Yagi Junji, Arimura Yutaka, Takatori Hiroaki, Nakajima Hiroshi, Iwamoto Itsuo, Uchiyama Takehiko
Department of Microbiology and Immunology, Tokyo Women's Medical University School of Medicine, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan.
Int Immunol. 2006 Dec;18(12):1681-90. doi: 10.1093/intimm/dxl102. Epub 2006 Oct 11.
Comparative studies using T(h)2-prone BALB/c and T(h)1-prone C57BL/6 mice were performed to clarify the influence of genetic background on T(h) cell differentiation. The results showed IL-4, the production of which is induced by IL-2, to be much more abundantly produced by BALB/c naive CD4(+) T cells than by C57BL/6 naive CD4(+) T cells, thereby leading to a tendency for differentiation toward T(h)2 in BALB/c naive CD4(+) T cells. This difference in IL-4 production between the two naive CD4(+) T cells appeared to be attributable to specific intracellular signaling events. Signal transducer and activator of transcription 5 (STAT5) was preferentially activated by IL-2 in CD4(+) T cells developing in BALB/c in contrast to the corresponding cells in C57BL/6. In addition, IL-4 also induced stronger STAT5 activation in CD4(+) T cells developing in BALB/c than in those developing in C57BL/6, whereas STAT6 was equally activated in these two cells. Further results supported the involvement of STAT5 in the difference in T(h) cell differentiation between BALB/c and C57BL/6 naive CD4(+) T cells. STAT5A(-)(/)(-) naive CD4(+) T cells with the BALB/c genetic background showed markedly less IL-2-induced IL-4 production than BALB/c naive CD4(+) T cells. Conversely, forced expression of the constitutively active forms of STAT5A and STAT5B in C57BL/6 naive CD4(+) T cells promoted the differentiation of T(h)2 cells. Thus, our results indicate IL-2-induced IL-4 production by naive CD4(+) T cells, in which STAT5 activation is involved and directly controlled by the genetic background, to influence T(h) cell differentiation in murine strains.
利用倾向于Th2的BALB/c小鼠和倾向于Th1的C57BL/6小鼠进行了比较研究，以阐明遗传背景对Th细胞分化的影响。结果显示，由IL-2诱导产生的IL-4，在BALB/c幼稚CD4(+) T细胞中的产生量比在C57BL/6幼稚CD4(+) T细胞中丰富得多，从而导致BALB/c幼稚CD4(+) T细胞有向Th2分化的趋势。两种幼稚CD4(+) T细胞在IL-4产生上的这种差异似乎归因于特定的细胞内信号转导事件。与C57BL/6中的相应细胞相比，信号转导和转录激活因子5（STAT5）在BALB/c发育的CD4(+) T细胞中被IL-2优先激活。此外，IL-4在BALB/c发育的CD4(+) T细胞中也比在C57BL/6发育的细胞中诱导更强的STAT5激活，而STAT6在这两种细胞中被同等激活。进一步的结果支持了STAT5参与BALB/c和C57BL/6幼稚CD4(+) T细胞在Th细胞分化上的差异。具有BALB/c遗传背景的STAT5A(-)(/)(-)幼稚CD4(+) T细胞显示出比BALB/c幼稚CD4(+) T细胞明显更少的IL-2诱导的IL-4产生。相反，在C57BL/6幼稚CD4(+) T细胞中强制表达组成型活性形式的STAT5A和STAT5B促进了Th2细胞的分化。因此，我们的结果表明，幼稚CD4(+) T细胞中由IL-2诱导的IL-4产生，其中STAT5激活参与且直接受遗传背景控制，影响小鼠品系中的Th细胞分化。
