Saunders Philippa M, Pymm Phillip, Pietra Gabriella, Hughes Victoria A, Hitchen Corinne, O'Connor Geraldine M, Loiacono Fabrizio, Widjaja Jacqueline, Price David A, Falco Michela, Mingari Maria Cristina, Moretta Lorenzo, McVicar Daniel W, Rossjohn Jamie, Brooks Andrew G, Vivian Julian P
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, Victoria 3010, Australia.
Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia.
J Exp Med. 2016 May 2;213(5):791-807. doi: 10.1084/jem.20152023. Epub 2016 Apr 4.
Natural killer (NK) cells play a key role in immunity, but how HLA class I (HLA-I) and killer cell immunoglobulin-like receptor 3DL1 (KIR3DL1) polymorphism impacts disease outcome remains unclear. KIR3DL1 (*001/005/015) tetramers were screened for reactivity against a panel of HLA-I molecules. This revealed different and distinct hierarchies of specificity for each KIR3DL1 allotype, with KIR3DL1005 recognizing the widest array of HLA-I ligands. These differences were further reflected in functional studies using NK clones expressing these specific KIR3DL1 allotypes. Unexpectedly, the Ile/Thr80 dimorphism in the Bw4-motif did not categorically define strong/weak KIR3DL1 recognition. Although the KIR3DL1001, 005, and 015 polymorphisms are remote from the KIR3DL1-HLA-I interface, the structures of these three KIR3DL1-HLA-I complexes showed that the broader HLA-I specificity of KIR3DL1005 correlated with an altered KIR3DL1005 interdomain positioning and increased mobility within its ligand-binding site. Collectively, we provide a generic framework for understanding the impact of KIR3DL1 polymorphism on the recognition of HLA-I allomorphs.
自然杀伤（NK）细胞在免疫中发挥关键作用，但人类白细胞抗原I类（HLA-I）和杀伤细胞免疫球蛋白样受体3DL1（KIR3DL1）多态性如何影响疾病结局仍不清楚。对KIR3DL1（001/005/015）四聚体进行筛选，以检测其对一组HLA-I分子的反应性。这揭示了每种KIR3DL1同种异型具有不同且独特的特异性等级，其中KIR3DL1005识别的HLA-I配体种类最多。这些差异在使用表达这些特定KIR3DL1同种异型的NK克隆进行的功能研究中得到进一步体现。出乎意料的是，Bw4基序中的Ile/Thr80二态性并不能明确界定KIR3DL1的强/弱识别。尽管KIR3DL1001、005和015多态性远离KIR3DL1-HLA-I界面，但这三种KIR3DL1-HLA-I复合物的结构表明，KIR3DL1005更广泛的HLA-I特异性与KIR3DL1*005结构域间定位的改变以及其配体结合位点内流动性的增加相关。总体而言，我们提供了一个通用框架，用于理解KIR3DL1多态性对HLA-I同种异型识别的影响。
