Killer cell immunoglobulin-like receptor 3DL1 polymorphism defines distinct hierarchies of HLA class I recognition

PM Saunders, P Pymm, G Pietra, VA Hughes… - Journal of Experimental …, 2016 - rupress.org
PM Saunders, P Pymm, G Pietra, VA Hughes, C Hitchen, GM O'Connor, F Loiacono…
Journal of Experimental Medicine, 2016rupress.org
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 KIR3DL1* 005 recognizing the widest array of HLA-I ligands.
These differences were further reflected in functional studies using NK clones expressing …
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 KIR3DL1*005 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 KIR3DL1*001, *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 KIR3DL1*005 correlated with an altered KIR3DL1*005 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.
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