Thus, the present study provides new insights into the genes/pathways in CD4 T-cells that collectively might play a role in diabetes development – resistance in NOR mice or susceptibility in NOD mice. The BCL2L1 pathway and the genes within Idd13, Idd9/11 and Idd27 that are altered at all 3 ages (Pldn, Trp53bp1, Tmem87a, Ctdspl2,

Gatm, Raly, Khdrbs1, and Trim12a and Trim5/12c) make particularly interesting candidate genes/pathways as they most likely represent basic genetic defects in the NOD mouse. While our find more study has highlighted prime candidate genes, future studies will confirm which of the NOD altered genes and/or their interacting partners or regulators act interactively to effect the diabetogenic activity of NOD CD4 T-cells. In our lab, we are investigating the genetic loci underlying the expression of the altered CD4 T-cell molecular network to define key regulatory loci. The majority of the CD4 T-cell NOD altered CHIR-99021 supplier genes were repressed, similar to the results of the spleen leukocyte study [25] and supported by many other studies

in both mice and humans [[36], [37], [38], [39], [40], [41] and [42]]. Kodama et al. [36] reported global repression of genes in various tissues of NOD mice (including spleen cells) in comparison to NOD.B10 controls, a strain in which the NOD MHC haplotype is replaced with that from the nondiabetic B10 mice. Liston et al. [37] also found a global dampening in gene expression in NOD thymocytes of the genes involved in T cell negative selection. They identified several differentially expressed type 1 diabetes candidate

genes, among them four genes (Ly6c, Prim2, Trim12, and Trim30) whose expression was also dampened in our study, thus providing supporting evidence for possible involvement of these candidate genes in CD4 T-cells as well. Heinig et al. [38], in a systems-genetics study investigating rat tissues and macrophages and human monocytes, discovered that the IRF7-driven inflammatory network (which is enriched for innate immune response genes) is associated with type 1 diabetes risk. Interestingly, homologs of 9 of the genes belonging to this network (Lcp2, Oas1a, Rtp4, Ifit1l, Ifit1, Ly6c1, Ifit3, Sp110, and Trim21) were also repressed in NOD mice, for suggesting a similar network may also be altered in CD4 T-cells of NOD mice and might contribute to diabetes development in the mouse. Similarly, in human T1D studies, Elo et al. [39] found early suppression of immune response gene expression in whole blood samples of children in the prediabetic phase who eventually developed clinical diabetes. Furthermore, Orban et al. [40] also found repression of all genes that were differentially expressed in whole untreated human peripheral blood CD4 T-cells from new onset T1D patients, including genes involved in key immune functions, such as adhesion molecules lymphocyte function-associated antigen 1 (LFA-1) and P-selectin.