All animal experiments were performed in accordance with UK Home Office regulations. == Phagocytosis Assay. see reference 1). These innate immune responses provide a critical, rapid defense mechanism that acts before the maturation of acquired immunity. However, there are occasions when PRRs become hijacked by pathogens and used to facilitate infection and circumvent immune detection. A recently identified example of this phenomenon is HIV-1 and Dengue virus usurping DC-specific intracellular adhesion molecule-grabbing nonintegrin (DC-SIGN; CD209) and DC-SIGNR molecules to facilitate infection (for review see reference 2). Therefore, these SIGN molecules appear to represent an immunological liability. This raises an unresolved question: what positive role, if any, do the SIGN molecules play in protective immunity? Human DC-SIGN is expressed on the surface of human dendritic cells and is believed to play a key role in Dactolisib Tosylate the initial interaction between DCs and naive T cells through interaction with ICAM-3 (3). However, it has also been demonstrated that HIV-1 exploits DC-SIGN, using it as a receptor to facilitate viral transport via DCs from mucosal surfaces to CD4+T cells in secondary lymphoid tissue (4) through its lectin domain interacting with gp120 (5,6). Recent studies have also highlighted a role for DC-SIGN in the infection of DCs by Ebola virus (7), human cytomegalovirus (8),Leishmania pifanoi(9),Mycobacterium tuberculosis(10), and Dactolisib Tosylate Dengue virus (11). After the description of DC-SIGN, the closely related molecule DC-SIGNR (DC-SIGN2, L-SIGN) was reported, with its gene mapping within a few tens of kilobases of both DC-SIGN and CD23 (another C-type lectin; references 12, 13). DC-SIGNR has also been shown to bind HIV-1 (14) and Dengue virus (11), and it has been suggested that its expression on liver sinusoidal endothelial cells may facilitate clearance of antigenic proteins from the circulation (15). The mouse genome encodes five DC-SIGN homologues that all map close to the mouse CD23 gene on mouse chromosome 8 (1618). These mouse genes have been termed DC-SIGN and SIGN-R1SIGNR4, with DC-SIGN mapping closest to Dactolisib Tosylate CD23 as in the human (16). The mouse DC-SIGN family contains highly homologous carbohydrate recognition domains (CRDs), but the individual members differ in the numbers of neck repeats or the presence of a transmembrane domain (16). Expression studies also suggest that these molecules are differentially expressed in various tissues, suggesting that they may play tissue-specific roles (1618). It is noteworthy that mouse DC-SIGN has been reported to be highly expressed by splenic DCs in a manner similar to that described for human DC-SIGN, whereas the other homologues are not as highly represented in the splenic DC compartment (1618). Furthermore, recent studies have reported that, despite their having related mannose-binding motifs, the various mouse SIGN molecules display differential ligand specificity with the potential to recognize different pathogens (19,20). The highly organized microarchitecture of the spleen is intimately involved with the effective clearance of Mouse monoclonal to BCL-10 pathogens by the immune system. The spleen is divided into regions of white and red pulp separated by the marginal zones (MZs). The cellular composition of the marginal zone includes reticular cells, MZ B cells, DCs, metallophilic macrophages, and MZ macrophages (MZMs). It is in the MZ that the blood flow is slowed down, as the terminal arterioles open into venous sinuses, producing an environment for the efficient entrapment of blood-borne particles by resident phagocytes (21). The MZMs are highly phagocytic cells that are found in layers dispersed throughout the MZ and are defined by their expression of the cell surface molecules recognized by the antibodies ER-TR9 and MARCO (22,23). Selective depletion of MZMs and metallophilic macrophages using clodronate liposomes identified that these cells are essential for trapping of microspheres andListeria monocytogenes(24). Furthermore, MZMs have been identified as critical phagocytes for the uptake of neutral polysaccharides, such as Ficoll and dextran, which represent thymus independent type 2 (TI-2) antigens (25). Significantly, this uptake has been demonstrated to be inhibited.
