Thymocyte development is normal in CTLA-4-deficient mice
Thymocyte development is normal in CTLA-4-deficient mice
复制标题
DOI：
10.1073/pnas.94.17.9296
复制
发表时间：
1997-08-19
影响因子：
11.1
通讯作者：
Allison, JP
中科院分区：
文献类型：
--
作者：
Chambers, CA;Cado, D;Allison, JP
近期研究表明，细胞毒性T淋巴细胞相关抗原4（CTLA - 4）与B7配体的相互作用向T淋巴细胞传递一种抑制信号。CTLA - 4基因纯合缺失突变的小鼠为CTLA - 4在体内的功能重要性提供了最显著的例子。这些动物会患上一种致命的淋巴细胞增殖性疾病，据报道其CD4(+)和CD8(+)胸腺细胞以及CD4(-)CD8(-)胸腺细胞增加，而CD4(+)CD8(+)胸腺细胞减少。基于这些观察结果，有人提出CTLA - 4对正常胸腺细胞发育是必需的。在本研究中，构建了CTLA - 4基因第3外显子插入突变的CTLA - 4缺陷小鼠。尽管这些小鼠表现出与先前报道相似的淋巴细胞增殖性疾病，但当将胸腺旁淋巴结从胸腺中排除时，胸腺细胞的分布没有改变。此外，在个体发育过程中和新生小鼠中胸腺细胞发育正常，胸腺细胞的产生没有增加。最后，通过检测近端和远端事件评估发现，CTLA - 4(-/-)动物的胸腺细胞中T细胞抗原受体信号传导没有改变。总之，这些结果清楚地表明，CTLA - 4缺陷小鼠中T细胞的异常扩增不是由于胸腺细胞发育改变所致，并提示先前描述的明显改变的胸腺表型是由于包含了胸腺旁淋巴结，以及在明显患病的动物中是由于活化的外周T细胞浸润胸腺所致。因此，CTLA - 4似乎主要参与外周T细胞活化的调节。
Recent studies indicate that CTLA-4 interaction with B7 ligands transduces an inhibitory signal to T lymphocytes. Mice homozygous for a null mutation in CTLA-4 have provided the most dramatic example of the functional importance of CTLA-4 in viva. These animals develop a fatal lymphoproliferative disorder and were reported to have an increase in CD4(+) and CD8(+) thymocytes and CD4(-)CD8(-) thymocytes, and a decrease in CD4(+)CD8(+) thymocytes. Based on these observations, it was proposed that CTLA-4 is necessary for normal thymocyte development. In this study, CTLA-4-deficient mice carrying an insertional mutation into exon 3 of the ctla-4 gene were generated. Although these mice display a lymphoproliferative disorder similar to previous reports, there was no alteration in the thymocyte profiles when the parathymic lymph nodes mere excluded from the thymi, Further, thymocyte development was normal throughout ontogeny and in neonates, and there was no increase in thymocyte production, Finally, T cell antigen receptor signaling, as assessed by proximal and distal events, was not altered in thymocytes from CTL-4-4(-/-) animals. Collectively, these results clearly demonstrate that the abnormal T cell expansion in the CTLA-4-deficient mice is not due to altered thymocyte development and suggest that the apparent altered thymic phenotype previously described was due to the inclusion of parathymic lymph nodes and, in visibly ill animals, to the infiltration of the thymus by activated peripheral T cells, Thus it appears that CTLA-4 is primarily involved in the regulation of peripheral T cell activation.