Matsumoto Koichiro, Inoue Hiromasa, Nakano Takako, Tsuda Miyuki, Yoshiura Yuki, Fukuyama Satoru, Tsushima Fumihiko, Hoshino Tomoaki, Aizawa Hisamichi, Akiba Hisaya, Pardoll Drew, Hara Nobuyuki, Yagita Hideo, Azuma Miyuki, Nakanishi Yoichi
Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
J Immunol. 2004 Feb 15;172(4):2530-41. doi: 10.4049/jimmunol.172.4.2530.
B7-H1 (PD-L1) and B7-DC (PD-L2) are the ligands for programmed death-1 (PD-1), which is a member of the CD28/CTLA-4 family and has been implicated in peripheral tolerance. We investigated the roles of B7-H1 and B7-DC in a murine OVA-induced allergic asthma model. B7-H1 was constitutively expressed on dendritic cells, macrophages, B cells, and T cells in the lungs of naive mice, and its expression could be dramatically increased after allergen challenge. In contrast, B7-DC expression was scarcely expressed on dendritic cells in naive mice, but was up-regulated after allergen challenge, although the up-regulation of B7-DC expression on macrophages was minimal. Treatment of mice with anti-B7-DC mAb at the time of allergen challenge, but not at the time of sensitization, significantly increased their airway hyper-reactivity and eosinophilia. Such treatment also resulted in the increased production of IL-5 and IL-13, and decreased IFN-gamma production in the lungs and draining lymph node cells. These changes were diminished when mice were depleted of IFN-gamma by anti-IFN-gamma mAb pretreatment. Interestingly, treatment with anti-B7-H1 or anti-PD-1 mAb did not significantly affect the asthmatic response. These results suggest a unique role for B7-DC in the regulation of asthmatic response through an IFN-gamma-dependent, but PD-1-independent, mechanism.
B7-H1（程序性死亡配体1，PD-L1）和B7-DC（程序性死亡配体2，PD-L2）是程序性死亡受体1（PD-1）的配体，PD-1属于CD28/细胞毒性T淋巴细胞相关抗原4（CTLA-4）家族，与外周免疫耐受有关。我们在小鼠卵清蛋白（OVA）诱导的过敏性哮喘模型中研究了B7-H1和B7-DC的作用。B7-H1在未接触过抗原的小鼠肺组织中的树突状细胞、巨噬细胞、B细胞和T细胞上组成性表达，在过敏原攻击后其表达可显著增加。相比之下，B7-DC在未接触过抗原的小鼠树突状细胞上几乎不表达，但在过敏原攻击后上调，尽管巨噬细胞上B7-DC表达的上调程度最小。在过敏原攻击时而非致敏时用抗B7-DC单克隆抗体治疗小鼠，可显著增加其气道高反应性和嗜酸性粒细胞增多。这种治疗还导致肺组织和引流淋巴结细胞中白细胞介素-5（IL-5）和白细胞介素-13的产生增加，干扰素-γ（IFN-γ）的产生减少。当通过抗IFN-γ单克隆抗体预处理使小鼠体内的IFN-γ耗竭时，这些变化减弱。有趣的是，用抗B7-H1或抗PD-1单克隆抗体治疗对哮喘反应没有显著影响。这些结果表明，B7-DC通过一种IFN-γ依赖性但PD-1非依赖性的机制在哮喘反应调节中发挥独特作用。
