[14] As a result of the decrease in recent thymic emigrants, it has been suggested that peripheral T cells in individuals with DS undergo increased homeostatic proliferation in comparison to the general population.[14]

Because of mixed genetic background in Ts65Dn mice, differences in recent thymic emigrants cannot be reliably measured. Nevertheless, the selleck chemicals llc data are consistent with a loss of thymic precursors in the Ts65Dn mice leading to altered peripheral T-cell populations. Defects in Ts65Dn peripheral T-cell function are most evident in the decreased proliferation in response to polyclonal stimulation. This loss of function may be consistent with immune dysfunction in DS, as lymphocytes from individuals with DS have also been shown to exhibit a decreased proliferative response to polyclonal stimuli such as phytohaemagglutinin,[47, 48] in addition to the documented decrease in responses in some individuals with DS to vaccinations.[49, 50] Vaccine studies have shown that IL-7 and TCR signalling can synergize to promote antigen-specific effector cell generation, especially when using subdominant antigens.[51] Therefore decreased IL-7Rα expression as well as the deficient Trichostatin A mw proliferation in response to TCR stimulation may

contribute to the T-cell dysfunction observed in DS. It is tempting to speculate that the impaired proliferation in the immature thymocyte subsets as a consequence of decreased IL-7Rα expression 4��8C may be one of the causes of accelerated thymic involution as well as decreased thymic output in DS. In turn, the increased, possibly excessive, homeostatic cycling of peripheral T

cells in individuals with DS may result in premature senescence and impaired function. The changes in lymphocyte responses were not limited to T cells as B-cell proliferation was also diminished in response to antigen receptor stimulation, but not lipopolysaccharide. This is consistent with an anergic/senescent phenotype in the peripheral lymphocyte pools. However, in contrast to thymic development, B-cell progenitors in the bone marrow and IL-7Rα expression on those cells were not altered in the Ts65Dn mice, suggesting a selective effect on T-lymphocyte precursors. It is interesting, but unclear, why the previously reported decrease in CLP in Ts65Dn bone marrow[6] only results in diminished T-cell progenitors. One postulate is that decreases in Notch signalling, due to BACH1-mediated inhibition of Nrf2 or increased DYRK1a[52] in DS, leads to impaired T-cell specification, but not B-cell development. The resultant changes in mature B-cell function and spleen subsets may be, as has been proposed previously,53 due to altered T-cell help.