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SIGN-R1, a recently discovered C-type lectin expressed at high levels on macrophages within the marginal zone of the spleen, mediates the uptake of dextran polysaccharides by these phagocytes. We now find that encapsulated Streptococcus pneumoniae are rapidly cleared by these macrophages from the bloodstream, and that capture also takes place when different cell lines express SIGN-R1 after transfection. To assess the role of the capsular polysaccharide of S. pneumoniae (CPS) in the interaction of SIGN-R1 with pneumococci, we first studied binding and uptake of serotype 14 CPS in transfected cells. Binding was observed and was of a much higher avidity (3,000-fold) for CPS 14 than dextran. The CPSs from four different serotypes were also cleared by marginal zone macrophages in vivo. To establish a role for SIGN-R1 in this uptake, we selectively down-regulated expression of the lectin by pretreatment of the mice with SIGN-R1 antibodies, including a newly generated hamster monoclonal called 22D1. For several days after this transient knockout, the marginal zone macrophages were unable to take up either CPSs or dextrans. Therefore, marginal zone macrophages in mice have a receptor that interacts with capsular pneumococcal polysaccharides, setting the stage for further studies of the functional consequences of this interaction.T he spleen functions at several points in innate and adaptive immunity. A major innate function is exerted by macrophages that are abundant in vascular regions termed the splenic red pulp, whereas adaptive functions are carried out by B and T lymphocytes, typically located in white pulp nodules. At the junction of each white pulp nodule with the red pulp is a specialized region called the marginal zone, which is composed of several concentric regions (1). Innermost is a ring of macrophages termed marginal metallophils, expressing a hemagglutinin termed sialoadhesin or CD169 (2, 3). Then there is a vascular sinus that receives blood via penetrating small arterial vessels from the white pulp. Surrounding the marginal sinus is a zone composed of large macrophages as well as specialized B lymphocytes (4). Within and surrounding the marginal zone are also dendritic cells (5, 6), possibly in the process of migrating from the blood to the T cell regions of the white pulp.With respect to host defense, the spleen plays a special role during blood-borne infection with encapsulated microorganisms, particularly Streptococcus pneumoniae bacteria (7-12). A critical role of the spleen is the formation of antibodies by marginal zone B cells (13-15), particularly complement-fixing antibodies (16)(17)(18)(19)(20). The role of macrophages in the processes of microbial clearance and resistance and antibody formation to S. pneumoniae needs to be considered (21), particularly given recent data that marginal zone macrophages interact and retain B cells in this region (22). Here we show that marginal zone macrophages express a receptor called SIGN-R1 that is able to bind and internalize the capsular pneumococcal polys...

The C-type lectin dendritic cell-specific ICAM 3-grabbing nonintegrin (DC-SIGN)/CD209 efficiently binds several pathogens, including HIV-1. DC-SIGN is expressed on monocyte-derived DCs in culture, and importantly, it is able to sequester HIV-1 within cells and facilitate transmission of virus to CD4+ T cells. To investigate DC-SIGN function, we have generated new mAbs. We report in this study that these and prior anti-DC-SIGN mAbs primarily label macrophages in the medullary sinuses of noninflamed human lymph node. In contrast, expression is not detected on most DCs in the T cell area, except for occasional cells. We also noted that IL-4 alone can induce expression of DC-SIGN in CD14+ monocytes and circulating blood DCs. However, blockade of DC-SIGN with Abs and DC-SIGN small interfering RNA did not result in a major reduction in the capacity of these DCs to transfer HIV to T cells, confirming significant DC-SIGN-independent mechanisms. The blocking approaches did reduce HIV-1 transmission by DC-SIGN-transfected cells by >90%. DC-SIGN blockade also did not reduce the ability of DCs to stimulate T cell proliferation in the MLR. These results indicate that DC-SIGN has the potential to contribute to macrophage function in normal human lymph node, and that DCs do not require DC-SIGN to transmit HIV or to initiate T cell responses.

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