This information is current as Diabetes Gene in Nonobese Diabetic Mice Is an Autoimmune Cd 101 Evidence

We have previously proposed that sequence variation of the CD101 gene between NOD and C57BL/6 mice accounts for the protection from type 1 diabetes (T1D) provided by the insulin-dependent diabetes susceptibility region 10 (Idd10), a ,1 Mb region on mouse chromosome 3. In this study, we provide further support for the hypothesis that Cd101 is Idd10 using haplotype and expression analyses of novel Idd10 congenic strains coupled to the development of a CD101 knockout mouse. Susceptibility to T1D was correlated with genotype-dependent CD101 expression on multiple cell subsets, including Foxp3 + regulatory CD4 + T cells, CD11c + dendritic cells, and Gr1 + myeloid cells. The correlation of CD101 expression on immune cells from four independent Idd10 haplotypes with the development of T1D supports the identity of Cd101 as Idd10. Because CD101 has been associated with regulatory T and Ag presentation cell functions, our results provide a further link between immune regulation and susceptibility to T1D. T ype 1 diabetes (T1D) in humans and in an animal model of T1D, the NOD mouse, is genetically complex: variation at a large number of genes influences disease susceptibility. Using a series of congenic strains, we previously mapped one such insulin-dependent diabetes (Idd) gene, Idd10, to a 950-kb region on mouse chromosome 3 (1). Sequencing of Cd101, one of seven genes within the Idd10 region, showed multiple variants between the NOD and C57BL/6 (B6) strains, including 10 single nucleotide polymorphisms (SNPs) causing amino acid substitutions. Four of the substitutions were nonconservative, with two of the four potentially causing an alteration in N-linked glycosylation (1). Although the biological functions of CD101 remain unclear, and there are no known ligands for CD101, this transmembrane molecule having seven Ig-like domains is expressed by multiple subsets of immune cells including Foxp3 + regulatory T cells (Tregs), ef-fector CD4 and CD8 T cells, granulocytes, dendritic cells, and monocytes in humans and mice (2–6). There are multiple lines of evidence using human cells suggesting that CD101 modulates T cell activation either directly or indirectly via dendritic cells that express CD101 (5–8). CD101 expression levels on mouse Tregs were demonstrated to be positively correlated with functional suppression (3). The online version of this article contains supplemental material. In this study, we have examined further the candidacy of CD101 as Idd10. We have performed a haplotype analysis using newly developed Idd10 congenic strains, results from which are consistent with the hypothesis …