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/

Two homozygous lines of transgenic NOD/Lt mice expressing MHC class II I-E molecules at quantitatively different levels were utilized to stu dy mechanisms of I-E-mediated diabetes prevention. In line 12, I-E exp ression on APC at levels comparable with that in BALB/cByJ controls co nferred only partial diabetes resistance, In line 5, greater than norm al I-E levels on APC correlated with nearly complete resistance. Level s of endogenously encoded I-A(g7) correlated inversely with transgene- induced I-E expression, T cell transfer experiments into NOD/severe co mbined immunodeficient mice demonstrated the presence of pathogenic T cells in I-E(+) donors, and that continuous expression of I-E on hemop oietically 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 dec arboxylase (GAD65) and two peptides derived from this protein prolifer ated when restimulated in vitro. However, reverse-transcription PCR an d ELISA measurements of cytokine mRNA and protein levels showed that t he GAD65-reactive T cells from both line 5 and line 12 mice produced h igher levels of IL-4 and lower levels of IFN-gamma than similar T cell s from standard NOD/Lt mice. Thus, the inverse relationship between I- E and I-A(g7) expression was associated with qualitative differences i n T cell responses to putative beta cell autoantigens. collectively, t hese 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.