Vĕtvicka V, Hanikýrová M, Vĕtvicková J, Ross G D
Division of Experimental Immunology and Immunopathology, Department of Pathology, University of Louisville, KY, USA.
Clin Exp Immunol. 1999 Feb;115(2):229-35. doi: 10.1046/j.1365-2249.1999.00800.x.
Phagocyte and NK cell CR3 functions as both an adhesion molecule and an iC3b receptor mediating cytotoxic responses to microorganisms. Cytotoxic activation of iC3b receptor function requires ligation of both a CD11b I-domain site for iC3b and a lectin site located in the C-terminus of CD11b. Because tumours lack the CR3-binding polysaccharides of bacteria and fungi, iC3b-opsonized tumours do not stimulate CR3-dependent cytotoxicity. Previous studies showed that NK cells could be induced to kill iC3b-opsonized tumours with small soluble beta-glucans that bound with high affinity to CR3, bypassing the absence of similar polysaccharides on tumour membranes. Because CR3 signalling requires several tyrosine phosphorylation events, it appeared possible that CR3-dependent killing of autologous tumour cells might be suppressed by NK cell inhibitory receptors for MHC class I (KIR and CD94/NKG2) whose action involves recruitment of SHP-1 and SHP-2 tyrosine phosphatases. In the current study, Epstein-Barr virus (EBV)-transformed B cells were used as targets following opsonization with iC3b. Soluble beta-glucan primed CR3 for killing of iC3b-coated B cells, but autologous class I-bearing targets were 84% more resistant than class I-deficient Daudi cells. Blockade of target cell class I with a MoAb specific for a domain recognized by both KIR and CD94/NKG2 resulted in comparable killing of class I+ B cells. By contrast, another MoAb to class II had no effect on cytotoxicity. These data suggest that NK cell recognition of class I suppresses CR3/tyrosine kinase-dependent cytotoxicity in the same way as it suppresses cytotoxicity mediated by other tyrosine kinase-linked receptors such as FcgammaRIIIA (CD16).
吞噬细胞和自然杀伤（NK）细胞的补体受体3（CR3）作为一种黏附分子和iC3b受体，介导对微生物的细胞毒性反应。iC3b受体功能的细胞毒性激活需要iC3b的CD11b I结构域位点和位于CD11b C末端的凝集素位点的连接。由于肿瘤缺乏细菌和真菌的CR3结合多糖，iC3b调理的肿瘤不会刺激CR3依赖性细胞毒性。先前的研究表明，NK细胞可以被小的可溶性β-葡聚糖诱导杀伤iC3b调理的肿瘤，这些β-葡聚糖与CR3具有高亲和力结合，绕过了肿瘤膜上缺乏类似多糖的情况。由于CR3信号传导需要几个酪氨酸磷酸化事件，因此CR3依赖性杀伤自体肿瘤细胞可能会被MHC I类NK细胞抑制性受体（KIR和CD94/NKG2）抑制，其作用涉及募集SHP-1和SHP-2酪氨酸磷酸酶。在当前的研究中，爱泼斯坦-巴尔病毒（EBV）转化的B细胞在用iC3b调理后用作靶细胞。可溶性β-葡聚糖引发CR3以杀伤iC3b包被的B细胞，但自体携带I类的靶细胞比I类缺陷的Daudi细胞耐药性高84%。用对KIR和CD94/NKG2都识别的结构域具有特异性的单克隆抗体阻断靶细胞I类，导致对I类+B细胞的杀伤相当。相比之下，另一种针对II类的单克隆抗体对细胞毒性没有影响。这些数据表明，NK细胞对I类的识别以与抑制其他酪氨酸激酶连接受体（如FcγRIIIA，CD16）介导的细胞毒性相同的方式抑制CR3/酪氨酸激酶依赖性细胞毒性。
