Blander & Medzhitov

Blander & Medzhitov - 2006 Nature Publishing Group...

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Unformatted text preview: 2006 Nature Publishing Group Toll-dependent selection of microbial antigens for presentation by dendritic cells J. Magarian Blander 1 & Ruslan Medzhitov 1 Dendritic cells constitutively sample the tissue microenvironment and phagocytose both microbial and host apoptotic cells 14 . This leads to the induction of immunity against invading pathogens or tolerance to peripheral self antigens, respectively 59 . The outcome of antigen presentation by dendritic cells depends on their activation status, such that Toll-like receptor (TLR)-induced dendritic cell activation makes them immunogenic, whereas steady-state presen- tation of self antigens leads to tolerance 5,6,8,10 . TLR-inducible expression of co-stimulatory signals is one of the mechanisms of self/non-self discrimination 5,11 . However, it is unclear whether or how the inducible expression of co-stimulatory signals would distinguish between self antigens and microbial antigens when both are encountered by dendritic cells during infection 6,8 . Here we describe a new mechanism of antigen selection in dendritic cells for presentation by major histocompatibility complex class II molecules (MHC II) that is based on the origin of the antigen. We show that the efficiency of presenting antigens from phagocytosed cargo is dependent on the presence of TLR ligands within the cargo. Furthermore, we show that the generation of peptideMHC class II complexes is controlled by TLRs in a strictly phagosome- autonomous manner. During infection, dendritic cells (DCs) encounter and phago- cytose both microbial and apoptotic cells. Without additional regulatory mechanisms, this could result in immunogenic presen- tation of self antigens. Here we investigated whether DCs are capable of distinguishing between the two sources of antigens for their selective presentation by MHC II. Bone-marrow-derived DCs phagocytose apoptotic cells and deliver them into LAMP1- (lysosomal-associated membrane protein 1), MHC II-positive compartments (Fig. 1a and Supplementary Figs 13a). Because apoptotic cells lack TLR ligands and do not induce DC maturation (which involves surface expression of MHC II and co-stimulatory molecules, and production of cytokines) 12,13 , MHC II remains intracellular, colocalizing with LAMP1 (Fig. 1a and Supplementary Figs 3a, 4). In contrast, phagocytosis of microbial cells, simultaneous phagocytosis of apoptotic and microbial cells, and phagocytosis of apoptotic cells accompanied by treatment with the bacterial endotoxin lipopolysaccharide (LPS) all result in DC maturation (Fig. 1bd and Supplementary Figs 3bd, 4 and 5). These differences reflect the transport of MHC II from late endosomal, LAMP1-positive compartments to the plasma membrane, a process that occurs upon stimulation of DCs with TLR ligands 14,15 . We also tested the effect of phagocytosis of apoptotic cells modified to contain the TLR4 ligand LPS. Live cells efficiently internalize and retain LPS 16,17 , and phagocytosis of apoptotic cells generated from...
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Blander & Medzhitov - 2006 Nature Publishing Group...

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