Spatial separation of HLA-DM/HLA-DR interactions within MIIC and phagosome-induced immune escape.
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.
Zwart
Wilbert
W
Division of Tumor Biology , Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Griekspoor
Alexander
A
Kuijl
Coenraad
C
Marsman
Marije
M
van Rheenen
Jacco
J
Janssen
Hans
H
Calafat
Jero
J
van Ham
Marieke
M
Janssen
Lennert
L
van Lith
Marcel
M
Jalink
Kees
K
Neefjes
Jacques
J
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
D006681:HLA-D Antigens; C084245:HLA-DM antigens; D006684:HLA-DR Antigens; D000949:Histocompatibility Antigens Class II