10+/+, but not IL-10−/−, mice exposed to respiratory antigen induced antigen-specific unresponsiveness in recipient mice. These studies show that IL-10 production by DCs is critical for the induction of tolerance, and that phenotypically mature pulmonary DCs mediate tolerance induced by respiratory exposure to antigen.

Regulatory T cells in the control of immune pathology.

Abstract: It is now well established that regulatory T (T(R)) cells can inhibit harmful immunopathological responses directed against self or foreign antigens. However, many key aspects of T(R) cell biology remain unresolved, especially with regard to their antigen specificities and the cellular and molecular pathways involved in their development and mechanisms of action. We will review here recent findings in these areas, outline a model for how T(R) cells may inhibit the development of immune pathology and discuss potential therapeutic benefits that may arise from the manipulation of T(R) cell function.

Sex differences in autoimmune disease

Abstract: Autoimmune diseases are more prevalent in women than men. A new interest in understanding the biology of this difference as well as funding opportunities have focused attention on research priorities in sex differences.

Lymphocyte traffic control by chemokines.

Abstract: In contrast to the remarkable chemokine responses of phagocytes and monocytes that were documented early on, lymphocytes have been considered for a long time to be poor targets for chemokine action. This view has changed dramatically with the discovery that peripheral blood T cells need to be activated before they can migrate in response to inflammatory chemokines. These chemokines do not act on the bulk of resting T cells that are in circulation. The identification of a new group of chemokines that selects resting, as opposed to effector, T and B cells was very exciting. These inflammation-unrelated chemokines affect transendothelial migration and localization of progenitor and mature lymphocytes in lymphoid and nonlymphoid tissues. Here, we summarize the current view of chemokine-mediated lymphocyte traffic and focus on the molecular mechanisms by which T cell responses to chemokines are modulated. Recent developments in this area justify the hypothesis that the distinct migration patterns of lymphocytes throughout their life cycle--that is, during lymphopoiesis, antigen-dependent priming, inflammation and immune surveillance--are finely tuned by changing sets of chemokines that are selective for developmentally regulated chemokine receptors. Thus, the chemokine system assures that cell traffic during inflammatory responses occurs in the proper spatial and temporal fashion and disturbance of this system, therefore, can lead to inflammatory disease.

Mouse type I IFN-producing cells are immature APCs with plasmacytoid morphology.

Abstract: We show here that mouse interferon-alpha (IFN-alpha)-producing cells (mIPCs) are a unique subset of immature antigen-presenting cells (APCs) that secrete IFN-alpha upon stimulation with viruses. mIPCs have a plasmacytoid morphology, can be stained with an antibody to Ly6G and Ly6C (anti-Ly6G/C) and are Ly6C+B220+CD11cloCD4+; unlike other dendritic cell subsets, however, they do not express CD8alpha or CD11b. Although mIPCs undergo apoptosis in vitro, stimulation with viruses, IFN-alpha or CpG oligonucleotides enhanced their survival and T cell stimulatory activity. In vivo, mIPCs were the main producers of IFN-alpha in cytomegalovirus-infected mice, as depletion of Ly6G+/C+ cells abrogated IFN-alpha production. mIPCs produced interleukin 12 (IL-12) in response to viruses and CpG oligodeoxynucleotides, but not bacterial products. Although different pathogens can selectively engage various APC subsets for IL-12 production, IFN-alpha production is restricted to mIPCs' response to viral infection.

Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self.

Abstract: Expression of peripheral antigens in the thymus has been implicated in T cell tolerance and autoimmunity. Here we identified medullary thymic epithelial cells as being a unique cell type that expresses a diverse range of tissue-specific antigens. We found that this promiscuous gene expression was a cell-autonomous property of medullary epithelial cells and was maintained during the entire period of thymic T cell output. It may facilitate tolerance induction to self-antigens that would otherwise be temporally or spatially secluded from the immune system. However, the array of promiscuously expressed self-antigens appeared random rather than selected and was not confined to secluded self-antigens.

