Genetic and functional data identifying Cd101 as a type 1 diabetes (T1D) susceptibility gene in nonobese diabetic (NOD) mice

摘要

Type 1 diabetes (T1D) is a chronic multi-factorial disorder characterized by the immune-mediated destruction of insulin-producing pancreatic beta cells. Variations at a large number of genes influence susceptibility to spontaneous autoimmune T1D in non-obese diabetic (NOD) mice, one of the most frequently studied animal models for human disease. The genetic analysis of these mice allowed the identification of many insulin-dependent diabetes ( Idd ) loci and candidate genes, one of them being Cd101 . CD101 is a heavily glycosylated transmembrane molecule which exhibits negative-costimulatory functions and promotes regulatory T (Treg) function. It is abundantly expressed on subsets of lymphoid and myeloid cells, particularly within the gastrointestinal tract. We have recently reported that the genotype-dependent expression of CD101 correlates with a decreased susceptibility to T1D in NOD.B6 Idd10 congenic mice compared to parental NOD controls. Here we show that the knockout of CD101 within the introgressed B6-derived Idd10 region increased T1D frequency to that of the NOD strain. This loss of protection from T1D was paralleled by decreased Gr1-expressing myeloid cells and FoxP3 ~(+) Tregs and an enhanced accumulation of CD4-positive over CD8-positive T lymphocytes in pancreatic tissues. As compared to CD101 ~(+/+) NOD.B6 Idd10 donors, adoptive T cell transfers from CD101 ~(?/?) NOD.B6 Idd10 mice increased T1D frequency in lymphopenic NOD scid and NOD.B6 Idd10 scid recipients. Increased T1D frequency correlated with a more rapid expansion of the transferred CD101 ~(?/?) T cells and a lower proportion of recipient Gr1-expressing myeloid cells in the pancreatic lymph nodes. Fewer of the Gr1 ~(+) cells in the recipients receiving CD101 ~(?/?) T cells expressed CD101 and the cells had lower levels of IL-10 and TGF-β mRNA. Thus, our results connect the Cd101 haplotype-dependent protection from T1D to an anti-diabetogenic function of CD101-expressing Tregs and Gr1-positive myeloid cells and confirm the identity of Cd101 as Idd10 . Author summary The complex interplay of environmental factors and genetic traits determines the susceptibility of an individual to autoimmune disease such as type 1 diabetes (T1D). Despite T1D being one of the most common and most studied polygenic autoimmune disorders, the mechanisms underlying the immune-mediated destruction of the insulin-producing pancreatic beta cells are still largely unknown. Genetic association studies identified many DNA sequence variants that confer risk to or protect from autoimmune disease. In this regard, we have identified a single gene, Cd101 , as a T1D susceptibility locus. In accordance with our previous studies in which we reported an association of allelic Cd101 variants on T1D prevalence, we observed here that deletion of Cd101 perpetuated the expansion of pathogenic, pancreas-infiltrating immune cells and subsequently enhanced T1D incidence. The mechanisms by which Cd101 variants interfere with autoimmune responses will allow us to understand the regulation of molecules in autoimmunity in general as diabetes susceptibility loci have been associated with other autoimmune diseases. Consequently, our work will help to identify therapeutic approaches that can be used to guide the development of effective therapies for T1D, but also allows the identification of common targets in autoimmune disease for clinical intervention in the future.