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缺乏干扰素调节因子4的小鼠中Th1而非Th2免疫反应的发育

Development of Th1 and not Th2 immune responses in mice lacking IFN-regulatory factor-4.

作者信息

Tominaga Norio, Ohkusu-Tsukada Kozo, Udono Heiichiro, Abe Ryo, Matsuyama Toshifumi, Yui Katsuyuki

机构信息

Division of Immunology, Department of Translational Medical Sciences, Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki University, Nagasaki 852-8523, Japan.

出版信息

Int Immunol. 2003 Jan;15(1):1-10. doi: 10.1093/intimm/dxg001.

Abstract

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.

摘要

干扰素调节因子(IRF)-4是转录因子IRF家族的成员之一,在淋巴细胞和巨噬细胞中表达。先前对IRF-4基因缺陷小鼠的研究表明,B细胞和T细胞的功能均存在严重缺陷。为了进一步研究IRF-4在CD4(+) T细胞功能中的作用,用细胞内病原体硕大利什曼原虫感染IRF-4(-/-)小鼠。在感染早期,这些小鼠对硕大利什曼原虫具有抵抗力,感染小鼠的CD4(+) T细胞在接触硕大利什曼原虫抗原后产生γ干扰素。然而,在感染后期,引流淋巴结中的淋巴细胞数量急剧减少,导致病变恶化,这表明IRF-4是针对硕大利什曼原虫感染的持续免疫反应所必需的。使用缺乏IRF-4基因的TCR转基因小鼠进一步研究了CD4(+) T细胞的功能。在体外Th1偏向条件下培养后,来自IRF-4(-/-)小鼠的CD4(+) T细胞产生γ干扰素并表达T-bet。然而,在Th2极化条件下培养后未观察到Th2细胞发育。IRF-4(-/-)小鼠中CD4(+) T细胞对IL-4的增殖减少,表明对IL-4的反应存在缺陷。此外,用IL-4刺激IRF-4(-/-) CD4(+) T细胞可诱导信号转导和转录激活因子6的激活,但不诱导生长因子独立蛋白1的表达。因此,CD4(+) T细胞亚群的发育对IRF-4的依赖性不同;Th1反应的诱导不依赖于IRF-4,而Th2反应则完全依赖于IRF-4。

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