IMMUNE REGULATION BY IMMUNOGLOBULIN-LIKE RECEPTORS

表达在B细胞和髓系细胞上的PIRS形成一种独特的“自我”识别。激活的PIR-A和抑制的PIR-B与多种小鼠MHC I类(H-2)分子结合。体外H-2四聚体刺激PIRS可诱导细胞内磷酸酪氨酸信号转导。移植异基因脾细胞的PIR-B缺陷小鼠表现出移植物抗宿主疾病的加重，这是由于受体的树突状细胞(DC)的增强激活，伴随着PIR-A的上调和干扰素的产生。Pir-A诱导的DC活化也导致供体细胞毒性T细胞的增殖增加。因此，PIR-A和PIR-B是在成功的组织移植中起关键作用的反向作用受体，在生理条件下可能以一种结构性的方式调节与自体组织无关的反应。为了分析DNAX蛋白12(DNAX Protein 12)缺陷小鼠轻度骨化症的病因，我们观察了FcRγ缺陷(Fcrγ-)和DAP12/Fcrγ双缺陷(DKO)小鼠的骨形态。组织学检查显示FCRγ--小鼠未出现明显的骨化病。然而，我们发现DKO小鼠表现出比DAP12-小鼠更严重的骨石化，这表明DAP12或FcRγ是正常骨重建所必需的。在破骨细胞前体细胞中，FcRγ和DAP12分别与OSCAR、PIR-A、TREM-2和Sirpβ1等多种Ig受体结合，并通过PLCγ激活Ca^2信号。因此，由多个IgLR激活的ITAM依赖的共刺激信号对于维持骨内环境的稳定是必不可少的，这表明RANK和M-CSF受体不足以激活破骨细胞形成所需的信号。

PIRs expressed on B and myeloid cells form a unique 'self' recognition. Activating PIR-A and inhibitory PIR-B were shown to bind various murine MHC class I (H-2) molecules. In vitro H-2 tetramer stimulation of PIRs induced intracellular phosphotyrosine signaling. PIR-B-deficient mice transferred with allogeneic splenocytes showed exacerbated graft-versus-host disease, which was due to the augmented activation of the recipient's dendritic cells (DCs) with the concomitant up-regulation of PIR-A and increased IFN-production. PIR-A-induced DC activation also led to increased proliferation of donor cytotoxic T cells. Thus, PIR-A and PIR-B are counter-acting receptors that play key roles for successful tissue transplantation, and may regulate irrelevant reaction to autologous tissues in a constitutive fashion under physiological circumstances.To analyze the etiology of mild osteopetrosis in DAP12 (DNAX protein 12)-deficient mice, we examined the bone morphology in FcRγ-deficient (FcRγ--) mice and DAP12/FcRγ double deficient (DKO) mice. Histological examination revealed that FcRγ--mice did not show any remarkable osteopetrosis. However, we found that DKO mice exhibited much more severe osteopetrosis than DAP12--mice, suggesting that either DAP12 or FcRγ is required for normal bone remodeling. In osteoclast precursor cells, FcRγ and DAP12 associate with multiple IgLRs including OSCAR and PIR-A ; and TREM-2 and SIRPβ1, respectively, and activate Ca^2 signal through PLCγ. Thus, ITAM-dependent costimulatory signals activated by multiple IgLRs are indispensable for the maintenance of bone homeostasis, indicating that RANK and M-CSF receptor are not sufficient to activate signals required for osteoclastogenesis.