Dendritic cells in allergy

Evolution has provided two distinct and highly sophisticated defense mechanisms to human beings for survival in a hostile environment. The innate immune system is aimed to react rapidly (from within minutes to a few hours) and in a rather simple way with little variation to attacks of pathogens. In contrast, the acquired immune system provides a more adaptive and highly specific defense response to foreign structures. In addition, it has the unique ability to induce tolerance of self-structures. The mechanisms of acquired immunity involve several steps of recognition and reactions in which various different cell types are engaged. Among antigen-presenting cells (APC), dendritic cells (DC) fulfill a pivotal function by providing information about invading pathogens under optimal conditions to other partners (e.g., effector cells) of the immune system. Thus, after having been neglected for years, DC research is experiencing a revival due to the central role of these cells in the complex machinery of the adaptive immune response. Moreover, understanding the role DC play in pathophysiologic conditions may be a key step in developing treatment strategies for several disease entities. Since many different DC types have been identified during the last years, including follicular DC and thymic DC, the present review will focus on the “classical” DC as they have been described initially by Steinman and Cohn. The first member of the DC system was described more than 100 years ago by Paul Langerhans (1868) and was originally thought to be a type of cutaneous nerve cell. After it had then been considered for a time to be an immature melanocyte, Birbeck (1) described the unique ultrastructural feature of the Langerhans cell (LC), which was named after him. Birbeck granules (BG) are rod-shaped structures with a central, periodically striated lamella and, depending on the section viewed, are tennis-racket shaped. BG are found exclusively in LC from man and other mammals, but not in other DC. They are considered the primary marker of epidermal LC. Nowadays, LC are best recognized in the skin by their CD1a expression. In the 1970s, Steinman & Cohn first described the structure and function of DC from mouse spleen suspensions (2). Morphologically, DC are characterized by their numerous thin, elongate cytoplasmic processes, which give them a veil-like appearance. They exhibit features of metabolically active cells with scattered mitochondria; a recognizable Golgi apparatus; some lysosomes, phagolysosomes, and lipid droplets; and a well-developed endoplasmic reticulum. They have large and often indented nuclei with heterochromatin preferentially deposited at the nuclear membrane (3). DC have been found in virtually all types of epithelia (skin, mucous membranes, lung) and as interstitial DC in the heart and kidney as well as in other organs. In addition, various subtypes of DC were also discovered in blood and in the lymphatic system (4). These represent different stages of maturation and are connected by circulatory pathways. Beside their typical dendritic structure in tissue and in suspension, DC were initially characterized mainly by their high expression of major histocompatibility complex (MHC) class II HLA-DR and their high stimulatory activity toward allogeneic T cells. Although they ultimately act as highly specialized APC, DC have to undergo four main stages of differentiation and maturation before they fulfill their main function in the lymphoid organs. Since the first demonstration that epidermal LC are derived from bone-marrow cells by Katz et al. (5), many efforts have been made to characterize the precursor cells of DC and LC in bone marrow and blood (Fig. 1). Thus, the ontogenesis and the development of techniques for in vitro generation of DC have been the focus in this field of research, especially considering possible therapeutic implications (see below). Ontogenesis of dendritic cells (DC). Before being able to activate naive T cells (Tn) (primary immune response), DC must undergo profound maturation step which occurs during their migration to regional lymph nodes. In peripheral tissue, DC may also trigger secondary immune response when encountering memory T cells (Tm) in transit through tissue. Although it is well established that DC derive from bone-marrow CD34+ stem cells, two main strategies have been followed over the past years. First, in 1992, Caux et al. described a system that generates CD1a+ LC-like DC from CD34+ stem cells by supplementing granulocyte/macrophage colony stimulating factor (GM-CSF) and tumor-necrosis factor alpha (TNF-α) (6). The generation of LC/DC was optimized later by adding stem cell factor (SCF) and/or FLT-3 ligand, resulting in a higher yield of CD1a+ cells, with a typical dendritic structure, strong expression of MHC class II antigens, CD4, CD40, CD54, CD58, CD80, CD83, and CD86, and the presence of BG in 10–20% of the cells. Most importantly, these cells exhibit a potent capacity to stimulate the proliferation of naive T cells and to present soluble antigens to clones of CD4+ T cells. On the other hand, in 1994, Sallusto & Lanzavecchia (7) were able to generate CD1a+ DC corresponding to interstitial DC in their phenotype by culturing monocytes with GM-CSF and interleukin (IL)-4. CD14+ monocytes undergo maturation into CD1a+ DC, which, however, lack BG and are therefore not considered LC but are more similar to dermal DC since they express CD11b, CD68, and the coagulation factor XIIIa. Typically, after 7 days of culture with GM-CSF and IL-4, monocytes give rise to immature DC which need further stimulation with CD40 ligand, endotoxin, or TNF-α to reach the full maturation stage of highly stimulatory DC. However, if monocytes are cultured with macrophage colony stimulating factor (M-CSF) alone, they differentiate into macrophage-like cells (CD14+, CD1a−, CD83−) and synthesize IL-10 (8). While these DC are now classified as myeloid DC because they are known to derive from myeloid precursors (see below), more recently, a novel type of so-called lymphoid DC has been described. These lymphoid DC derive from CD4+/CD3−/CD11c− plasmocytoid cells from the blood and the tonsils (9, 10). These precursors do not differentiate into macrophages with GM-CSF or M-CSF. Lymphoid DC are dependent on IL-3, but not on GM-CSF, and are less active in phagocytosis. When localized in peripheral blood or in nonlymphoid tissue, DC are considered to be functionally immature. This refers to the fact that DC in tissues are highly specialized for capturing and processing foreign or autologous protein antigens or haptens. Uptake of high-molecular-weight antigens by DC may occur through macropinocytosis or more specifically through a number of membrane