Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI.
Wisconsin National Primate Research Center, University of Wisconsin-Madison.
J Immunol. 2023 Jun 1;210(11):1815-1826. doi: 10.4049/jimmunol.2200954.
Definition of MHC class I ligands of rhesus macaque killer cell Ig-like receptors (KIRs) is fundamental to NK cell biology in this species as an animal model for infectious diseases, reproductive biology, and transplantation. To provide a more complete foundation for studying NK cell responses, rhesus macaque KIRs representing common allotypes of lineage II KIR genes were tested for interactions with MHC class I molecules representing diverse Macaca mulatta (Mamu)-A, -B, -E, -F, -I, and -AG alleles. KIR-MHC class I interactions were identified by coincubating reporter cell lines bearing chimeric KIR-CD3ζ receptors with target cells expressing individual MHC class I molecules and were corroborated by staining with KIR IgG-Fc fusion proteins. Ligands for 12 KIRs of previously unknown specificity were identified that fell into three general categories: interactions with multiple Mamu-Bw4 molecules, interactions with Mamu-A-related molecules, including allotypes of Mamu-AG and the hybrid Mamu-B045:03 molecule, or interactions with Mamu-A1012:01. Whereas most KIRs found to interact with Mamu-Bw4 are inhibitory, most of the KIRs that interact with Mamu-AG are activating. The KIRs that recognize Mamu-A1012:01 belong to a phylogenetically distinct group of macaque KIRs with a 3-aa deletion in the D0 domain that is also present in human KIR3DL1/S1 and KIR3DL2. This study more than doubles the number of rhesus macaque KIRs with defined MHC class I ligands and identifies interactions with Mamu-AG, -B045, and -A1*012. These findings support overlapping, but nonredundant, patterns of ligand recognition that reflect extensive functional diversification of these receptors.
恒河猴杀伤细胞免疫球蛋白样受体（KIR）的 MHC Ⅰ类配体的定义是该物种 NK 细胞生物学的基础，因为它是传染病、生殖生物学和移植的动物模型。为了为 NK 细胞反应的研究提供更完整的基础，对恒河猴 KIR 进行了测试，这些 KIR 代表了 II 类 KIR 基因的常见同种异型，以与代表不同 Macaca mulatta（Mamu）-A、-B、-E、-F、-I 和 -AG 等位基因的 MHC Ⅰ类分子相互作用。通过共孵育带有嵌合 KIR-CD3ζ 受体的报告细胞系与表达单个 MHC Ⅰ类分子的靶细胞，鉴定 KIR-MHC Ⅰ类相互作用，并通过 KIR IgG-Fc 融合蛋白染色加以证实。鉴定出 12 种以前未知特异性的 KIR 的配体，它们分为三类：与多个 Mamu-Bw4 分子相互作用、与 Mamu-A 相关分子相互作用，包括 Mamu-AG 的同种异型和杂交 Mamu-B045:03 分子，或与 Mamu-A1012:01 相互作用。虽然发现与 Mamu-Bw4 相互作用的大多数 KIR 是抑制性的，但与 Mamu-AG 相互作用的大多数 KIR 是激活性的。识别 Mamu-A1012:01 的 KIR 属于一组在 D0 结构域中具有 3 个氨基酸缺失的具有系统发育差异的恒河猴 KIR，该缺失也存在于人类 KIR3DL1/S1 和 KIR3DL2 中。这项研究使具有定义明确的 MHC Ⅰ类配体的恒河猴 KIR 数量增加了一倍以上，并鉴定出与 Mamu-AG、-B045 和 -A1*012 的相互作用。这些发现支持这些受体的配体识别具有重叠但非冗余的模式，反映了这些受体的广泛功能多样化。
