Interferon-gamma rapidly increases peptide transporter (TAP) subunit expression and peptide transport capacity in endothelial cells.
Human cytotoxic T lymphocytes (CTL) recognize specific complexes of HLA class I molecules and peptides, which assemble when nascent class I molecules bind peptides transported from the cytoplasm into the endoplasmic reticulum by the heterodimeric transporter associated with antigen processing (TAP). Increased class I molecule expression on the cell surface increases the efficiency of CTL lysis. The kinetics of interferon (IFN)-gamma induction of TAP, peptide transport capacity, and HLA class I molecule expression was determined in endothelial cells, which are targets of CTL following transplantation or viral infection. TAP mRNAs are induced rapidly, increasing 20-fold (TAP1) or 10-fold (TAP2) by 12 h, whereas HLA class I mRNA is induced more slowly, increasing 10-fold in 24 h. TAP1 and TAP2 proteins are also induced rapidly, increasing 10-fold in 24 h, whereas HLA class I heavy chain proteins and surface expression increase more slowly. Peptide transport capacity in endothelial and HeLa cells increases within 6 h of IFN-gamma treatment, suggesting that the IFN-gamma-induced TAP heterodimers are functional. Therefore, the IFN-gamma-induced increase in TAP proteins is accompanied by an increased peptide transport capacity, which may be important in supporting the subsequent rise in HLA class I protein expression.
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W
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Department of Pathology and Program in Molecular Cardiobiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Lehner
P J
PJ
Cresswell
P
P
Pober
J S
JS
Johnson
D R
DR
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis* / Q000235:genetics; D001692:Biological Transport; D004730:Endothelium, Vascular / Q000378:metabolism*; D005805:Genes, MHC Class I; D006367:HeLa Cells; D015395:Histocompatibility Antigens Class I / Q000032:analysis / Q000502:physiology; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D010455:Peptides / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters; D015395:Histocompatibility Antigens Class I; D010455:Peptides; D012333:RNA, Messenger; C073119:TAP1 protein, human; C071692:TAP2 protein, human; D007371:Interferon-gamma