The Host-Pathogen Interaction New Themes from Dendritic Cell Biology

the observations that DCs are recruited to the lamina propria of the small intestine after bacterial infection, and the number of DCs recruited depends on the pathoMaria Rescigno1,3 and Persephone Borrow2,3 1 Department of Bioscience and Biotechnology U3 University of Milano-Bicocca genicity of the microorganisms encountered. In line with Piazza della Scienza, 2 this, it has been shown that bacterial components such 20126 Milano as flagellin can be transcytosed across the epithelium Italy and can induce the release of proinflammatory media2 The Edward Jenner Institute for Vaccine Research tors and chemotactic factors. Although both pathogenic Compton, Newbury and nonpathogenic bacteria can release flagellin, only Berkshire RG20 7NN invasive pathogens allow its efficient transcytosis (GeUnited Kingdom wirtz et al., 2001). This would suggest that pathogens could facilitate entrance of otherwise noninvasive microbes via this route. It is likely that some sexually transmitted pathogens Dendritic cells (DCs) have evolved to monitor the envimay also enter the host in the absence of damage to ronment, detect pathogens, and trigger T cell activation, providing a link between the innate and adaptive imthe local epithelial cell barrier via one or another of the mune systems. In turn, many pathogens have evolved routes for antigen sampling at mucosal surfaces. For to exploit DC biology in their dissemination within the example, atraumatic application of simian immunodefibody, and/or to interfere with DC functions to block or ciency virus to the tonsils of macaques resulted in virus delay their elimination by the host. In this review, we do uptake and replication close to the antigen-transporting not attempt to provide a detailed account of every asepithelium of the tonsillar crypts (Stahl-Hennig et al., pect of the interaction between pathogens and DCs, but 1999). The mechanism by which the virus accessed this instead aim to highlight some of the recent developsite was not defined. However, human immunodefiments and new themes emerging in this area. ciency virus type 1 (HIV-1) can be captured and transThe Sentinel Role of DCs Involves Ready Access ported in an infectious form by DCs after binding to a to Incoming Pathogens DC C-type lectin highly expressed on DCs in mucosal The mucosae of the airways and the gastrointestinal tissues, DC-specific ICAM3-grabbing nonintegrin (DCtract are continuously exposed to a myriad of antigens SIGN), raising the possibility that virus may have been and microorganisms, only a limited number of which captured by DC processes outside the epithelium and enter the body and cause disease. This is due in part carried across the epithelial barrier. Local tissue trauma to the fact that epithelial cells are connected by tight could enhance infection, both by introducing breaches junctions, forming a barrier that impedes the paracellular into the epithelial barrier and also because the associmovement of microbes and their metabolites. In the gut, ated inflammatory signals may promote local DC-medientry of pathogenic microorganisms occurs mainly via M ated virus uptake. Transmission of some infections is cells, which are concentrated in the follicle-associated known to involve breaching of the epithelium. For examepithelium overlying the Peyer’s Patches (PPs). M cells ple, pathogens spread by arthropod vectors are delivare very selective and do not allow entry of all microorered across this barrier. Recent studies of the initial ganisms. Thus, only pathogens and bacterial toxins that events in infection with two unrelated mosquito-borne can exploit preexisting intracellular trafficking pathways viruses, dengue virus and Venezuelan equine encephalior induce de novo mechanisms for their phagocytosis tis virus (VEE), suggest that Langerhans cells are the penetrate the gut epithelium via M cells (reviewed by first site of replication of both viruses. Thus, DCs are Neutra, 1999). DCs and macrophages are located in located at epithelial sites throughout the body, and conintraepithelial pockets below the M cells: incoming tact pathogens during the very early stages of infection. pathogens are thus delivered directly to DCs. In some cases, this may be exploited by pathogens to An additional mechanism by which DCs can monitor facilitate their entry and initial replication. the contents of the intestinal lumen was recently deTriggering of DC Activation/Maturation scribed (Rescigno et al., 2001). DCs send dendrites outin Response to Infection side the epithelium, like periscopes. The integrity of the Infection stimulates the release of a variety of soluble epithelial barrier is preserved, however, as the DCs exfactors, including chemokines, which promote the repress tight-junction proteins and form new tight-junccruitment of DC precursors, and cytokines that are powtion-like structures with neighboring epithelial cells (Figerful mediators of DC activation. DCs themselves are ure 1). It is not clear whether this mechanism is also important producers of type 1 interferons (IFNs), constitutively active or induced in response to signals tumor necrosis factor (TNF), and interleukin 1 (ILfrom epithelial cells that have been in contact with 1 ), which can act in an autocrine fashion to promote pathogens or high numbers of nonpathogenic bacteria DC activation. In humans, a small population of cells in in the lumen. An inducible mechanism is suggested by the blood which produce particularly high levels of IFNduring virus infections have been identified as plas3 Correspondence: [email protected] [M.R.]; persephone.