Full restoration of peripheral Foxp3+ regulatory T cell pool by radioresistant host cells in scurfy bone marrow chimeras
Full restoration of peripheral Foxp3+ regulatory T cell pool by radioresistant host cells in scurfy bone marrow chimeras
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DOI：
10.1073/pnas.0702004104
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发表时间：
2007-05-22
影响因子：
11.1
通讯作者：
Hori, Shohei
中科院分区：
文献类型：
--
作者：
Komatsu, Noriko;Hori, Shohei
编码转录因子Foxp3的基因突变会导致小鼠和人类致命的自身免疫性病理，这与Foxp3(+)调节性T细胞(Trg)的缺乏有关-也有人提出，非造血组织，特别是胸腺上皮中的Foxp3失活是发病所必需的，因为Foxp3突变使骨髓细胞无法将疾病传播到致命性照射的WT宿主。我们在这里证明，在这些辐射嵌合体中缺乏病理是由于宿主的抗辐射包膜Foxp3(+)T(Reg)的存在。此外，仅在非造血细胞中携带鳞屑突变的嵌合体没有自身免疫病理的证据。因此，非造血细胞中的Foxp3缺乏与鳞屑病无关。此外，我们对辐射嵌合体的分析表明，外周T(Reg)池完全和特异地由抗辐射的包涵体T(Reg)恢复和维持，或者在没有头皮屑供体骨髓细胞产生T(Reg)的情况下，通过“内稳态”增殖过继转移外源性Treg。因此，这些结果提供了证据，证明Scrfy小鼠的自身免疫病理确实是T(Reg)缺乏的结果，并说明了一种强大的稳态机制，该机制通过微调稳态增殖来严格控制外周Treg池的大小。
Mutations in the gene encoding the transcription factor Foxp3 lead to fatal autoimmune pathology in mice and humans, which is associated with a deficiency in Foxp3(+) regulatory T cells (Trg)- It has also been proposed that Foxp3 inactivation in nonhematopoietic tissues, particularly in thymic epithelium, is required for the pathogenesis, because Foxp3 mutantscurfy bone marrow cells fail to transmit the disease to lethally irradiated WT hosts. We demonstrate here that the lack of pathology in these radiation chimeras is due to the presence of radioresistant enclogenous Foxp3(+) T(reg) Of the host. In addition, chimeras carrying the scurfy mutation only in nonhematopoietic cells exhibit no evidence of autoimmune pathology. Thus, Foxp3 deficiency in nonhematopoietic cells does not contribute to the scurfy disease. Furthermore, our analyses of radiation chimeras revealed that the peripheral T(reg) Pool is fully and specifically restored and maintained by radioresistant enclogenous T(reg) or adoptively transferred exogenous Treg through "homeostatic" proliferation in the absence of T(reg) production from scurfy donor bone marrow cells. These results thus provide evidence that the autoimmune pathology in scurfy mice results indeed from a T(reg) deficiency and illustrate a robust homeostatic mechanism that strictly controls the size of peripheral Treg pool by fine-tuning of homeostatic proliferation.