Interestingly, the grafting of purified TEC from embryos of NOD mice to newborn C57BL/6 nude mice results in the development of insulitis, suggesting GSI-IX mouse a functional anomaly in TEC from NOD mice cells [59]. During negative selection, developing T cells interact with thymic epithelium- and bone marrow-derived antigen-presenting cells (APCs), in particular thymic medullary dendritic cells. Thus, aberrant negative selection results essentially from anomalies affecting thymic APCs. Like the majority of ubiquitous or organ-specific autoantigens, several islet β cell antigens involved in T1D, such as

glutamic acid decarboxylase (GAD) and proteins of the insulin family, are expressed promiscuously in the thymus to be presented to thymocytes during education [60,61]. The decreased expression of these antigens can disturb the negative selection

of autoreactive T lymphocytes, which may predispose to the development of autoimmunity. In humans, susceptibility to T1D is associated with a polymorphism in the 5′ region of the insulin gene, which influences the rate of expression of peptides derived from insulin by APCs in the thymus. The protective allele is associated with a high level of thymic expression of insulin and the susceptibility allele to a low level [61]. NOD mice which express neither the pro-insulin 2 nor the islet-cell antigen 69 (ICA69) in the thymus develop diabetes rapidly [62,63], as in BioBreeding Diabetes Prone (BBDP) BAY 80-6946 in vivo rats, which do not express type 2 insulin-like growth factor (Igf2) in thymus [64]. Furthermore, depletion of Ins2 expression in medullary TEC is sufficient to break central tolerance and induce anti-insulin autoimmunity and rapid diabetes

onset in mouse [65]. Interestingly, intrathymic transplantation of pancreatic islet cells reduces autoimmunity towards β cells and prevents diabetes development in NOD/Lt mice [66]. Thus, the thymus could also play a role in acquired tolerance and may be a potential candidate in the therapeutics of autoimmune diseases. Negative selection might also be affected owing to antigen-processing defects. A defect of peptide presentation can result from the weak affinity of TCR for unstable MHC–peptide PRKACG complexes and/or from a defect in antigen processing by proteases of thymic APCs [58,67]. Major defects in the architecture of the thymic stroma found in animal models of diabetes are also thought to contribute to a defect in negative selection [58,67]. In NOD mice, for example, medullar TEC are present in the cortex, and large areas devoid of TEC and expression of MHC molecules are observed in the thymus [68]. Multiple thymocyte migration-related abnormalities have also been observed in the NOD mouse thymus [69].