Defective Central Tolerance Induction in NOD Mice: Genomics and Genetics

Abstract

The genetic determinism of type-1 diabetes in NOD mice likely involves complementary defects in central T cell tolerance induction and peripheral immunoregulation. To study the contribution of the NOD genetic background to central tolerance, we followed the behavior of BDC2.5 clonotype thymocytes in fetal thymic organ cultures (FTOC). The NOD genetic background encodes a quantitative deficiency in the ability to delete these self-reactive thymocytes and to divert them to the CD8alphaalpha lineage. In genetic analyses, comparing NOD and B6.H2g7 FTOCs, the NOD defect incorporated the influence of several loci (notably ones on chr1 and 3). Microarray analyses assessing FTOCs from the same two strains argued that the NOD abnormality reflects the combined effects of turning down the gene expression program that provokes apoptosis and turning on a new program promoting cell survival. Intersection of the data from the two approaches points to a small set of attractive candidate genes.

Anti-apoptotic effect of hyperglycemia can allow survival of potentially autoreactive T cells

“…Glucose-mediated upregulation of anti-apoptotic genes has been reported previously in vascular smooth muscle cells 15 and Bcl-2 (a NF-kB-dependent gene) has also been shown to be upregulated in NOD thymocytes. 34 In line with these previous observations, we also found a glucose-dependent increase in Bcl-2 and the IAP family of anti-apoptotic molecules under hyperglycemic conditions. Interestingly, transgenic mice over expressing XIAP or Bcl2 have decreased thymocyte apoptosis.…”

Do the peptide-binding properties of diabetogenic class II molecules explain autoreactivity?

“…While these studies have pointed to a MHC-centric role for I-A g7 in thymic selection, other reports have identified a role for the NOD background genes in generating a compromised thymic selection milieu [34][35][36]. Kishimoto et al noted that NOD thymocytes were more resistant to deletion upon crosslinking of the TCR via monoclonal antibodies [34], while other studies with CD4+ TCR transgenic mice concluded that antigen encounter resulted in inefficient deletion of thymocytes on the NOD background when compared to non-NOD strains [35,36].…”

“…Kishimoto et al noted that NOD thymocytes were more resistant to deletion upon crosslinking of the TCR via monoclonal antibodies [34], while other studies with CD4+ TCR transgenic mice concluded that antigen encounter resulted in inefficient deletion of thymocytes on the NOD background when compared to non-NOD strains [35,36]. It is likely that both MHC and non-MHC background genes contribute towards selection of a self-reactive T cell repertoire.…”

Central tolerance: Essential for preventing autoimmune disease?

“…There are several reports that point to failing central tolerance in diabetes-prone mouse strains [43][44][45]. Analyses point to failing deletion of antigen-specific thymocytes due to diminished expression of pro-apoptotic genes and enhanced expression of survival factors.…”