Bipartite regulation of different components of the MHC class I antigen-processing machinery during dendritic cell maturation.
Dendritic cells (DC) are professional antigen-presenting cells (APC) which proceed from immature to a mature stage during their final differentiation. Immature DC are highly effective in terms of antigen uptake and processing, whereas mature DC become potent immunostimulatory cells. Until now, the expression profiles of the major components of the MHC class I antigen-processing machinery (APM) during DC development have not been well characterized. In this study, the mRNA and protein expression levels of the IFN-gamma inducible proteasome subunits, of the proteasome activators PA28, and of key components required for peptide transport and MHC class I-peptide complex assembly have been evaluated in immature and mature stages of human monocyte-derived DC using semiquantitative RT-PCR and Western blot analyses. The IFN-gamma-responsive immunoproteasome subunits LMP2, LMP7 and MECL1 are up-regulated in immature DC, whereas the other components of the MHC class I presentation machinery, such as PA28, TAP, tapasin, and HLA heavy and light chains, were found to be more abundant in mature DC. These findings support the hypothesis that immature DC produced by the differentiation of monocytes in response to IL-4 and granulocyte macrophage colony stimulating factor first increase their capacity to capture antigens and process them into peptides, thereby switching from housekeeping to immunoproteasomes, while mature DC rather up-regulate the components required for peptide translocation and MHC class I-peptide complex formation, and thus specialize in antigen presentation. Our results establish that MHC class I, like MHC class II surface expression, is markedly regulated during DC development and maturation.
Li
J
J
Third Department of Internal Medicine, Johannes Gutenberg University, 55131 Mainz, Germany.
Schuler-Thurner
B
B
Schuler
G
G
Huber
C
C
Seliger
B
B
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis; D017951:Antigen Presentation; D017920:Antiporters / Q000096:biosynthesis; D002454:Cell Differentiation / Q000276:immunology; D003546:Cysteine Endopeptidases / Q000096:biosynthesis; D003713:Dendritic Cells / Q000166:cytology* / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D015536:Down-Regulation / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D007136:Immunoglobulins / Q000096:biosynthesis; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis; D026901:Membrane Transport Proteins; D009000:Monocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D009124:Muscle Proteins; D010455:Peptides / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D014176:Protein Biosynthesis; D021381:Protein Transport / Q000276:immunology; D011506:Proteins / Q000037:antagonists & inhibitors; D015854:Up-Regulation / Q000276:immunology
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D017920:Antiporters; D015395:Histocompatibility Antigens Class I; D007136:Immunoglobulins; D018950:Lipopolysaccharide Receptors; D026901:Membrane Transport Proteins; D009097:Multienzyme Complexes; D009124:Muscle Proteins; C085047:PSME1 protein, human; D010455:Peptides; D011506:Proteins; C073119:TAP1 protein, human; C107762:tapasin; C071313:LMP-2 protein; D003546:Cysteine Endopeptidases; C077436:LMP7 protein; C098948:PSMB10 protein, human; D046988:Proteasome Endopeptidase Complex