Defective thymic progenitor development and mature T-cell responses in a mouse model for Down syndrome
Defective thymic progenitor development and mature T-cell responses in a mouse model for Down syndrome
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DOI：
10.1111/imm.12092
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发表时间：
2013-08-01
期刊：
影响因子：
6.4
通讯作者：
Williams, Mark S.
中科院分区：
文献类型：
--
作者：
Lorenzo, Laureanne P. E.;Shatynski, Kristen E.;Williams, Mark S.
除了典型的认知缺陷外，唐氏综合征(DS)的特征是淋巴细胞发育和功能改变，包括胸腺过早退化和感染发生率增加。然而，这些变化的潜在机制尚未完全阐明。目前的研究使用了DS的Ts65Dn小鼠模型来评估T细胞发育的缺陷和可能的分子变化。Ts65Dn小鼠表现出胸腺过早退化，未成熟、双阴性胸腺细胞前体细胞的数量和比例减少了三到四倍。此外，Ts65Dn胸腺中的双阳性胸腺细胞和CD4单阳性胸腺细胞的数量也减少了一倍。反映胸腺功能缺陷的是，脾中的幼稚T细胞较少，外周T细胞的多克隆刺激表现出明显的增殖减少，表明是衰老的表型。相反，Ts65Dn小鼠骨髓中的B细胞前体细胞没有变化，但在脾中，移行B细胞和滤泡B细胞减少，这些细胞在抗原受体刺激下增殖较少，但对脂多糖没有反应。作为胸腺功能减弱的潜在机制，未成熟胸腺细胞群体表达细胞因子受体白细胞介素7Rα水平降低，这与增殖减少和凋亡增加有关。氧化应激增加和Notch途径的抑制被认为是Ts65Dn小鼠IL-7Rα表达降低的可能中介。这些数据表明，未成熟胸腺细胞缺陷是DS免疫功能障碍的原因，氧化应激增加和细胞因子信号减少可能会改变Ts65Dn小鼠的淋巴细胞发育。
In addition to archetypal cognitive defects, Down syndrome (DS) is characterized by altered lymphocyte development and function, including premature thymic involution and increased incidence of infections. However, the potential mechanisms for these changes have not been fully elucidated. The current study used the Ts65Dn mouse model of DS to assess deficiencies in T-cell development and possible molecular alterations. Ts65Dn mice exhibited premature thymic involution and a threefold to fourfold decrease in the number and proportion of immature, double-negative thymocyte progenitors. In addition, there were twofold fewer double- positive and CD4 single-positive thymocytes in Ts65Dn thymuses. Reflecting this deficient thymic function, there were fewer naive T cells in the spleen and polyclonal stimulation of peripheral T cells exhibited a marked reduction in proliferation, suggesting a senescent phenotype. In contrast, B-cell progenitors were unchanged in the bone marrow of Ts65Dn mice, but in the spleen, there were decreased transitional and follicular B cells and these cells proliferated less upon antigen receptor stimulus but not in response to lipopolysaccharide. As a potential mechanism for diminished thymic function, immature thymocyte populations expressed diminished levels of the cytokine receptor interleukin-7R alpha, which was associated with decreased proliferation and increased apoptosis. Increased oxidative stress and inhibition of the Notch pathway were identified as possible mediators of decreased interleukin-7R alpha expression in Ts65Dn mice. The data suggest that immature thymocyte defects underlie immune dysfunction in DS and that increased oxidative stress and reduced cytokine signalling may alter lymphocyte development in Ts65Dn mice.