TIRAP: an adapter molecule in the Toll signaling pathway.

Abstract: Mammalian Toll-like receptors (TLRs) recognize conserved products of microbial metabolism and activate NF-kappa B and other signaling pathways through the adapter protein MyD88. Although some cellular responses are completely abolished in MyD88-deficient mice, TLR4, but not TLR9, can activate NF-kappa B and mitogen-activated protein kinases and induce dendritic cell maturation in the absence of MyD88. These differences suggest that another adapter must exist that can mediate MyD88-independent signaling in response to TLR4 ligation. We have identified and characterized a Toll-interleukin 1 receptor (TIR) domain-containing adapter protein (TIRAP) and have shown that it controls activation of MyD88-independent signaling pathways downstream of TLR4. We have also shown that the double-stranded RNA-binding protein kinase PKR is a component of both the TIRAP- and MyD88-dependent signaling pathways.

Costimulation of CD8alphabeta T cells by NKG2D via engagement by MIC induced on virus-infected cells.

Abstract: NKG2D is an activating receptor that stimulates innate immune responses by natural killer cells upon engagement by MIC ligands, which are induced by cellular stress. Because NKG2D is also present on most CD8αβ T cells, it may modulate antigen-specific T cell responses, depending on whether MIC molecules—distant homologs of major histocompatibility complex (MHC) class I with no function in antigen presentation—are induced on the surface of pathogen-infected cells. We found that infection by cytomegalovirus (CMV) resulted in substantial increases in MIC on cultured fibroblast and endothelial cells and was associated with induced MIC expression in interstitial pneumonia. MIC engagement of NKG2D potently augmented T cell antigen receptor (TCR)-dependent cytolytic and cytokine responses by CMV-specific CD28− CD8αβ T cells. This function overcame viral interference with MHC class I antigen presentation. Combined triggering of TCR-CD3 complexes and NKG2D induced interleukin 2 production and T cell proliferation. Thus NKG2D functioned as a costimulatory receptor that can substitute for CD28.

Naïve CTLs require a single brief period of antigenic stimulation for clonal expansion and differentiation

Abstract: In defense of the host, the immune system must often raise an effective cytotoxic T lymphocyte (CTL) response from a small number of clonal precursors. The degree to which activation stimuli regulate the expansion and differentiation of naive CTLs, however, remains unknown. Using an engineered antigen-presenting cell (APC) system that allows control over antigenic stimulation, we studied the signaling duration requirements for priming and clonal expansion of naive CTLs. We found that naive CTLs become committed after as little as 2 h of exposure to APCs and that their subsequent division and differentiation can occur without the need for further antigenic stimulation of the daughter cells, whether priming is in vitro or in vivo. These data show that after a brief interaction with stimulatory APCs, naive CTLs initiate a program for their autonomous clonal expansion and development into functional effectors.

B7-H3: A costimulatory molecule for T cell activation and IFN-γ production

Abstract: We describe here a newly identified member of the human B7 family, designated B7 homolog 3 (B7-H3), that shares 20-27% amino acid identity with other B7 family members. B7-H3 mRNA is not detectable in peripheral blood mononuclear cells, although it is found in various normal tissues and in several tumor cell lines. Expression of B7-H3 protein, however, can be induced on dendritic cells (DCs) and monocytes by inflammatory cytokines and a combination of phorbol myristate acetate (PMA) + ionomycin. Soluble B7-H3 protein binds a putative counter-receptor on activated T cells that is distinct from CD28, cytotoxic T lymphocyte antigen 4 (CTLA-4), inducible costimulator (ICOS) and PD-1. B7-H3 costimulates proliferation of both CD4+ and CD8+ T cells, enhances the induction of cytotoxic T cells and selectively stimulates interferon gamma (IFN-gamma) production in the presence of T cell receptor signaling. In contrast, inclusion of antisense B7-H3 oligonucleotides decreases the expression of B7-H3 on DCs and inhibits IFN-gamma production by DC-stimulated allogeneic T cells.Thus, we describe a newly identified costimulatory pathway that may participate in the regulation of cell-mediated immune responses.

