Naturally processed T cell epitopes from human glutamic acid decarboxylase identified using mice transgenic for the type 1 diabetes-associated human MHC class II allele, DRB1*0401.
The identification of class II binding peptide epitopes from autoimmune disease-related antigens is an essential step in the development of antigen-specific immune modulation therapy. In the case of type 1 diabetes, T cell and B cell reactivity to the autoantigen glutamic acid decarboxylase 65 (GAD65) is associated with disease development in humans and in nonobese diabetic (NOD) mice. In this study, we identify two DRB1*0401-restricted T cell epitopes from human GAD65, 274-286, and 115-127. Both peptides are immunogenic in transgenic mice expressing functional DRB1*0401 MHC class II molecules but not in nontransgenic littermates. Processing of GAD65 by antigen presenting cells (APC) resulted in the formation of DRB1*0401 complexes loaded with either the 274-286 or 115-127 epitopes, suggesting that these naturally derived epitopes may be displayed on APC recruited into pancreatic islets. The presentation of these two T cell epitopes in the islets of DRB1*0401 individuals who are at risk for type 1 diabetes may allow for antigen-specific recruitment of regulatory cells to the islets following peptide immunization.
Wicker
L S
LS
Department of Autoimmune Diseases Research, Merck Research Laboratories, Rahway, New Jersey 07065-0900, USA. linda_wicker@merck.com
Chen
S L
SL
Nepom
G T
GT
Elliott
J F
JF
Freed
D C
DC
Bansal
A
A
Zheng
S
S
Herman
A
A
Lernmark
A
A
Zaller
D M
DM
Peterson
L B
LB
Rothbard
J B
JB
Cummings
R
R
Whiteley
P J
PJ
D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001323:Autoantibodies / Q000032:analysis*; D001402:B-Lymphocytes / Q000276:immunology; D002460:Cell Line; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology*; D000939:Epitopes / Q000032:analysis* / Q000737:chemistry; D005802:Genes, MHC Class II; D005968:Glutamate Decarboxylase / Q000096:biosynthesis / Q000276:immunology*; D006684:HLA-DR Antigens / Q000096:biosynthesis / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006801:Humans; D008213:Lymphocyte Activation; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
D001323:Autoantibodies; D000939:Epitopes; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C553505:HLA-DRB1*04:01 antigen; D010446:Peptide Fragments; D011994:Recombinant Proteins; D005968:Glutamate Decarboxylase