Recognition of posttranslationally modified GAD65 epitopes in subjects with type 1 diabetes.
Posttranslational modification (PTM) of self-proteins has been shown to elicit clinically relevant immune responses in rheumatoid arthritis and celiac disease. Accumulating evidence suggests that recognition of modified self-proteins may also be important in type 1 diabetes. Our objective was to identify posttranslationally modified GAD65 peptides, which are recognized by subjects with type 1 diabetes, and to assess their disease relevance. We show that citrullination and transglutamination of peptides can enhance their binding to DRB1*04:01, a diabetes-susceptible HLA allele. These and corresponding modifications to amino acids at T-cell contact positions modulated the recognition of multiple GAD65 peptides by self-reactive T cells. Using class II tetramers, we verified that memory T cells specific for these modified epitopes were detectable directly ex vivo in the peripheral blood of subjects with type 1 diabetes at significantly higher frequencies than healthy controls. Furthermore, T cells that recognize these modified epitopes were either less responsive or nonresponsive to their unmodified counterparts. Our findings suggest that PTM contributes to the progression of autoimmune diabetes by eliciting T-cell responses to new epitope specificities that are present primarily in the periphery, thereby circumventing tolerance mechanisms.
Benaroya Research Institute at Virginia Mason, Seattle, WA.
John W
JW
McGinty
Benaroya Research Institute at Virginia Mason, Seattle, WA.
I-Ting
IT
Chow
Benaroya Research Institute at Virginia Mason, Seattle, WA Department of Medicine, University of Washington, Seattle, WA.
Carla
C
Greenbaum
Benaroya Research Institute at Virginia Mason, Seattle, WA.
Jared
J
Odegard
Benaroya Research Institute at Virginia Mason, Seattle, WA Department of Medicine, University of Washington, Seattle, WA.
William W
WW
Kwok
Benaroya Research Institute at Virginia Mason, Seattle, WA ejames@benaroyaresearch.org.
Eddie A
EA
James
D000328:Adult; D000595:Amino Acid Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005968:Glutamate Decarboxylase / Q000276:immunology* / Q000378:metabolism; D059811:HLA-DRB1 Chains / Q000276:immunology; D006801:Humans; D050417:Insulin-Secreting Cells / Q000276:immunology; D011499:Protein Processing, Post-Translational
D018984:Epitopes, T-Lymphocyte; D059811:HLA-DRB1 Chains; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2