Chemokines: immunology's high impact factors.

Abstract: Chemokines facilitate leukocyte migration and positioning as well as other processes such as angiogenesis and leukocyte degranulation. The burgeoning knowledge on chemokines and their receptors has influenced many aspects of immunology, in part because cell migration is intimately related to leukocyte function. This overview assesses the impact that chemokines have had on our understanding of immunology and infectious diseases. These include the role of chemokines in leukocyte–endothelial cell interactions; dendritic cell function; T cell differentiation and function; inflammatory diseases; mucosal and subcutaneous immunity; and subversion of immune responses by viruses, including HIV-1. This knowledge heralds new opportunities for the manipulation of immune responses and the development of new anti-inflammatory therapies. It has also provided a new perspective on the functioning of the immune system.

A fresh look at tumor immunosurveillance and immunotherapy

Abstract: Despite major advances in our understanding of adaptive immunity and dendritic cells, consistent and durable responses to cancer vaccines remain elusive and active immunotherapy is still not an established treatment modality. The key to developing an effective anti-tumor response is understanding why, initially, the immune system is unable to detect transformed cells and is subsequently tolerant of tumor growth and metastasis. Ineffective antigen presentation limits the adaptive immune response; however, we are now learning that the host's innate immune system may first fail to recognize the tumor as posing a danger. Recent descriptions of stress-induced ligands on tumor cells recognized by innate effector cells, new subsets of T cells that regulate tumor tolerance and the development of spontaneous tumors in mice that lack immune effector molecules, beckon a reflection on our current perspectives on the interaction of transformed cells with the immune system and offer new hope of stimulating therapeutic immunity to cancer.

Sonic hedgehog induces the proliferation of primitive human hematopoietic cells via BMP regulation

Abstract: A pool of stem cells that arise from the mesoderm during embryogenesis initiates hematopoiesis. However, factors that regulate the expansion of blood stem cells are poorly understood. We show here that cytokine-induced proliferation of primitive human hematopoietic cells could be inhibited with antibodies to hedgehog (Hh). Conversely, Sonic hedgehog (Shh) treatment induced the expansion of pluripotent human hematopoietic repopulating cells detected in immunodeficient mice. Noggin, a specific inhibitor of bone morphogenetic protein 4 (BMP-4), was capable of inhibiting Shh-induced proliferation in a similar manner to anti-Hh; however, anti-Hh had no effect on BMP-4–induced proliferation. Our study shows that Shh functions as a regulator of primitive hematopoietic cells via mechanisms that are dependent on downstream BMP signals.

Chemokines as regulators of T cell differentiation

Abstract: Chemokines play well established roles as attractants of naive and effector T cells. New studies indicate that chemokines also have roles in regulating T cell differentiation. Blocking Gi protein-coupled receptor signaling by pertussis toxin as well as deficiencies in G alpha 12, chemokine receptor 2 (CCR2), CCR5, chemokine ligand 2 (CCL2, also known as monocyte chemoattractant protein 1, or MCP-1), CCL3 (macrophage inflammatory protein 1 alpha, or MIP-1 alpha) and CCL5 (RANTES) have all been found to have effects on the magnitude and cytokine polarity of the T cell response. Here we focus on findings in the CCL2-CCR2 and CCL3-CCR5 ligand-receptor systems. The roles of these molecules in regulating T cell fate include possible indirect effects on antigen-presenting cells and direct effects on differentiating T cells. Models to account for the action of chemokines and G protein-coupled receptor signals in regulating T cell differentiation are discussed.

Leptospiral lipopolysaccharide activates cells through a TLR2-dependent mechanism.

