Kitada Shoko, Kayama Hisako, Okuzaki Daisuke, Koga Ritsuko, Kobayashi Masao, Arima Yasunobu, Kumanogoh Atsushi, Murakami Masaaki, Ikawa Masahito, Takeda Kiyoshi
Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
J Exp Med. 2017 May 1;214(5):1313-1331. doi: 10.1084/jem.20161076. Epub 2017 Mar 29.
Inappropriate IL-17 responses are implicated in chronic tissue inflammation. IL-23 contributes to -specific IL-17 production, but the molecular mechanisms underlying regulation of the IL-23-IL-17 axis during infection are poorly understood. Here, we demonstrate a novel function of BATF2 as a negative regulator of in innate immune cells. IL-17, but not IFN-γ, was more highly produced by CD4 T cells from spleens and livers of -infected mice than by those of wild-type mice. In this context, mice showed severe multiorgan pathology despite reduced parasite burden. -induced IL-23 production was increased in innate immune cells. The -induced enhanced Th17 response was abrogated in mice. The interaction of BATF2 with c-JUN prevented c-JUN-ATF-2 complex formation, inhibiting expression. These results demonstrate that IFN-γ-inducible BATF2 in innate immune cells controls Th17-mediated immunopathology by suppressing IL-23 production during infection.
不适当的白细胞介素-17反应与慢性组织炎症有关。白细胞介素-23有助于特异性白细胞介素-17的产生，但在感染期间白细胞介素-23-白细胞介素-17轴调控的分子机制仍知之甚少。在此，我们证明了BATF2在先天免疫细胞中作为感染的负调节因子的新功能。与野生型小鼠相比，感染寄生虫的小鼠脾脏和肝脏中的CD4 T细胞产生的白细胞介素-17而非干扰素-γ水平更高。在此背景下，尽管寄生虫负担减轻，但感染寄生虫的小鼠仍表现出严重的多器官病理变化。在先天免疫细胞中，感染诱导的白细胞介素-23产生增加。在感染寄生虫的小鼠中，感染诱导的增强的辅助性T细胞17反应被消除。BATF2与c-JUN的相互作用阻止了c-JUN-ATF-2复合物的形成，抑制了表达。这些结果表明，先天免疫细胞中干扰素-γ诱导的BATF2通过在感染期间抑制白细胞介素-23的产生来控制辅助性T细胞17介导的免疫病理学。
