First signature of islet beta-cell-derived naturally processed peptides selected by diabetogenic class II MHC molecules.
The diversity of Ags targeted by T cells in autoimmune diabetes is unknown. In this study, we identify and characterize a limited number of naturally processed peptides from pancreatic islet beta-cells selected by diabetogenic I-A(g7) molecules of NOD mice. We used insulinomas transfected with the CIITA transactivator, which resulted in their expression of class II histocompatibility molecules and activation of diabetogenic CD4 T cells. Peptides bound to I-A(g7) were isolated and examined by mass spectrometry: some peptides derived from proteins present in secretory granules of endocrine cells, and a number were shared with cells of neuronal lineage. All proteins to which peptides were identified were expressed in beta cells from normal islets. Peptides bound to I-A(g7) molecules contained the favorable binding motif characterized by acidic amino acids at the P9 position. The draining pancreatic lymph nodes of prediabetic NOD mice contained CD4 T cells that recognized three different natural peptides. Furthermore, four different peptides elicited CD4 T cells, substantiating the presence of such self-reactive T cells. The overall strategy of identifying natural peptides from islet beta-cells opens up new avenues to evaluate the repertoire of self-reactive T cells and its role in onset of diabetes.
Suri
Anish
A
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Walters
James J
JJ
Rohrs
Henry W
HW
Gross
Michael L
ML
Unanue
Emil R
ER
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D001327:Autoimmune Diseases / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000276:immunology* / Q000378:metabolism*; D007340:Insulinoma / Q000276:immunology / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D008969:Molecular Sequence Data; D010455:Peptides / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding / Q000276:immunology; D011499:Protein Processing, Post-Translational / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
D000949:Histocompatibility Antigens Class II; C407099:I-A g7 antigen; D010455:Peptides