title: Spatial separation of HLA-DM/HLA-DR interactions within MIIC and phagosome-induced immune escape.
abstract: Major Histocompatibility Complex (MHC) class II molecules, including Human Leukocyte Antigen (HLA)-DR, present peptide fragments from proteins degraded in the endocytic pathway. HLA-DR is targeted to late-endocytic structures named MHC class II-containing Compartments (MIIC), where it interacts with HLA-DM. This chaperone stabilizes HLA-DR during peptide exchange and is critical for successful peptide loading. To follow this process in living cells, we have generated cells containing HLA-DR3/Cyan Fluorescent Protein (CFP), HLA-DM/Yellow Fluorescent Protein (YFP), and invariant chain. HLA-DR/DM interactions were observed by Fluorescence Resonance Energy Transfer (FRET). These interactions were pH insensitive, yet occurred only in internal structures and not at the limiting membrane of MIIC. In a cellular model of infection, phagosomes formed a limiting membrane surrounding internalized Salmonella. HLA-DR and HLA-DM did not interact in Salmonella-induced vacuoles, and HLA-DR was not loaded with antigens. The absence of HLA-DR/DM interactions at the limiting membrane prevents local loading of MHC class II molecules in phagosomes. This may allow these bacteria to successfully evade the immune system.
authors.affiliation: Division of Tumor Biology , Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Wilbert
authors.initials: W
authors.lastname: Zwart
authors.forename: Alexander
authors.initials: A
authors.lastname: Griekspoor
authors.forename: Coenraad
authors.initials: C
authors.lastname: Kuijl
authors.forename: Marije
authors.initials: M
authors.lastname: Marsman
authors.forename: Jacco
authors.initials: J
authors.lastname: van Rheenen
authors.forename: Hans
authors.initials: H
authors.lastname: Janssen
authors.forename: Jero
authors.initials: J
authors.lastname: Calafat
authors.forename: Marieke
authors.initials: M
authors.lastname: van Ham
authors.forename: Lennert
authors.initials: L
authors.lastname: Janssen
authors.forename: Marcel
authors.initials: M
authors.lastname: van Lith
authors.forename: Kees
authors.initials: K
authors.lastname: Jalink
authors.forename: Jacques
authors.initials: J
authors.lastname: Neefjes
mesh_terms: D002460:Cell Line; D004705:Endocytosis; D031541:Fluorescence Resonance Energy Transfer; D006681:HLA-D Antigens / Q000737:chemistry / Q000276:immunology* / Q000648:ultrastructure; D006684:HLA-DR Antigens / Q000737:chemistry / Q000276:immunology* / Q000648:ultrastructure; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007108:Immune Tolerance / Q000276:immunology*; D007425:Intracellular Membranes / Q000276:immunology / Q000378:metabolism; D008854:Microscopy, Electron; D008958:Models, Molecular; D015388:Organelles / Q000276:immunology / Q000378:metabolism*; D010588:Phagosomes / Q000276:immunology*; D017434:Protein Structure, Tertiary
chemical_list: D006681:HLA-D Antigens; C084245:HLA-DM antigens; D006684:HLA-DR Antigens; D000949:Histocompatibility Antigens Class II