title: Modulatory role of DR4- to DQ8-restricted CD4 T-cell responses and type 1 diabetes susceptibility.
abstract: This study addressed an important biological question, namely how certain HLA molecules modulate the disease risk conferred by other HLA molecules. The HLA molecules under investigation were HLA-DQ8 and -DR4, the two most prevalent HLA class II alleles found in Caucasian type 1 diabetic patients. A panel of human GAD (hGAD65)-specific CD4 T-cell lines and hybridomas was generated to serve as detection reagents for evaluating the peptide occupancy of DQ8 and DR4. Results indicated that DQ8 and DR4 (0401) were able to bind the same hGAD65 peptides. The coexpression of DR4 (0401) diminished DQ8-restricted T-cell responses. In addition, we also demonstrated that the diminished T-cell response varied according to the specific DRB1*04 alleles. Taken together, this study provides evidence that DR4 is able to modulate DQ8-restricted T-cell responses, possibly by competing for peptides. Given that DQ8 is a primary genetic determinant of type 1 diabetes, the decreased DQ8-restricted CD4 T-cell activity due to peptide competition may be the mechanism explaining the modulation effect of DR4 to type 1 diabetes susceptibility.
authors.affiliation: Rangos Research Center, Children's Hospital of Pittsburgh, 3460 5th Ave., Pittsburgh, PA 15213, USA.
authors.forename: Xinhui
authors.initials: X
authors.lastname: Ge
authors.forename: Jon D
authors.initials: JD
authors.lastname: Piganelli
authors.forename: Hubert M
authors.initials: HM
authors.lastname: Tse
authors.forename: Suzanne
authors.initials: S
authors.lastname: Bertera
authors.forename: Clayton E
authors.initials: CE
authors.lastname: Mathews
authors.forename: Massimo
authors.initials: M
authors.lastname: Trucco
authors.forename: Li
authors.initials: L
authors.lastname: Wen
authors.forename: William A
authors.initials: WA
authors.lastname: Rudert
mesh_terms: D000595:Amino Acid Sequence; D000938:Antigen-Presenting Cells / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D020022:Genetic Predisposition to Disease; D005968:Glutamate Decarboxylase / Q000276:immunology; D006683:HLA-DQ Antigens / Q000276:immunology*; D015804:HLA-DR4 Antigen / Q000276:immunology*; D006801:Humans; D007527:Isoenzymes / Q000276:immunology; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry
chemical_list: D006683:HLA-DQ Antigens; C109756:HLA-DQ8 antigen; D015804:HLA-DR4 Antigen; D007527:Isoenzymes; D010446:Peptide Fragments; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2