Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.
Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, VIC, Australia.
Nat Commun. 2021 Apr 12;12(1):2173. doi: 10.1038/s41467-021-22359-x.
The closely related inhibitory killer-cell immunoglobulin-like receptors (KIR), KIR2DL2 and KIR2DL3, regulate the activation of natural killer cells (NK) by interacting with the human leukocyte antigen-C1 (HLA-C1) group of molecules. KIR2DL2, KIR2DL3 and HLA-C1 are highly polymorphic, with this variation being associated with differences in the onset and progression of some human diseases. However, the molecular bases underlying these associations remain unresolved. Here, we determined the crystal structures of KIR2DL2 and KIR2DL3 in complex with HLA-C07:02 presenting a self-epitope. KIR2DL2 differed from KIR2DL3 in docking modality over HLA-C07:02 that correlates with variabilty of recognition of HLA-C1 allotypes. Mutagenesis assays indicated differences in the mechanism of HLA-C1 allotype recognition by KIR2DL2 and KIR2DL3. Similarly, HLA-C1 allotypes differed markedly in their capacity to inhibit activation of primary NK cells. These functional differences derive, in part, from KIR2DS2 suggesting KIR2DL2 and KIR2DL3 binding geometries combine with other factors to distinguish HLA-C1 functional recognition.
密切相关的抑制性杀伤细胞免疫球蛋白样受体（KIR），KIR2DL2 和 KIR2DL3，通过与人类白细胞抗原-C1（HLA-C1）分子群相互作用来调节自然杀伤细胞（NK）的激活。KIR2DL2、KIR2DL3 和 HLA-C1 高度多态性，这种变异与一些人类疾病的发病和进展的差异有关。然而，这些关联的分子基础仍未解决。在这里，我们确定了与 HLA-C07:02 呈递自身表位结合的 KIR2DL2 和 KIR2DL3 的晶体结构。KIR2DL2 在与 HLA-C07:02 的对接模式上与 KIR2DL3 不同，这与 HLA-C1 同种型的识别变异性相关。突变分析表明，KIR2DL2 和 KIR2DL3 识别 HLA-C1 同种型的机制存在差异。同样，HLA-C1 同种型在抑制原代 NK 细胞激活的能力上也有显著差异。这些功能差异部分源自 KIR2DS2，表明 KIR2DL2 和 KIR2DL3 的结合几何形状与其他因素结合，以区分 HLA-C1 的功能识别。
