Attenuation of HLA-DR expression by mononuclear phagocytes infected with Mycobacterium tuberculosis is related to intracellular sequestration of immature class II heterodimers.
MHC class II expression was examined in macrophages infected with Mycobacterium tuberculosis. IFN-gamma increased the surface expression of class II molecules in THP-1 cells and this was markedly reduced in cells infected with M. tuberculosis. Despite this effect, steady state levels of HLA-DRalpha, HLA-DRbeta, and invariant (Ii) chains were equivalent in control and infected cells. Metabolic labeling combined with pulse-chase experiments and biochemical analysis showed that the majority of class II molecules in infected cells became resistant to endoglycosidase H, consistent with normal Golgi processing. However, results of intracellular staining and dual color confocal microscopy revealed a significant defect in transport of newly synthesized class II molecules through the endocytic compartment. Thus, compared with findings in control cells, class II molecules in infected cells colocalized to a minimal extent with a lysosomal-associated membrane protein-1+ endosomal compartment. In addition, in contrast to control cells, class II molecules in infected cells failed to colocalize with endocytosed BSA under conditions where this marker is known to label late endosomes, lysosomes, and the MHC class II compartment. Consistent with defective transport along the endocytic pathway, the maturation of SDS-stable class II alphabeta dimers--dependent upon removal of Ii chain and peptide loading of class II dimers in the MHC class II compartment--was markedly impaired in M. tuberculosis-infected cells. These findings indicate that defective transport and processing of class II molecules through the endosomal/lysosomal system is responsible for diminished cell surface expression of MHC class II molecules in cells infected with M. tuberculosis.
Hmama
Z
Z
Department of Medicine, The British Columbia Cancer Agency, Faculty of Medicine, University of British Columbia, Research Institute of Vancouver Hospital and Health Sciences Center, Canada.
Gabathuler
R
R
Jefferies
W A
WA
de Jong
G
G
Reiner
N E
NE
D000944:Antigens, Differentiation, B-Lymphocyte / Q000096:biosynthesis / Q000737:chemistry; D001692:Biological Transport; D019281:Dimerization; D011992:Endosomes / Q000378:metabolism*; D006031:Glycosylation; D006056:Golgi Apparatus / Q000378:metabolism; D006684:HLA-DR Antigens / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics; D006596:Hexosaminidases / Q000494:pharmacology; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis / Q000737:chemistry; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000209:etiology; D007371:Interferon-gamma / Q000494:pharmacology; D007948:Leukemia, Monocytic, Acute / Q000473:pathology; D008247:Lysosomes / Q000378:metabolism; D018613:Microscopy, Confocal; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000382:microbiology*; D009169:Mycobacterium tuberculosis / Q000502:physiology*; D009687:Nuclear Proteins; D010587:Phagocytosis; D055503:Protein Multimerization; D011499:Protein Processing, Post-Translational; D011994:Recombinant Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015534:Trans-Activators / Q000378:metabolism; D014376:Tuberculosis / Q000150:complications / Q000276:immunology; D014407:Tumor Cells, Cultured; D014617:Vacuoles / Q000378:metabolism
D000944:Antigens, Differentiation, B-Lymphocyte; D006684:HLA-DR Antigens; D000949:Histocompatibility Antigens Class II; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D011994:Recombinant Proteins; D015534:Trans-Activators; C045084:invariant chain; D007371:Interferon-gamma; D006596:Hexosaminidases; D013755:Tetradecanoylphorbol Acetate