Abstract: Leptospira interrogans are zoonotic pathogens that have been linked to a recent increased incidence of morbidity and mortality in highly populated tropical urban centers. They are unique among invasive spirochetes in that they contain outer membrane lipopolysaccharide (LPS) as well as lipoproteins. Here we show that both these leptospiral outer membrane constituents activate macrophages through CD14 and the Toll-like receptor 2 (TLR2). Conversely, it seems that TLR4, a central component for recognition of Gram-negative LPS, is not involved in cellular responses to L. interrogans. We also show that for intact L. interrogans, it is LPS, not lipoprotein, that constitutes the predominant signaling component for macrophages through a TLR2 pathway. These data provide a basis for understanding the innate immune response caused by leptospirosis and demonstrate a new ligand specificity for TLR2.

Dermcidin: a novel human antibiotic peptide secreted by sweat glands.

Abstract: Antimicrobial peptides are an important component of the innate response in many species. Here we describe the isolation of the gene Dermcidin, which encodes an antimicrobial peptide that has a broad spectrum of activity and no homology to other known antimicrobial peptides. This protein was specifically and constitutively expressed in the sweat glands, secreted into the sweat and transported to the epidermal surface. In sweat, a proteolytically processed 47–amino acid peptide was generated that showed antimicrobial activity in response to a variety of pathogenic microorganisms. The activity of the peptide was maintained over a broad pH range and in high salt concentrations that resembled the conditions in human sweat. This indicated that sweat plays a role in the regulation of human skin flora through the presence of an antimicrobial peptide. This peptide may help limit infection by potential pathogens in the first few hours following bacterial colonization.

Dancing to the tune of chemokines.

Abstract: Since their discovery 13 years ago, chemokines have emerged as the most important regulators of leukocyte trafficking. On target cells, chemokines bind to seven-transmembrane-domain receptors that are coupled to heterotrimeric Gi proteins. The common response of all cells to chemokine stimulation is chemotaxis. In addition, leukocyte activation triggers diverse signal transduction cascades; which cascade is triggered depends on the chemokine and receptor engaged. The selective activation of distinct pathways suggests that the receptors couple not only to G proteins but also to additional downstream effectors. This review discusses recent advances in the elucidation of the signal transduction that occurs in proximity to receptors and that leads to the early biochemical events in leukocyte activation.

Multiple sclerosis: a two-stage disease

Abstract: The pathogenesis of multiple sclerosis consists of an inflammatory and neurodegnerative phase. Better understanding of these stages has aided the development of specific therapeutic targets.

Dendritic cell lineage, plasticity and cross-regulation

Abstract: Dendritic cells (DCs) are professional antigen-presenting cells that have an extraordinary capacity to stimulate naive T cells and initiate primary immune responses. Here we review progress in understanding the additional functions of DCs in regulating the types of T cell-mediated immune responses and innate immunity to microbes. In addition, evidence for the existence of myeloid and lymphoid DC lineages and their different functions are summarized. We propose that the diverse functions of DCs in immune regulation are dictated by the instructions they received during innate immune responses to different pathogens and from their evolutionary lineage heritage.

Systemic lupus erythematosus: an autoimmune disease of B cell hyperactivity.

Abstract: B cells can regulate many aspects of immune reactivity, as well as differentiate into antibody-producing cells. In SLE, a systemic autoimmune disease, recent research suggests enhanced B cell function is the defining pathogenic event.

Collaboration of epithelial cells with organized mucosal lymphoid tissues

Abstract: Immune surveillance of mucosal surfaces requires the delivery of intact macromolecules and microorganisms across epithelial barriers to organized mucosal lymphoid tissues. Transport, processing and presentation of foreign antigens, as well as local induction and clonal expansion of antigen-specific effector lymphocytes, involves a close collaboration between organized lymphoid tissues and the specialized follicle-associated epithelium. M cells in the follicle-associated epithelium transport foreign macromolecules and microorganisms to antigen-presenting cells within and under the epithelial barrier. Determination of the earliest cellular interactions that occur in and under the follicle-associated epithelium could greatly facilitate the design of effective mucosal vaccines in the future.