CD72 Negatively Regulates KIT-Mediated Responses in Human Mast Cells
CD72 Negatively Regulates KIT-Mediated Responses in Human Mast Cells
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DOI：
10.4049/jimmunol.0902450
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发表时间：
2010-03-01
影响因子：
4.4
通讯作者：
Gilfillan, Alasdair M.
中科院分区：
文献类型：
--
作者：
Kataoka, Tatsuki R.;Kumanogoh, Atsushi;Gilfillan, Alasdair M.
KIT通过其配体干细胞因子的结合而活化，对于正常肥大细胞生长、分化和存活至关重要。此外，KIT也可能有助于肥大细胞归巢和细胞因子的产生。KIT的激活突变导致与骨髓增生性疾病肥大细胞增多症相关的肥大细胞生长失调。我们研究了通过肥大细胞抑制性受体激活下调这种反应的可能性。在这项研究中，我们报告，B细胞相关的ITIM抑制性受体，CD 72，在人类肥大细胞中表达。CD 72与激动性Ab、BU 40或与其天然配体重组人CD 100（rCD 100）的连接诱导了CD 72的磷酸化，导致其与含酪氨酸磷酸酶SH 2结构域的磷酸酶-1的结合增加。这反过来又导致KIT诱导的Src家族激酶和细胞外调节激酶（ERK 1/2）磷酸化的抑制。作为这些作用的结果，KIT介导的肥大细胞增殖，趋化性和趋化因子的产生显着减少BU 40和rCD 100。此外，BU 40和rCD 100还下调HMC 1.2人肥大细胞系的生长。因此，靶向CD 72可以提供一种抑制肥大细胞疾病如肥大细胞增多症的新方法。免疫学杂志，2010，184：2468-2475。
KIT activation, through binding of its ligand, stem cell factor, is crucial for normal mast cell growth, differentiation, and survival. Furthermore, KIT may also contribute to mast cell homing and cytokine generation. Activating mutations in KIT lead to the dysregulated mast cell growth associated with the myeloproliferative disorder, mastocytosis. We investigated the potential of downregulating such responses through mast cell inhibitory receptor activation. In this study, we report that the B cell-associated ITIM-containing inhibitory receptor, CD72, is expressed in human mast cells. Ligation of CD72 with the agonistic Ab, BU40, or with recombinant human CD100 (rCD100), its natural ligand, induced the phosphorylation of CD72 with a resulting increase in its association with the tyrosine phosphatase SH2 domain-containing phosphatase-1. This, in turn, resulted in an inhibition of KIT-induced phosphorylation of Src family kinases and extracellular-regulated kinases (ERK1/2). As a consequence of these effects, KIT-mediated mast cell proliferation, chemotaxis, and chemokine production were significantly reduced by BU40 and rCD100. Furthermore, BU40 and rCD100 also downregulated the growth of the HMC1.2 human mast cell line. Thus, targeting CD72 may provide a novel approach to the suppression of mast cell disease such as mastocytosis. The Journal of Immunology, 2010, 184: 2468-2475.