Spatial separation of HLA-DM/HLA-DR interactions within MIIC and phagosome-induced immune escape

Immunity. 2005 Feb;22(2):221-33. doi: 10.1016/j.immuni.2005.01.006.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Endocytosis
  • Fluorescence Resonance Energy Transfer
  • HLA-D Antigens / chemistry
  • HLA-D Antigens / immunology*
  • HLA-D Antigens / ultrastructure
  • HLA-DR Antigens / chemistry
  • HLA-DR Antigens / immunology*
  • HLA-DR Antigens / ultrastructure
  • Histocompatibility Antigens Class II / immunology*
  • Humans
  • Hydrogen-Ion Concentration
  • Immune Tolerance / immunology*
  • Intracellular Membranes / immunology
  • Intracellular Membranes / metabolism
  • Microscopy, Electron
  • Models, Molecular
  • Organelles / immunology
  • Organelles / metabolism*
  • Phagosomes / immunology*
  • Protein Structure, Tertiary


  • HLA-D Antigens
  • HLA-DM antigens
  • HLA-DR Antigens
  • Histocompatibility Antigens Class II