Differential signal transduction, membrane trafficking, and immune effector functions mediated by FcgammaRI versus FcgammaRIIa.
Differential signal transduction, membrane trafficking, and immune effector functions mediated by FcgammaRI versus FcgammaRIIa.
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DOI：
10.1182/blood-2008-10-184457
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发表时间：
2009-07-09
期刊：
影响因子：
20.3
通讯作者：
MacAry PA
中科院分区：
文献类型：
--
作者：
Dai X;Jayapal M;Tay HK;Reghunathan R;Lin G;Too CT;Lim YT;Chan SH;Kemeny DM;Floto RA;Smith KG;Melendez AJ;MacAry PA
免疫球蛋白-G (FcγRS) 片段可结晶区的受体在连接免疫反应的体液和细胞臂方面发挥着重要作用。在这项研究中，我们对 2 种人类 Fc 受体 FcγRI 和 FcγRIIa 进行了全面的功能比较。 FcγRI 的激活会产生一种新的信号级联，将 U937 细胞和原代人单核细胞中的磷脂酶 D1 与鞘氨醇激酶 1 连接起来。这会诱导促炎介质的表达，并与免疫复合物运输到人白细胞抗原-DM 阳性抗原加工区室中以及改善的 MHC II 类介导的 T 淋巴细胞抗原呈递有关。相反，FcγRIIa 的激活通过磷脂酶 Cγ1 引发信号传导，导致细胞内钙增加、烟酰胺腺嘌呤二核苷酸磷酸氧化爆发的激活以及差异膜运输与受损的抗原呈递和促炎细胞因子表达相结合。这些数据提供了对免疫中与 Fc 受体相关的不同活动的机制见解，即通过刺激促炎信号传导和抗原呈递来增强免疫反应，与通过免疫复合物的非炎症清除来维持免疫稳态。
Receptors for the fragment crystallizable region of immunoglobulin-G (FcγRS) play an important role in linking the humoral and cellular arms of the immune response. In this study, we present a comprehensive functional comparison of 2 human Fc-receptors, FcγRI and FcγRIIa. Activation of FcγRI results in a novel signaling cascade that links phospholipase D1 to sphingosine kinase-1 in U937 cells and primary human monocytes. This induces the expression of proinflammatory mediators and is associated with trafficking of immune complexes into human leukocyte antigen-DM positive antigen-processing compartments coupled with improved MHC class II–mediated antigen presentation to T lymphocytes. In contrast, activation of FcγRIIa elicits signaling through phospholipase Cγ1, resulting in increases in intracellular calcium, activation of nicotinamide adenine dinucleotide phosphateoxidative burst, and differential membrane trafficking combined with impaired antigen presentation and proinflammatory cytokine expression. These data provide a mechanistic insight into the disparate activities associated with Fc receptors in immunity, namely, reinforcement of immune responses through stimulation of proinflammatory signaling and antigen presentation, versus the maintenance of immunologic homeostasis through the noninflammatory clearance of immune complexes.