Following Bacillus Calmette-Guerin (BCG)-vaccination GMM-reactive T cells produce IFN and TNF in a CD1b-restricted manner (6). containing C80 GMM more potently activated CD1b-restricted T cell line relative to Mo-DCs pulsed with free lipid antigen or antigenic liposomes without Siglec-7 ligand. These data suggest that the endocytic function of Siglec-7 can be exploited to deliver glycolipids antigens to their target cell and increase the efficiency of display to T cells. infected cells (8, 9). Several studies show that group 1 CD1-restricted T cells expand and persist within individuals with tuberculosis (4, 5, 10), as well as animals vaccinated with the antigenic lipids (11, 12). These studies, along with the lack of common polymorphism of CD1 proteins in human populations, now provide the basis for considering lipid antigens as vaccines or immunodulatory agents that may provide protection from mycobacterial infections. Glucose-6-monomycolates (GMMs), which have acyl chains attached to a glucose head group, are abundant lipid components present in the cell wall of all mycobacterial species studied to date (13). They bind to CD1b by their acyl chains, and although the acyl chains of GMMs vary by mycobacterial species, they are all completely buried in the lipophilic groove of CD1b (14). As a result, the glucose head group is exposed as a common antigenic epitope (14). Accordingly T cells which recognize GMM from one source as their matched antigen also react to GMM from other sources (9). Further, animal studies suggest that GMM is an Atosiban immunodominant antigen during natural infection (15, 16), and recent studies with CD1b tetramers prove that polyclonal populations of GMM-reactive T cells exist in human tuberculosis patients (4, 7). Of note, conserved germline-encoded, mycolyl lipid-reactive (GEM) T cells have been identified as high-affinity responders to GMM in humans (7). While GMM-specific T cells including GEM T cells are found at a low frequency in healthy Atosiban individuals (0.002%), their expansion is commonly observed in active and latent tuberculosis infection, accounting for 0.01% of T cells (4, 7, 17). In addition, a second type of polyclonal GMM-reactive T cell type is known as LDN5-like T cells. LDN5 like T cells are so named because they express TCRs and cytokine patterns that are similar to those associated with a T cell clone named LDN5 (18). GEM T cells are defined by high affinity TRAV1-2+ TCRs, Tgfb3 whereas TRBV4-1+ LDN5-like T cells have intermediate affinity for CD1b and GMM (7, 18). Following Bacillus Calmette-Guerin (BCG)-vaccination GMM-reactive T cells produce IFN and TNF in a CD1b-restricted manner (6). Therefore, vaccination activating GMM-reactive T cells is now being studied as a new method to alter immunity to infection (21). Thus, as is also the case for MHC I and II, myeloid DCs are thought to be the main functionally important APC in the periphery (22). For DC-targeted antigen delivery, antibodies toward the cell surface receptors have been investigated for delivery of protein antigens conjugated to the antibody, some of which have been in human clinical trials for tumor and HIV vaccines (23, 24). However, more suitable delivery platforms for hydrophobic lipid antigens are yet to be developed and tested. Previously we have developed a targeting platform based on liposomal nano-particles bearing glycan ligands of sialic acid-binding immunoglobulin-like lectins (siglecs) capable of delivery of both hydrophilic and hydrophobic agents to siglec-expressing immune cells (25C28). Siglecs are a cell surface lectin family that recognize sialic acids as ligands and are expressed on human leukocytes in a cell-type restricted manner (29C31). Among human siglecs, Siglec-7 is expressed on DCs as well as on other human leukocytes including natural killer (NK) cells, neutrophils, Atosiban monocytes, and macrophages (31C33). Based on the restricted expression of Siglec-7, it has been proposed as an attractive target for cell-targeted therapies directed to myeloid cells (30, 34). We have recently developed a glycan ligand of high affinity and selectivity for Siglec-7 suitable for use for targeting cells expressing this siglec (35). In this report, we investigated the potential for efficient delivery of GMM to CD1b+ human monocyte-derived DCs (Mo-DCs) using antigenic liposomes bearing ligands of Siglec-7. We found that targeted liposomes were.