Research Institute of the McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada.
Division of Experimental Medicine, McGill University, Montreal, Quebec H4A 3J1, Canada.
J Immunol. 2018 Jul 1;201(1):113-123. doi: 10.4049/jimmunol.1701370. Epub 2018 May 9.
NK cells elicit important responses against transformed and virally infected cells. Carriage of the gene encoding the activating killer Ig-like receptor KIR3DS1 is associated with slower time to AIDS and protection from HIV infection. Recently, open conformers of the nonclassical MHC class Ib Ag HLA-F were identified as KIR3DS1 ligands. In this study, we investigated whether the interaction of KIR3DS1 on primary NK cells with HLA-F on the HLA-null cell line 721.221 (221) stimulated KIR3DS1 NK cells. We used a panel of Abs to detect KIR3DS1CD56 NK cells that coexpressed the inhibitory NK cell receptors KIR2DL1/L2/L3, 3DL2, NKG2A, and ILT2; the activating NK cell receptors KIR2DS1/S2/S3/S5; and CCL4, IFN-γ, and CD107a functions. We showed that both untreated and acid-pulsed 221 cells induced a similar frequency of KIR3DS1 cells to secrete CCL4/IFN-γ and express CD107a with a similar intensity. A higher percentage of KIR3DS1 than KIR3DS1 NK cells responded to 221 cells when either inclusive or exclusive (i.e., coexpressing none of the other inhibitory NK cell receptors and activating NK cell receptors detected by the Ab panel) gating strategies were employed to identify these NK cell populations. Blocking the interaction of HLA-F on 221 cells with KIR3DS1-Fc chimeric protein or anti-HLA-F Abs on exclusively gated KIR3DS1 cells reduced the frequency of functional cells compared with that of unblocked conditions for stimulated KIR3DS1 NK cells. Thus, ligation of KIR3DS1 activates primary NK cells for several antiviral functions.
自然杀伤 (NK) 细胞针对转化细胞和病毒感染细胞产生重要反应。携带编码激活杀伤免疫球蛋白样受体 KIR3DS1 的基因与艾滋病发病时间延迟和免受 HIV 感染有关。最近，非经典 MHC Ⅰ类 Ag HLA-F 的开放构象被鉴定为 KIR3DS1 的配体。在这项研究中，我们研究了主要 NK 细胞上的 KIR3DS1 与 HLA-null 细胞系 721.221（221）上的 HLA-F 的相互作用是否刺激了 KIR3DS1 NK 细胞。我们使用了一组 Ab 来检测共表达抑制性 NK 细胞受体 KIR2DL1/L2/L3、3DL2、NKG2A 和 ILT2、激活 NK 细胞受体 KIR2DS1/S2/S3/S5 以及 CCL4、IFN-γ 和 CD107a 功能的 KIR3DS1 CD56 NK 细胞。我们表明，未经处理和酸脉冲处理的 221 细胞诱导相似频率的 KIR3DS1 细胞分泌 CCL4/IFN-γ 和以相似强度表达 CD107a。当使用包容性或排他性（即，共同表达 Ab 面板检测到的其他抑制性 NK 细胞受体和激活 NK 细胞受体均不表达）门控策略来识别这些 NK 细胞群时，与 KIR3DS1 NK 细胞相比，更高比例的 KIR3DS1 细胞对 221 细胞作出反应。用 KIR3DS1-Fc 嵌合蛋白阻断 221 细胞上 HLA-F 与 KIR3DS1 的相互作用，或在用排他性门控 KIR3DS1 细胞上的抗 HLA-F Ab 阻断后，与刺激的 KIR3DS1 NK 细胞的未阻断条件相比，功能细胞的频率降低。因此，KIR3DS1 的配体结合激活了针对几种抗病毒功能的原代 NK 细胞。
