Development of Th1 and not Th2 immune responses in mice lacking IFN-regulatory factor-4
Development of Th1 and not Th2 immune responses in mice lacking IFN-regulatory factor-4
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DOI：
10.1093/intimm/dxg001
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发表时间：
2003-01-01
影响因子：
4.4
通讯作者：
Yui, K
中科院分区：
文献类型：
--
作者：
Tominaga, N;Ohkusu-Tsukada, K;Yui, K
ifn调节因子(IRF)-4是在淋巴细胞和巨噬细胞中表达的IRF转录因子家族成员。先前使用IRF-4基因缺失的小鼠进行的研究显示，B细胞和T细胞的功能都存在严重缺陷。为了进一步研究IRF-4在CD4(+) T细胞功能中的作用，我们用细胞内病原菌利什曼原虫（Leishmania major）攻击IRF-4（-/-）小鼠。小鼠在感染的早期阶段对L. major有保护作用，感染小鼠的CD4(+) T细胞对L. major抗原产生ifn - γ。然而，在感染后期，引流淋巴结的淋巴细胞数量急剧减少，导致病变恶化，这表明IRF-4是对L. major感染持续免疫应答所必需的。利用缺乏IRF-4基因的TCR转基因小鼠进一步研究CD4(+) T细胞的功能。IRF-4（-/-）小鼠CD4(+) T细胞在体外T(h)1偏斜条件下培养后产生ifn - γ并表达T-bet。然而，在T(h)2极化条件下培养后，未观察到T(h)2细胞发育。在IRF-4（-/-）小鼠中，CD4(+) T细胞对IL-4的增殖减少，提示对IL-4的反应性存在缺陷。此外，用il -4刺激IRF-4(-/-) CD4(+) T细胞可诱导信号换能器和转录激活因子的激活6，但不表达生长因子独立的1。因此，CD4(+) T细胞亚群的发育差异依赖于IRF-4；T(h)1反应的诱导不依赖于IRF-4，而T(h)2反应的诱导完全依赖于IRF-4。
IFN-regulatory factor (IRF)-4 is a member of the IRF family of transcription factors expressed in lymphocytes and macrophages. The previous studies using mice deficient in the IRF-4 gene showed profound defects in function of both B and T cells. To further investigate the role of IRF-4 in CD4(+) T cell function, IRF-4(-/-) mice were challenged with the intracellular pathogen Leishmania major. The mice were protected against L. major during the early phase of the infection and CD4(+) T cells of the infected mice produced IFN-gamma in response to L. major antigen. However, during the late phase of infection, lymphocyte numbers were dramatically reduced in the draining lymph nodes, resulting in the deterioration of the lesion, indicating that IRF-4 was required for sustained immune responses against L. major infection. The function of CD4(+) T cells was further investigated using TCR transgenic mice lacking the IRF-4 gene. CD4(+) T cells from IRF-4(-/-) mice produced IFN-gamma and expressed T-bet after culture under T(h)1-skewing conditions in vitro. However, T(h)2 cell development was not observed after culture under T(h)2-polarizing conditions. Proliferation of CD4(+) T cells to IL-4 was reduced in IRF-4(-/-) mice, suggesting the defects in the responsiveness to IL-4. Furthermore, stimulation of the IRF-4(-/-) CD4(+) T cells with IL-4-induced activation of signal transducer and activator of transcription 6, but not expression of growth factor independent-1. Thus, development of CD4(+) T cell subsets differentially depends on IRF-4; induction of T(h)1 response does not depend on IRF-4, while T(h)2 response depends entirely on IRF-4.