Identification of candidate genes for type 1 diabetes by microarray expression analysis of islet-specific CD4+ T cells (IRM6P.726)

Abstract

Abstract Type 1 diabetes (T1D) is a complex genetic disease, resulting from the interplay of multiple insulin dependent diabetes loci (Idd) in both humans and nonobese diabetic (NOD) mice. NOD.B10 Idd9 congenic mice contain the Idd9 from T1D-resistant C57BL/10 mice, mediating significant T1D protection compared to NOD mice. However, the genes and the pathways by which Idd9 controls T1D development remain to be fully elucidated. We have developed novel NOD.B10 Idd9 congenic mice that harbor predominantly islet-specific CD4+ T cells expressing the BDC2.5 T cell receptor (BDC-Idd9.905 mice). To establish functional links between Idd9 genotype and its phenotype, we have performed microarray gene expression analyses of purified CD4+ T cells from these mice and BDC2.5 NOD control mice. We found that among the limited number of differentially expressed genes, those located within the Idd9 region were greatly enriched. Bioinformatics analyses identified Eno1, Rbbp4 and Mtor as differentially expressed Idd9 genes that were part of significant gene networks involved in T cell growth and development. Accordingly, antigen-specific proliferation and Th1 and Th17 responses between BDC-Idd9.905 and BDC2.5 splenocytes differed significantly and were impaired in BDC-Idd9.905 splenocytes. Our findings suggest that these Idd9 genes differentially control proliferation and differentiation of islet-specific CD4+ T cells in the two strains, which may contribute to their differential T1D development.