The NOD Idd9 Genetic Interval Influences the Pathogenicity of Insulitis and Contains Molecular Variants of Cd30, Tnfr2, and Cd137

Abstract

Previous analyses of NOD mice have shown that some genes control the development of both insulitis and diabetes, while other loci influence diabetes without reducing insulitis. Evidence for the existence of a gene only influencing diabetes, Idd9 on mouse chromosome 4, is provided here by the development of a novel congenic mouse strain, NOD.B10 Idd9. NOD.B10 Idd9 mice display profound resistance to diabetes even though nearly all develop insulitis. Subcongenic analysis has demonstrated that alleles of at least three B10 genes, Idd9.1, Idd9.2, and Idd9.3 are required to produce Idd9-mediated diabetes resistance. Candidate genes with amino acid differences between the NOD and B10 strains have been localized to the 5.6 cM Idd9.2 interval (Tnfr2, Cd30) and to the 2.0 cM Idd9.3 interval (Cd137).

Reduced Regulatory T Cell Diversity in NOD Mice Is Linked to Early Events in the Thymus

“…They proposed a costimulatory function for these molecules, which, in conjunction with the signal received through the TCR, induces maturation of DP thymocytes. Sequencing of the 4-1BB gene identified three coding differences between NOD and NOD Idd9 (20). These changes do not influence the surface expression level of 4-1BB, but they affect T cell activation, with NOD T cells showing reduced proliferation in response to simultaneous stimulation through TCR and 4-1BB (44).…”

“…Our analyses of NOD and the congenic strain NOD Idd9 demonstrate that TCR diversity within the nTreg population is controlled by a gene encoded within a 38-Mbp region of chromosome 4. The Idd9 congenic region offers significant protection from disease and contains at least three subregions that independently influence type I diabetes (Idd9.1, Idd9.2, and Idd9.3), which include the candidate genes Lck and 4-1BB (20). Studies using the NOD Idd9 congenic strain have shown that the Idd9 interval is involved in maintaining tolerance within the isletspecific pancreatic CD8 + T cell population (28) and that expression of Idd9 alleles in CD4 + T cells prevents the expansion of pathogenic CD8 + T cells (29).…”

“…Lck and the TNFR superfamily member 4-1BB have previously been suggested as Idd9 candidate genes (20). The role of Lck in disease development is controversial.…”

“…In these strains, genomic segments from the type I diabetes-resistant strains B6 and C57BL/ 10 have been introgressed into chromosomes 3 and 4 of NOD mice, respectively. Congenic mice have been instrumental in identifying genetic loci associated with disease susceptibility, and these two strains are largely protected from disease (20,21). Because it is known that Tregs play an important role in disease protection, we investigated the role of these loci in TCR repertoire selection.…”

Leukocyte attraction through the CCR5 receptor controls progress from insulitis to diabetes in non‐obese diabetic mice

“…In addition to loci that influence both insulitis and diabetes, independent loci have been reported that influence insulitis without affecting diabetes. Thus, NOD mice congenic for the Idd9 genetic interval have been generated; these animals develop insulitis, but not diabetes [22]. The role of CCR5 in islet protection has indeed been established, as islet allografts survive significantly longer in CCR5 -/-mice [23].…”