The loss of DN thymocytes was accompanied by a decrease in the proportion and absolute number of cells expressing IL-7Rα in the lineage negative and DN populations. This was also associated with decreased proliferation and increased apoptosis of the immature DN2 and DN3 populations. Interleukin-7 signalling has been shown to be essential for DN thymocyte proliferation and survival,[18]

and previous Y-27632 clinical trial studies have shown that lack of IL-7 or IL-7Rα results in an overall decrease in thymic cellularity.[17, 42] Therefore, diminished IL-7Rα expression and/or IL-7 signalling may be causing proliferative and survival defects in the DN thymocyte populations and contributing to Ts65Dn thymic hypocellularity. The loss of IL-7Rα expression, however, was selective for T-cell progenitors rather than cells committed to the T-cell lineage. Cells that had already undergone β-selection had similar cell surface expression levels of IL-7Rα comparing Ts65Dn with euploid controls. This

is also reflected in the periphery, where there were small decreases in IL-7Rα expression in the spleens of Ts65Dn mice. The IL-7 signalling pathway plays an essential role in peripheral T-cell homeostasis[43, 44] as well as the generation and maintenance of memory T cells.[45] Previous reports indicated increased plasma IL-7 in individuals with DS,[13] but although assay sensitivity precluded measuring IL-7 protein in Ts65Dn mice, IL-7 mRNA levels were not changed. Therefore, selleck compound the modest changes in IL-7Rα in the periphery may result in the observed changes in naive and central memory T cells. It is unclear why there is decreased IL-7Rα expression selectively in immature lymphoid progenitors, but the current results have identified potential regulators of IL-7Rα expression. One potential mechanism for regulation of IL-7Rα expression may be increases in oxidative stress. Previous data suggested that exposure of IL-7Rα+ cells to pro-oxidants in vitro decreased the percentage of IL-7Rα+ cells.[6] Existing[10, 41] and current

data suggest the presence of increased oxidative stress in Ts65Dn thymus, and the results suggest that decreased antioxidant defences, including glutathione and antioxidant Amino acid enzymes, promote pro-oxidant conditions in Ts65Dn mice. Inefficient induction of antioxidant enzyme defences may also contribute to increased oxidative stress in Ts65Dn thymus. Decreased NQO1 expression reflects diminished signalling through Nrf2-antioxidant response element-dependent gene expression.[34] Nrf2-antioxidant response element-induced expression of cytoprotective enzymes is a major mechanism for cellular defence against xenobiotics and oxidative stress. A possible mechanism for decreased NQO1 expression is the triplication of BACH1 on mouse chromosome 16 in the Ts65Dn mouse.