Complexity of human immune response profiles for CD4+ T cell epitopes from the diabetes autoantigen GAD65.
Complex protein antigens contain multiple potential T cell recognition epitopes, which are generated through a processing pathway involving partial antigen degradation via proteases, binding to MHC molecules, and display on the APC surface, followed by recognition via the T cell receptor. We have investigated recognition of the GAD65 protein, one of the well-characterized autoantigens in type I diabetes, among individuals carrying the HLA-DR4 haplotypes characteristic of susceptibility to IDDM. Using sets of 20-mer peptides spanning the GAD65 molecule, multiple immunostimulatory epitopes were identified, with diverse class II DR molecules functioning as the restriction element. The majority of T cell responses were restricted by DRB1 molecules; however, DRB4 restricted responses were also observed. Antigen-specific T cell clones and lines were derived from peripheral blood samples of pre-diabetic and IDDM patients and T cell recognition and response were measured. Highly variable proliferative and cytokine release profiles were observed, even among T cells specific for a single GAD65 epitope.
Masewicz
S A
SA
Virginia Mason Research Center, Seattle, WA 98101, USA.
Meldrum
N
N
Gersuk
V
V
Gaur
L
L
Hagopian
W
W
Moriarity
L
L
Nepom
G T
GT
D000595:Amino Acid Sequence; D001323:Autoantibodies / Q000097:blood; D001324:Autoantigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte; D005968:Glutamate Decarboxylase / Q000276:immunology*; D006684:HLA-DR Antigens / Q000276:immunology; D006801:Humans; D007527:Isoenzymes / Q000276:immunology*; D008969:Molecular Sequence Data
D001323:Autoantibodies; D001324:Autoantigens; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D006684:HLA-DR Antigens; D007527:Isoenzymes; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2