receptors such as FcγRII and FcεRI loaded with the adequate antibodies. DC also express membrane receptors bearing multiple lectin domains such as the mannose receptor and the DEC-205 molecule(11). These structures enable DC to internalize antigens by receptor-mediated endocytosis, a pathway which leads to antigen uptake into specialized compartments inside DC and allows efficient processing and subsequent loading of these antigens on MHC class II molecules. In contrast, uptake of low-molecular-weight haptens, e.g., DNCB or oxazolone (12, 13), mostly occurs via binding to surface glycoproteins and subsequent internalization. Experiments with MHC knockout mice suggest that presentation of such haptens is achieved through MHC class I molecules to CD8+ T cells rather than via MHC class II. A further characteristic of DC is the high stability of MHC class I or class II molecules on their cell surface, allowing them to be loaded for a long time with defined antigens. At this stage of maturation, DC are able to stimulate memory T cells trafficking through the tissue, initiating a secondary immune response at the site of contact with the captured antigen. However, since macrophages and other cells are as efficient as DC in this type of stimulatory activity, it is assumed that triggering a secondary immune response is not the primary task of DC under normal conditions. In recent years, it has become clear that the migration of many cell types including DC is tightly regulated by chemokines. The expression of chemokines at different anatomic sites and in different pathologic states in combination with the differential expression of chemokine receptors on cells during different maturation stages is the basis of a complex signaling network that orchestrates cell migration and cell interaction in the immune response (14). Specifically for DC, it has been shown that the chemokine receptor profile expressed on immature DC (CCR1, CCR2, CCR5, and CCR6) mainly recognizes chemokines that are released during inflammatory processes. This allows the accumulation of DC that are geared toward antigen uptake at sites of inflammation. Release of cytokines such as IL-1 and TNF-α further perpetuates this process by inducing immature DC to release even more inflammatory chemokines. Conversely, mature DC downregulate their receptors for inflammatory chemokines and express different chemokine receptors (CCR4, CCR7, CXCR4, SLC, and ELC). These allow them to receive signals which will attract them to the regional lymphatics and eventually to the T-cell-rich areas of the lymph node. Thus, after antigen uptake, tissue DC migrate to the regional lymph nodes. For example, LC seem to be able to migrate quite fast; i.e., several millimeters within 30 min (15). On their way to the lymph node, DC begin a profound metamorphosis, leading to significant changes in their structure and phenotype. In the afferent lymphatic vessels, DC have been described as so-called veiled cells and as interdigitating cells in the T-cell-rich paracortical zones of secondary lymphoid tissues. As DC mature, they lose their antigen uptake capacity and their function shifts toward antigen presentation. One of the hallmarks of this development is the upregulation of peptide-loaded MHC class II and costimulatory molecules (CD80, CD86) on the surface of these cells. In the meantime, DC rapidly downregulate and sometimes completely abolish the expression of Fc receptors. Migration and maturation of DC seem to be linked processes in vivo since factors such as lipopolysaccharides (LPS), TNF-α, and IL-1 induce both processes In TNF-α has been shown to induce maturation of DC, also leading to upregulation of CD80, CD86, CD83, and MHC class II. these molecules are for efficient antigen presentation to naive T cells. of naive T cells is of the that DC have to do DC and naive T cells have to in the paracortical of the lymph nodes. was the fact that naive T cells express chemokine receptors (e.g., that allow them to receive the signals by mature DC which release and chemokines After having the a DC of naive T cells. In this to MHC class II or MHC class I on DC are to T cells via the receptor complex it clear in to the signals via the costimulatory signals are of key in initiating and a response. of the costimulatory molecules and with their on T cells, i.e., or this stimulation will in an proliferation of T cells or factors present at the site of interaction such as IL-10 may signaling by in leading to tolerance was that DC release This is in the of a response. other cytokines such as may induce a has been shown to the response toward This capacity to the type of response may some antigens induce an and do is that the cytokines and factors released during also induce a different chemokine receptor on T cells. cells express CCR2, CCR5, and cells are characterized by the expression of CCR2, and (14). The differential expression may these cells to specific types of and which other cell types may be in a inflammatory response. 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This leads to the of both CD4+ and CD8+ T cells reactions are by CD4+ effector cells, contact is by CD8+ effector cells cytokines released during the process have been in the type of immune response by T cells. has been shown that IL-10 LC/DC from potent of a primary immune response to cells. A significant in signals for and TNF-α the role of this in contact reactions On the other hand, which is released by and by DC is known as a strong of the response. After a contact with a contact memory T cells be by DC or by less potent than DC (e.g., macrophages or and, due to their specific an immune response at the anatomic is characterized by major i.e., and and is with Thus, it is assumed that mechanisms e.g., of and are of in specific may play a role in the of these conditions. 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While it clear that by DC is mainly for the to it was a of which cells may be the of IL-4, which shifts response to the et al. some that may be the which cells to the type recently, et al. have shown that myeloid DC are for T cells into to as lymphoid DC T cells into in an way to as (Fig. Moreover, mechanisms are these DC and T cells. of the mechanisms of stimulation by lymphoid or other and/or costimulatory will understanding of has the immune system to an of immune types of dendritic cells and DC types seem to derive from different and are to and has been that and myeloid express the receptor for lymphoid this structure has not been The FcεRI on LC and several from this receptor on effector cells of i.e., cells and it is not expressed on these cells but to be regulated by signals of the inflammatory the cells. 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