Functional analysis of a novel inhibitory receptor expressed on plasmacytoid dendritic cells

抑制性受体通过负性调节细胞功能，在精细调节和终止免疫应答中发挥关键作用。已经在各种类型的细胞上鉴定了许多抑制性受体。特别是，自然杀伤细胞上的抑制性受体已经得到很好的表征。据推测，通过抑制性NK受体识别靶细胞上的MHC I类或相关分子，允许NK细胞防止自我杀伤，但破坏具有降低水平的MHC I类的不适当的细胞。Ly 49 Q是一种携带ITIM的抑制性受体，属于Ly 49家族，该家族被称为NK受体的亚家族之一。尽管Ly 49 Q由于其高度的结构相似性和染色体位置而被归类为Ly 49家族，但Ly 49 Q具有不同于其他Ly 49家族成员的独特特征。Ly 49 Q在NK和NKT细胞上不表达，但主要在巨噬细胞和浆细胞树突状细胞上表达。ly 49 q有一个abi ...更多信息 Ly 49 Q与SHP-1和SHP-2均以酪氨酸磷酸化依赖的方式结合，我们在此证明Ly 49 Q的不同表达水平决定了骨髓PDCs的连续成熟阶段。此外，我们根据Ly 49 Q的表达鉴定了功能不同的PDCs亚群。脾和淋巴结中大多数CD 11 c ^+B220^+PDCs表达高水平的Ly 49 Q。然而，BM、血液、肝脏和肺中的显著部分的PDC缺乏Ly 49 Q表达。与Ly 49 Q ^+ PDCs相比，Ly 49 Q ^-PDCs对TLR配体产生IFN-αβ/、IL-6和IL-12 p70的能力较低。然而，有趣的是，当暴露于CpG和HVJ时，Ly 49 Q ^- PDCs具有产生与Ly 49 Q ^+ PDCs相同水平的TNF-α的能力。因此，Ly 49 Q是一个有用的标志物，以揭示PDCs的成熟过程和区分功能不同的PDCs的子集。我们的研究结果表明，PDCs的细胞因子谱在其成熟过程中发生变化，PDCs发挥不同的免疫功能，这取决于其成熟阶段。为了了解Ly 49 Q的功能相关性以及巨噬细胞和树突状细胞对MHC I类的识别，我们开始建立表达Ly 49 Q的转基因小鼠。少

Inhibitory receptors play crucial roles for fine regulation and termination of immune responses by negatively regulating cellular functions. A number of inhibitory receptors have been identified on various types of cells. In particular, inhibitory receptors on natural killer cells have been well characterized. It has been postulated that recognition of MHC class I, or related molecules, on target cells by inhibitory NK receptors allows NK cells to prevent self killing but destroy inappropriate cells possessing decreased levels of MHC class I.Ly49Q is an ITIM-bearing inhibitory receptor belonging to Ly49 family that is known as one of subfamilies of NK receptors. Even though Ly49Q is classified into Ly49 family because of highly structural similarities and of its chromosomal location, Ly49Q has unique features different from other Ly49 family members. Ly49Q is not expressed on NK and NKT cells, but predominantly expressed on macrophages and plasmacytodi dendritic cells. Ly49Q has an abi … More lity to associate with both SHP-1 and SHP-2 in a tyrosine phosphorylation-dependent manner.We here demonstrate that different expression levels of Ly49Q defined sequential maturational stages of PDCs in bone marrow. Moreover, we identified functionally different subsets of PDCs according to the expression of Ly49Q. Most CD11c^+B220^+PDCs in spleen and lymph node expressed high levels of Ly49Q. However, a significant portion of PDCs in BM, blood, liver and lung lacked Ly49Q expression. Ly49Q^- PDCs possessed lower abilities to produced IFN-αβ/, IL-6 and IL-12 p70 than Ly49Q^+ PDCs in response to TLR ligands. Interestingly, however, Ly49Q^- PDCs bore an ability to produce equivalent levels of TNF-α to Ly49Q^+ PDCs when exposed to CpG and HVJ. Thus, Ly49Q is a useful marker to reveal maturation process of PDCs and to distinguish functionally different subsets of PDCs. Our results suggest that cytokine profiles of PDCs alter during their maturational processes and that PDCs play different immunological functions depending on their maturational stages. To understand functional relevance of Ly49Q as well as MHC class I recognition by macrophages and dendritic cells, we started to establish transgenic mice expressing Ly49Q. Less