This study identifies a dendritic cell (DC) subset that constitutively transports apoptotic intestinal epithelial cell remnants to T cell areas of mesenteric lymph nodes in vivo. Rat intestinal lymph contains two DC populations. Both populations have typical DC morphology, are major histocompatibility complex class IIhi, and express OX62, CD11c, and B7. CD4+/OX41+ DCs are strong antigen-presenting cells (APCs). CD4−/OX41− DCs are weak APCs and contain cytoplasmic apoptotic DNA, epithelial cell–restricted cytokeratins, and nonspecific esterase (NSE)+ inclusions, not seen in OX41+ DCs. Identical patterns of NSE electrophoretic variants exist in CD4−/OX41− DCs, intestinal epithelial cells, and mesenteric node DCs but not in other DC populations, macrophages, or tissues. Terminal deoxynucleotidyl transferase–mediated dUTP-biotin nick-end labeling (TUNEL)-positive DCs and strongly NSE+ DCs are present in intestinal lamina propria. Peyer's patches and mesenteric but not other lymph nodes contain many strongly NSE+ DCs in interfollicular and T cell areas. Similar DCs are seen in the ileum and in T cell areas of mesenteric nodes in gnotobiotic rats. These results show that a distinct DC subset constitutively endocytoses and transports apoptotic cells to T cell areas and suggest a role for these DCs in inducing and maintaining peripheral self-tolerance.

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Numerous immature thymocytes undergo apoptosis and are rapidly engulfed by phagocytic thymic macrophages. The macrophage surface receptors involved in apoptotic thymocyte recognition are unknown. We have examined the role of the class A macrophage scavenger receptor (SR-A) in the engulfmnent of apoptotic thymocytes. Uptake of steroid-treated apoptotic thymocytes by thymic and inflammatory-elicited SR-A positive macrophages is partially inhibited by an anti-SR-A mAb and more completely by a range of scavenger receptor ligands. Thymic macrophages from mice with targeted disruption of the SR-A gene show a 50% reduction in phagocytosis of apoptotic thymocytes in vitro. These data suggest that SR-A may play a role in the clearance of dying cells in the thymus.Apoptosis or programmed cell death is now recognized as the physiologic mechanism by which large numbers of unwanted cells are deleted from the body (1). However, examination of tissues with ongoing programmed cell death highlights the scant evidence of dying cells in situ, a paradox that is explained by the existence of mechanisms for the specific and rapid removal of apoptotic cells by phagocytes. One of the earliest markers of commitment to undergo programmed cell death is phagocytosis of the apoptotic cell. In contrast to our knowledge of the process of apoptosis itself, relatively little is known of the clearance process by which dying cells are removed from the body in a manner that has no apparent inflammatory consequence. Examination of apoptotic cells in situ has shown that they are taken up and degraded by phagocytes, in particular macrophages (M+) (2). This activity can be observed in MO-like cells from species such as Drosophila, suggesting this is an important and conserved process (3) The process is specific, in that only cells committed to die are phagocytosed, and rapid, so that uptake is completed before the integrity of the apoptotic cell membrane is lost. Two essential components are required for the successful ingestion of the apoptotic cells: (i) specific receptor(s) on the surface of the phagocyte to mediate rapid recognition and ingestion and (ii) the presence of appropriate ligands on apoptotic cells that permit their distinction from healthy neighbors. The consensus that can be drawn from the relatively small number of reported studies on apoptotic cell recognition is that just like the regulation of apoptosis itself, it is complex and that there is not a single receptor-ligand system that explains apoptotic cell removal by all phagocytes (4).The thymus is the organ where the repertoire of mature T cells is selected from a much larger number of immature thymocytes and extensive apoptotic cell death occurs in the immature thymocyte populations. Although numerous immature thymocytes undergo apoptosis (5-7), few dead cells are observed in situ due to rapid engulfment by phagocytic M4 in the thymic stroma (8-10). A recent study (11), using the sensitive terminal deoxynucleotidyltransferase-mediated UTP end labeling (TUNEL) technique ...

During gram-negative bacterial infections, lipopolysaccharide (LPS) stimulates primed macrophages (Mφ) to release inflammatory mediators such as tumor necrosis factor (TNF)-α, which can cause hypotension, organ failure, and often death. Several different receptors on Mφ have been shown to bind LPS, including the type A scavenger receptor (SR-A). This receptor is able to bind a broad range of polyanionic ligands such as modified lipoproteins and lipoteichoic acid of gram-positive bacteria, which suggests that SR-A plays a role in host defense. In this study, we used mice lacking the SR-A (SRKO) to investigate the role of SR-A in acquired immunity using a viable bacillus Calmette Guérin (BCG) infection model. We show that activated Mφ express SR-A and that this molecule is functional in assays of adhesion and endocytic uptake. After BCG infection, SRKO mice are able to recruit Mφ to sites of granuloma formation where they become activated and restrict BCG replication. However, infected mice lacking the SR-A are more susceptible to endotoxic shock and produce more TNF-α and interleukin-6 in response to LPS. In addition, we show that an antibody which blocks TNF-α activity reduces LPS-induced mortality in these mice. Thus SR-A, expressed by activated Mφ, plays a protective role in host defense by scavenging LPS as well as by reducing the release by activated Mφ of proinflammatory cytokines. Modulation of SR-A may provide a novel therapeutic approach to control endotoxic shock.