Role of LAIR-1, -2, and IRp60 Inhibitory Receptors in Re

该项目的目标是了解细胞表面受体及其配体之间的相互作用如何影响免疫系统中的细胞功能。特别是，我们对抑制受体如何控制免疫细胞反应感兴趣。抑制性受体在免疫反应中起调控作用，以避免可增强自身免疫的过度炎症反应。最近描述的两种抑制受体是白细胞相关的igg样受体-1 （lir -1，也称为CD305）和IRp60（也称为CD300a， LMIR1, CMRF35H）。LAIR-1和IRp60均在多种细胞类型中表达，包括T细胞、B细胞和NK细胞、肥大细胞、中性粒细胞、嗜酸性粒细胞、单核/巨噬细胞、树突状细胞和干细胞。LAIR-1的配体最近被确定为胶原蛋白，而IRp60的配体是未知的。体外研究表明，这两种受体都能下调激活信号。到目前为止，我们已经发表了LAIR-1在几种人类T细胞亚群中的表达差异，其中幼稚T细胞表达量最高，并且其结扎可以抑制T细胞受体（TCR）介导的钙释放和杀伤。我们已经证明，IRp60在粒细胞发育过程中表达得非常早，并且在外周血中性粒细胞中表达得非常高。GM-CSF和LPS刺激诱导细胞内IRp60池向中性粒细胞细胞表面的易位。虽然IRp60不能抑制LPS和fMLP介导的活性氧（ROS）的产生，但它可以抑制Fc？RIIa以钙介导的方式介导ROS的产生。除此之外，体内研究表明，在过敏性腹膜炎模型中，IRp60结扎可以抑制IgE介导的肥大细胞脱颗粒，以及嗜酸性粒细胞和肥大细胞向腹膜的募集。

The goal of this project is to understand how the interactions between cell surface receptors and their ligands affect cellular functions in the immune system. In particular, we are interested in how inhibitory receptors control immune cell responses. Inhibitory receptors act as a govenor on the immune response to avoid hyper inflammatory reactions that can potentiate autoimmunity. Two recently described inhibitory receptors are leukocyte-associated Ig-like receptor-1 (LAIR-1, also known as CD305) and IRp60 (also known as CD300a, LMIR1, CMRF35H). Both LAIR-1 and IRp60 are expressed by many cell types, including T, B and NK cells, mast cells, neutrophils, eosinophils, monocytes/macrophages, dendritic cells and stem cells. The ligand for LAIR-1 has recently been established as collagen(s), while the ligand for IRp60 is unknown. In vitro studies have shown that both receptors are able to down-regulate activation signals. So far, we have published that LAIR-1 is expressed differentially in several subsets of human T cells, with naive T cells expressing the highest amounts and that its ligation can inhibit T cell receptor (TCR) mediated calcium release and killing. We have shown that IRp60 is expressed very early during the granulocyte development and that it is very highly expressed in peripheral blood neutrophils. Stimulation with GM-CSF and LPS induces the translocation of an intracellular pool of IRp60 to the cell surface of neutrophils. While IRp60 can not inhibit LPS and fMLP mediated reactive oxygen species (ROS) production, it inhibits the Fc?RIIa mediated ROS production in calcium mediated manner. In addition to that, in vivo studies have shown that IRp60 ligation can inhibit IgE mediated mast cell degranulation and recruitment of eosinophils and mast cells into the peritoneum in a model of allergic peritonitis.