National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, 200433, China.
National Key Laboratory of Medical Molecular Biology & Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, 100730, China.
Sci China Life Sci. 2016 Dec;59(12):1259-1269. doi: 10.1007/s11427-016-0357-1. Epub 2016 Dec 6.
Kupffer cells, tissue-resident macrophage lineage cell, are enriched in vertebrate liver. The mouse F4/80 Kupffer cells have been subclassified into two subpopulations according to their phenotype and function: CD68 subpopulation with potent reactive oxygen species (ROS) production and phagocytic capacities, and CD11b subpopulation with a potent capacity to produce T helper 1 cytokines. In addition, CD11b Kupffer cells/macrophages may be migrated from the bone marrow or spleen, especially in inflammatory conditions of the liver. For analyzing diverse Kupffer cell subsets, we infected mice with Listeria monocytogenes and analyzed the phenotype variations of hepatic Kupffer cells. During L. monocytogenes infection, hepatic CD69 Kupffer cells were significantly induced and expanded, and CD69 Kupffer cells expressed higher level of CD11b, and particularly high level of membrane-bound TGF-β1 (mTGF-β1) but lower level of F4/80. We also found that clodronate liposome administration did not eliminate hepatic CD69 Kupffer cell subset. We consider the hepatic CD69 Kupffer cell population corresponds to CD11b Kupffer cells, the bone marrow-derived population. Hepatic CD69 Kupffer cells suppressed Ag-nonspecific and OVA-specific CD4 T cell proliferation through mTGF-β1 both in vitro and in vivo, meanwhile, they did not interfere with activation of CD4 T cells. Thus, we have identified a new subset of inflammation-induced CD69 Kupffer cells which can feedback inhibit CD4 T cell response via cell surface TGF-β1 at the late stage of immune response against infection. CD69 Kupffer cells may contribute to protect host from pathological injure by preventing overactivation of immune response.
枯否细胞（Kupffer cells）是组织驻留的巨噬细胞谱系细胞，在脊椎动物肝脏中丰富存在。根据表型和功能，小鼠 F4/80 枯否细胞已被细分为两个亚群：具有强大活性氧（ROS）产生和吞噬能力的 CD68 亚群，以及具有强大产生辅助性 T 细胞 1 细胞因子能力的 CD11b 亚群。此外，CD11b 枯否细胞/巨噬细胞可能来自骨髓或脾脏，尤其是在肝脏炎症情况下。为了分析不同的枯否细胞亚群，我们用李斯特菌（Listeria monocytogenes）感染小鼠，并分析肝枯否细胞的表型变化。在李斯特菌感染期间，肝 CD69 枯否细胞显著诱导和扩增，CD69 枯否细胞表达更高水平的 CD11b，特别是高水平的膜结合 TGF-β1（mTGF-β1），但低水平的 F4/80。我们还发现，氯膦酸盐脂质体给药不能消除肝 CD69 枯否细胞亚群。我们认为肝 CD69 枯否细胞群体对应于 CD11b 枯否细胞，即骨髓来源的群体。肝 CD69 枯否细胞通过 mTGF-β1 在体外和体内均抑制 Ag 非特异性和 OVA 特异性 CD4 T 细胞增殖，同时不干扰 CD4 T 细胞的激活。因此，我们已经鉴定出一种新的炎症诱导的 CD69 枯否细胞亚群，它可以通过细胞表面 TGF-β1 在感染后免疫反应的晚期反馈抑制 CD4 T 细胞反应。CD69 枯否细胞可能通过防止免疫反应过度激活，有助于保护宿主免受病理性损伤。
