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Studies on the regulatory mechanisms of type I interferons for T cell functions.

I型干扰素对T细胞功能调节机制的研究。

基本信息

批准号：
13670313
负责人：
TAKI Shinsuke
金额：
$ 2.5万
依托单位：
Shinshu University (2002)Chiba University (2001)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670313/
关键词：
interferons signal transaction receptors CD4+ T cells CD8+ T cells Th1 Th2 memory T cells interlenkin-4 T細胞免疫記憶加齢 CD8 IRF 転写因子遺伝子発現

项目摘要

CD4+ T cells in mice lacking the transcription factor interferon regulatory factor (IRF)-2, which we have shown to be a physiological negative regulator of the type I interferon (IFN-α/β) system, exhibited Th2 shift. We established here IRF-2-deficient mice expressing DO11.10 T cell receptor transgene, and examined in detail Th1/Th2 differentiation of CD4+ T cells in these mice. We found that IRF-2-deficient CD4+ T cells themselves were normal in terms of Th1/Th2 differentiation, and instead the environment wherein CD4+ T cells undergo differentiation affected the Th1/Th2 balance, and that splenic basophils produce initial IL-4, thereby inducing the Th2 shift. In mice lacking IRF-2 and the IFN-α/β receptor, basophils did not produce much IL-4, whereas in mice lacking both IRF-2 and signal transducer and activator of transcription (STAT)-6, the initial IL-4 production was not diminished. These results indicate that the Th2 shift in IRF-2-deficient mice is dependent oa IFN-α/β signals but not IL-4/IL-13. On the other hand, polydonal memory phenotype CD4+ and CD8+ T cells were accumulated in IRF-2-deficient mice to a higher extent than in wild-type mice within several months after birth, indicating that IRF-2 plays a role in regulating memory T cell homeostasis. We found that IRF-2 functions in a T cell-intrinsic manner, independent of continuous stimulation with endogenous or environmental antigens. Moreover, the mechanism for the memory T cell regulation by IRF-2 was found to be a novel one, distinct from that for the regulation of IFN-α/β signals.

在缺乏转录因子干扰素调节因子（IRF）-2的小鼠中，CD 4 + T细胞表现出Th 2漂移，我们已经证明IRF-2是I型干扰素（IFN-α/β）系统的生理负调节因子。我们在此建立了表达DO11.10 T细胞受体转基因的IRF-2缺陷小鼠，并详细检查了这些小鼠中CD 4 + T细胞的Th 1/Th 2分化。我们发现，IRF-2缺陷的CD 4 + T细胞本身在Th 1/Th 2分化方面是正常的，而不是CD 4 + T细胞经历分化的环境影响Th 1/Th 2平衡，并且脾嗜碱性粒细胞产生初始IL-4，从而诱导Th 2偏移。在缺乏IRF-2和IFN-α/β受体的小鼠中，嗜碱性粒细胞不产生大量IL-4，而在缺乏IRF-2和信号转导和转录激活因子（STAT）-6的小鼠中，初始IL-4产生并没有减少。这些结果表明，IRF-2缺陷型小鼠中的Th 2偏移依赖于IFN-α/β信号，而不是IL-4/IL-13。另一方面，在出生后几个月内，IRF-2缺陷型小鼠中多链体记忆表型CD 4+和CD 8 + T细胞的积累程度高于野生型小鼠，表明IRF-2在调节记忆T细胞稳态中起作用。我们发现，IRF-2功能的T细胞内在的方式，独立于连续刺激内源性或环境抗原。IRF-2对记忆性T细胞的调控机制与IFN-α/β信号的调控机制不同。