Expression of CTLA-4 and FOXP3 in cis protects from lethal lymphoproliferative disease
Expression of CTLA-4 and FOXP3 in cis protects from lethal lymphoproliferative disease
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DOI：
10.1002/eji.200737159
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发表时间：
2007-05-01
影响因子：
5.4
通讯作者：
Bluestone, Jeffrey A.
中科院分区：
文献类型：
--
作者：
Chikuma, Shunsuke;Bluestone, Jeffrey A.
CTLA-4缺陷型和FoxP 3缺陷型小鼠由于大量淋巴细胞增殖（LP）和系统性自身免疫样综合征而表现出短寿命。虽然它已被假定，这两种疾病的结果从调节性T细胞（Treg）的缺陷，一直没有直接的互补研究，以阐明它们之间的关系，在新生儿时期的稳态淋巴细胞增殖。在这项研究中，用CTLA-4缺陷或FoxP 3缺陷骨髓（BM）重建亚致死剂量辐照的RAG KO小鼠导致LP疾病，分别与CTLA-4 KO或Scurfy小鼠中观察到的相似。尽管来自野生型小鼠的BM的共注射抑制了CTLA-4缺陷型或FoxP 3缺陷型T细胞的活化，并通过T-reg细胞的外在调节机制改善了LP疾病，但接受Scurfy和CTLA-4 KO BM的BM混合物的小鼠最终死于不完全保护。这些结果表明这两种疾病的共同属性，但CTLA-4和FoxP 3在相同细胞亚群上的表达对于完全预防LP疾病是必不可少的。
Both CTLA-4-deficient and FoxP3-deficient mice exhibit a short life span due to massive lymphoproliferation (LP) and a systemic autoimmune-like syndrome. Although it has been postulated that both diseases result from regulatory T cell (Treg) defects, there have been no direct complementation studies to elucidate their relationship in homeostatic lymphocyte proliferation during the neonatal period. In this study, reconstitution of sublethally irradiated RAG KO mice with either CTLA-4-deficient or FoxP3-deficient bone marrow (BM) resulted in LP disease similar to that observed in CTLA-4 KO or Scurfy mice, respectively. Although co-injection of BM from wild-type mice inhibited the activation of CTLA-4-deficient or FoxP3-deficient T cells and ameliorated LP disease through extrinsic regulatory mechanisms by T-reg cells, mice that had received the BM mixture of Scurfy and CTLA-4 KO BM eventually died of incomplete protection. These results suggest common attributes of both diseases, but expression of both CTLA-4 and FoxP3 on the same cell subset is essential to fully prevent LP disease.