Thymus dysfunction and chronic inflammatory disease in gp39 transgenic mice
Thymus dysfunction and chronic inflammatory disease in gp39 transgenic mice
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DOI：
10.1093/intimm/9.8.1111
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发表时间：
1997-08-01
影响因子：
4.4
通讯作者：
Hollenbaugh, D
中科院分区：
文献类型：
--
作者：
Clegg, CH;Rulffes, JT;Hollenbaugh, D
gp39 在活化 T 细胞上的表达在外周淋巴组织中提供共刺激信号，调节体液和细胞介导的免疫。 gp39及其受体CD40在胸腺中的功能仍不清楚，在此我们报道转基因小鼠胸腺中gp39的过度表达引起胸腺细胞数量的剂量依赖性下降（>500倍）、皮质上皮的损失和CD40（+）髓质细胞的扩张。将转基因骨髓移植到正常小鼠体内表明，在“正常”胸腺环境中，gp39 显着降低了胸腺细胞的活力。转基因小鼠的外周组织也以转基因剂量依赖性方式积累异常，涉及炎症和淋巴组织肥大。转基因拷贝数最高的动物获得了致命的炎症性肠病，其特征是 gp39(+) T 细胞和 CD40(+) 细胞浸润到患病组织中。对过表达 gp39 的细胞的检查表明，这些缺陷部分是由将 gp39 隔离在非激活细胞内的机制饱和引起的，从而保护免疫系统免受不适当的 gp39-CD40 相互作用的影响。这些结果确立了 gp39 的调节作用。胸腺功能和介导慢性炎症性疾病的因果关系。
Expression of gp39 on activated T cells provides a co-stimulatory signal in peripheral lymphoid tissue that regulates humoral and cell-mediated immunity. The function of gp39 and its receptor CD40 in thymus remains uncertain, Here we report that overexpression of gp39 in transgenic mouse thymus caused a dose-dependent decline in thymocyte numbers (>500 fold), loss of cortical epithelium and expansion of CD40(+) medullary cells. Transplantation of transgenic bone marrow into normal mice indicated that gp39 significantly diminished thymocyte viability in the context of a 'normal' thymic environment. The peripheral tissues of transgenic mice also accumulated abnormalities in a transgene dose-dependent manner that involved inflammation and lymphoid tissue hypertrophy. Animals with the highest transgene copy numbers acquired a lethal inflammatory bowel disease marked by the infiltration of gp39(+) T cells and CD40(+) cells into diseased tissues, Examination of cells overexpressing gp39 suggested that these defects were caused, in part, by the saturation of a mechanism that sequesters gp39 inside non-activated cells and thus protects the immune system from inappropriate gp39-CD40 interaction, These results establish a regulatory role for gp39 in thymus function and a causal relationship in mediating chronic inflammatory disease.