Abnormal class I assembly and peptide presentation in the nonobese diabetic mouse.
Presentation of self-antigens by major histocompatibility complex (MHC) class I molecules requires the function of the MHC class II-linked genes Tap-1 and Tap-2. Evidence suggests that interruption of self-peptide presentation results in reduced cell surface expression of MHC class I molecules and the interruption correlates with progression to diabetic autoimmunity in nonobese diabetic (NOD) mice and humans. NOD mice possess a rare Tap-1 allele (Tap-1b); this is associated with reduced Tap-1 mRNA abundance in lymphocytes from diabetes-prone females and decreased conformationally correct class I molecules on the cell surface. In this study, we demonstrate that, similar to lymphoma cell lines with mutations in Tap-1 or Tap-2, the reduced expression of class I molecules on the surface of lymphocytes from diabetes-prone female NOD mice was normalized by incubation at low temperatures or by exposure to class I allele-specific peptides. As would be expected for cells that express surface class I molecules not associated with peptide, female NOD lymphocytes were resistant to lysis by class I-restricted, peptide-specific cytotoxic T lymphocytes. Furthermore, the rate of class I exit from the endoplasmic reticulum of lymphocytes from female NOD mice was delayed as demonstrated by delayed glycosylation. Male NOD mice, which are not prone to diabetes, lacked these functional defects in class I assembly and had near-normal levels of Tap-1 mRNA and exhibited normal density of class I epitopes that were peptide filled. These results are consistent with the possibility that the rare Tap-1b allele is associated with a quantitative defect in Tap-1 expression that influences disease course.
Immunobiology Laboratories of the Diabetes Unit, Massachusetts General Hospital-East, Charlestown 02129.
F
F
Li
J
J
Guo
Y
Y
Fu
G
G
Yan
D
D
Faustman
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D002451:Cell Compartmentation; D003602:Cytotoxicity, Immunologic; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006183:H-2 Antigens / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D007111:Immunity, Cellular; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD / Q000276:immunology* / Q000378:metabolism; D010455:Peptides / Q000276:immunology*; D011485:Protein Binding; D011487:Protein Conformation; D012333:RNA, Messenger / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D013696:Temperature
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D006183:H-2 Antigens; D010455:Peptides; D012333:RNA, Messenger; C073119:TAP1 protein, human; C486171:Tap1 protein, mouse