title: CD4+ T cells from type 1 diabetic and healthy subjects exhibit different thresholds of activation to a naturally processed proinsulin epitope.
abstract: Recent studies suggest that insulin is a primary autoantigen for type 1 diabetes. Several studies have identified preproinsulin (PPI) 76-90 as an immunodominant CD4+ T cell epitope. We developed a class II tetramer reagent using a modified PPI peptide with a lysine to serine substitution at position 88 (PPI 78-90(88S)) that has high binding affinity to DRA1*0101/DRB1*0401 (DR0401). Using this tetramer, positive responses were observed from both DR0401 healthy and type 1 diabetic subjects when T cells were stimulated with the PPI 78-90(88S) peptide. Seventy percent of these T cells proliferated in response to both the wild type PPI 76-90 and PPI 78-90(88S) peptides. However, when T cells were stimulated with wild type peptide and assayed with DR0401/PPI 78-90(88S), positive responses were only detected in the diabetic group but not in healthy subjects. When highly purified CD4+CD25-CD45RA+ T cells were stimulated with PPI 78-90(88S) peptide in the absence of antigen-presenting cells, T cells from the diabetic group were able to respond to peptide stimulation, while T cells from healthy subjects were not. These data suggest that T cells from type 1 diabetic subjects have a lower threshold of activation in response to PPI peptide stimulation as compared to healthy subjects.
authors.affiliation: Benaroya Research Institute at Virginia Mason, 1201 Ninth Ave, Seattle, WA 98101, USA.
authors.forename: Junbao
authors.initials: J
authors.lastname: Yang
authors.forename: Nancy
authors.initials: N
authors.lastname: Danke
authors.forename: Michelle
authors.initials: M
authors.lastname: Roti
authors.forename: Laurie
authors.initials: L
authors.lastname: Huston
authors.forename: Carla
authors.initials: C
authors.lastname: Greenbaum
authors.forename: Catherine
authors.initials: C
authors.lastname: Pihoker
authors.forename: Eddie
authors.initials: E
authors.lastname: James
authors.forename: William W
authors.initials: WW
authors.lastname: Kwok
mesh_terms: D000293:Adolescent; D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D006684:HLA-DR Antigens / Q000737:chemistry / Q000276:immunology*; D059811:HLA-DRB1 Chains; D006801:Humans; D007328:Insulin / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology; D017493:Leukocyte Common Antigens / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D054730:Protein Interaction Domains and Motifs / Q000276:immunology; D011498:Protein Precursors / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology
chemical_list: D018984:Epitopes, T-Lymphocyte; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C553505:HLA-DRB1*04:01 antigen; D007328:Insulin; D011498:Protein Precursors; C013737:preproinsulin; D017493:Leukocyte Common Antigens