title: Quantitative thresholds of MHC class II I-E expressed on hemopoietically derived antigen-presenting cells in transgenic NOD/Lt mice determine level of diabetes resistance and indicate mechanism of protection.
abstract: Two homozygous lines of transgenic NOD/Lt mice expressing MHC class II I-E molecules at quantitatively different levels were utilized to study mechanisms of I-E-mediated diabetes prevention. In line 12, I-E expression on APC at levels comparable with that in BALB/cByJ controls conferred only partial diabetes resistance. In line 5, greater than normal I-E levels on APC correlated with nearly complete resistance. Levels of endogenously encoded I-Ag7 correlated inversely with transgene-induced I-E expression. T cell transfer experiments into NOD/severe combined immunodeficient mice demonstrated the presence of pathogenic T cells in I-E+ donors, and that continuous expression of I-E on hemopoietically derived APC was required to block their pathogenic function. T cells from transgenic and nontransgenic NOD/Lt mice primed in vivo against the beta cell autoantigen 65-kDa isoform of glutamic acid decarboxylase (GAD65) and two peptides derived from this protein proliferated when restimulated in vitro. However, reverse-transcription PCR and ELISA measurements of cytokine mRNA and protein levels showed that the GAD65-reactive T cells from both line 5 and line 12 mice produced higher levels of IL-4 and lower levels of IFN-gamma than similar T cells from standard NOD/Lt mice. Thus, the inverse relationship between I-E and I-Ag7 expression was associated with qualitative differences in T cell responses to putative beta cell autoantigens. Collectively, these data indicate quantitative increases in I-E expression on APC may block insulin-dependent diabetes mellitus by altering the balance of cytokines produced by beta cell autoreactive T cells.
authors: The Jackson Laboratory, Bar Harbor, ME 04609, USA.
authors: M S
authors: MS
authors: Hanson
authors: M
authors: M
authors: Cetkovic-Cvrlje
authors: V K
authors: VK
authors: Ramiya
authors: M A
authors: MA
authors: Atkinson
authors: N K
authors: NK
authors: Maclaren
authors: B
authors: B
authors: Singh
authors: J F
authors: JF
authors: Elliott
authors: D V
authors: DV
authors: Serreze
authors: E H
authors: EH
authors: Leiter
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology; D015152:Blotting, Northern; D015247:Deoxyribonuclease HindIII / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D005968:Glutamate Decarboxylase / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis / Q000276:immunology*; D007113:Immunity, Innate / Q000276:immunology; D015847:Interleukin-4 / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology; D019076:Transgenes / Q000235:genetics
chemical_list: D001324:Autoantigens; D000949:Histocompatibility Antigens Class II; C024138:I-E-antigen; D015847:Interleukin-4; D015247:Deoxyribonuclease HindIII; D005968:Glutamate Decarboxylase