Diabetes Resistance/Susceptibility in T Cells of Nonobese Diabetic Mice Conferred by MHC and MHC-Linked Genes

Abstract

Polymorphism of MHC and MHC-linked genes is tightly associated with susceptibility to type 1 diabetes (T1D) in human and animal models. Despite the extensive studies, however, the role of MHC and MHC-linked genes expressed by T cells on T1D susceptibility remains unclear. Because T cells develop from TCR− thymic precursor (pre-T) cells that undergo MHC restriction mediated by thymic stroma cells, we reconstituted the T cell compartment of NOD.scid-RIP-B7.1 mice using pre-T cells isolated from NOD, NOR, AKR, and C57BL/6 (B6) mice. T1D developed rapidly in the mice reconstituted with pre-T cells derived from NOD or NOR donors. In contrast, most of the NOD.scid-RIP-B7.1 mice reconstituted with pre-T cells from AKR or B6 donors were free of T1D. Further analysis revealed that genes within MHC locus of AKR or B6 origin reduced incidence of T1D in the reconstituted NOD.scid-RIP-B7.1 mice. The expression of MHC class I genes of k, but not b haplotype, in T cells conferred T1D resistance. Replacement of an interval near the distal end of the D region in T cells of B6 origin with an identical allele of 129.S6 origin resulted in T1D development in the reconstituted mice. These results provide evidence that the expression of MHC class I and MHC-linked genes in T cells of NOD mice indeed contributes to T1D susceptibility, while expression of specific resistance alleles of MHC or MHC-linked genes in T cells alone would effectively reduce or even prevent T1D.

Enhanced Early Expansion and Maturation of Semi-Invariant NK T Cells Inhibited Autoimmune Pathogenesis in Congenic Nonobese Diabetic Mice

“…Because the positive selection for iNKT cells takes place among double positive thymocytes, a deficient positive selection in NOD mice is likely intrinsic for the T lineage. Therefore, the result of present study is consistent with early studies in which we and others found that development of iNKT cells in the NOD.scid reconstituted with pre-T cells depended on the donor origin (31,36,37). The positive selection of iNKT cells depends on endogenous lipid Ags displayed by CD1d molecules, and also requires homotypic interactions of Slam receptors and downstream recruitment of the adaptor SLAM-associated protein (SAP) (2,6,38).…”

Transgenic Insulin (B:9-23) T-Cell Receptor Mice Develop Autoimmune Diabetes Dependent Upon RAG Genotype, H-2g7 Homozygosity, and Insulin 2 Gene Knockout

“…Similar to a number of other transgenic models and T-cell lines (32,33), spontaneous progression to diabetes is enhanced by homozygosity for H-2 g7 , consistent with a major histocompatibility complex gene-dose effect in these mice (32,34). Because spontaneous diabetes occurs in unmanipulated BDC12-4.1 transgenic RAG Ϫ/Ϫ mice in spite of severe lymphopenia and a lack of CD8 and B-cells, these transgenic CD4 ϩ T-cells specific for B:9-23 are sufficient for disease in NOD mice (without in vitro activation).…”