The inhibitory receptor IRp60 (CD300a) suppresses the effects of IL-5, GM-CSF, and eotaxin on human peripheral blood eosinophils
The inhibitory receptor IRp60 (CD300a) suppresses the effects of IL-5, GM-CSF, and eotaxin on human peripheral blood eosinophils
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DOI：
10.1182/blood-2005-07-2926
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发表时间：
2006-03-01
期刊：
影响因子：
20.3
通讯作者：
Levi-Schaffer, F
中科院分区：
文献类型：
--
作者：
Munitz, A;Bachelet, I;Levi-Schaffer, F
由嗜酸性粒细胞进行的过敏、炎症和免疫反应受激活和抑制信号之间的串扰调节。虽然已经获得了许多关于激活信号的数据，但这些细胞上的抑制性受体却很少受到关注。因此，我们使用单克隆抗体（mab）筛选人外周血嗜酸性粒细胞表面的抑制受体，这些单克隆抗体是先前生成的，用于识别人自然杀伤细胞上的受体。所有供体的嗜酸性粒细胞均表达抑制受体IRp60、LIR3/ILT5、Fc γ RIIB和p75/AIRM，但不表达LIR1/ILT2、p58.1、p58.25、p70或NKG2A/CD94 （n = 15）。有趣的是，25%的供体表达p140。IRp60交联以不依赖钙的方式抑制嗜酸性粒细胞依赖eotaxin的迁移。此外，在IL-5/GM-CSF存在的情况下，lRp60与嗜酸性粒细胞的交联抑制了这些细胞因子的抗凋亡作用，并阻断了tnf - α、IL-11 β、ifn - γ、IL-4和3T3成纤维细胞的增殖。lRp60交联抑制IL-5介导的JAK2磷酸化，以及eotaxin和IL-5/ gm - csf介导的ERK1/2和p38磷酸化。此外，在交联后，IRp60经历了酪氨酸磷酸化，并募集了SHP-1而不是SHP-2。这些发现证明了一种抑制人类嗜酸性粒细胞活性的新途径，从而表明IRp60是治疗过敏性和嗜酸性粒细胞相关疾病的未来潜在靶点。
Allergic, inflammatory, and immune responses carried out by eosinophils are regulated by the cross talk between activatory and inhibitory signals. While much data has been obtained on activatory signals, inhibitory receptors on these cells have received scant attention. Therefore, we screened the surface of human peripheral blood eosinophils for inhibitory receptors using monoclonal antibodies (mAbs) previously generated to recognize receptors on human natural killer cells. Eosinophils from all of the donors examined expressed the inhibitory receptors IRp60, LIR3/ILT5, Fc gamma RIIB, and p75/AIRM but not LIR1/ILT2, p58.1, p58.25 p70, or NKG2A/CD94 (n = 15). Interestingly, 25% of the donors expressed p140. IRp60 cross-linking inhibited eotaxin-dependent transmigration of eosinophils in a calcium-independent fashion. In addition, cross-linking of lRp60 on the eosinophils in the presence of IL-5/GM-CSF inhibited the antiapoptotic effect of these cytokines and blocked the release of TNF-alpha, IL-11 beta, IFN-gamma, IL-4, and 3T3 fibroblast proliferation. Cross-linking of lRp60 inhibited IL-5-mediated JAK2 phosphorylation as well as eotaxin- and IL-5/GM-CSF-mediated ERK1/2 and p38 phosphorylation. Furthermore, upon cross-linking, IRp60 underwent tyrosine phosphorylation and recruited SHP-1 but not SHP-2. These findings demonstrate a novel pathway for suppressing the activity of human eosinophils, thus indicating IRp60 as a future potential target for the treatment of allergic and eosinophil-associated diseases.