Arrowheads inDindicate white areas of triple colocalized FcRn, IgG, and LAMP1, a phenomenon seen in 50% of cells investigated, and the arrow indicates yellow area of FcRn colocalized with LAMP1. == Hematopoietic Cell-Dependent Degradation SNS-314 of IgG in Multimeric Immune Complexesin Vivo. lysosomes, Ag NFKBIA fragments are loaded onto MHC class II molecules and presented to T cells. DCs express several types of Fc receptors (FcR) that bind the Fc portion of IgG molecules with different binding affinities (14). Ags incorporated in immune complexes (ICs) are taken up and presented by DC more efficiently than soluble Ags alone, an effect that has been attributed to the stimulatory signals mediated by activating FcRs and increased uptake efficiency of Ag when receptor-mediated uptake via FcR, in particular FcRII, is engaged (2). The neonatal Fc receptor for IgG (FcRn) is an Fc-binding molecule that is structurally and functionally different from the FcR. FcRn is related to the MHC class I protein and consists of a glycosylated heavy chain in noncovalent association with 2-microglobulin (5). FcRn binds its two major ligands, IgG and serum albumin, in a pH-dependent manner, in which efficient binding is seen only at acidic pH <6.5 and not at neutral pH >7.0 (6,7). The FcRn-binding site on IgG involves several histidine residues at the CH2-CH3 domain interface of the Fc fragment and is distinct from binding sites for FcR (8,9). The main biological functions for FcRn have been identified to be protecting IgG from catabolism by diverting bound IgG molecules away from a degradative fate in lysosomes, a similar protective function for serum albumin, and transport of IgG across epithelial and endothelial barriers that is responsible for transmission of IgG from mother to infant and IgG mediated uptake of Ags across epithelial barriers (7,1012). In rodents, intestinal expression of FcRn within the epithelium is down-regulated upon weaning, whereas human intestinal epithelial cells continue to express FcRn into adulthood (13). In addition, human FcRn is expressed in other adult parenchymal cells such as kidney and bronchial epithelial and endothelial cells (14,15). The expression of human FcRn has been identified in hematopoietic cells such as small intestinal macrophages, monocytes, and monocyte-derived DC but not other closely related immune cells such as B and T cells (16). Similar to human APC (16), adult murine DC express FcRn (17). The specific expression of this recently discovered Fc-binding receptor in professional APC prompted us to investigate whether FcRn may be involved in the uptake and presentation of Fc-containing Ags. In this study, we show that FcRn in human and murine DC enhances the uptake and presentation of Ag-antibody ICs indicative of a previously uncharacterized function for FcRn; a role in adaptive immunity. == Results == == FcRn Is Expressed in Adult Murine APC. == Similar to earlier reports of human SNS-314 FcRn expression in professional APC (16), we observed FcRn mRNA expression in adult WT B6 murine bone marrow (BM), macrophages, and BM-derived DC [supporting information (SI) Fig. S1A]. Western blot analysis of WT splenic DC lysates confirmed FcRn protein expression as defined by a 50-kDa band that was absent in DC lysates from FcRn-deficient mice (Fig. S1B). These studies show that FcRn is expressed in both mouse SNS-314 and human DC in agreement with previous reports (16,17). == FcRn Enhances Ag Presentation of Murine DC Bothin Vitroandin Vivo. == We next sought to determine whether FcRn within mouse DC affected Ag presentation. We took advantage of the fact that mouse FcRn is able to bind human IgG1Fc with high affinity (18). We used a chimeric antibody that contains a murine Fab specific for the hapten 4-hydroxy-3-iodo-5-nitrophenylacetic acid (NIP) and WT Fc derived from human IgG1(19). We further engineered this chimeric antibody to bear Fc mutations in three critical amino acids [I253A, H310A, and H435A (IHH)] (14) that disable binding to murine (20,21) and human FcRn (22). As shown inFig. 1, whereas the WT form of this chimeric antibody could.