Activating killer cell immunoglobulin-like receptor 2DS2 binds to HLA-A*11

Area of Science:

• Immunology
• Structural Biology
• Molecular Interactions

Background:

• Killer cell Ig-like receptors (KIRs) are crucial immune receptors involved in natural killer cell regulation.
• While inhibitory KIRs primarily recognize HLA-C and Bw4 group ligands, the ligands for activating KIRs, like KIR2DS2, remain largely unknown.

Purpose of the Study:

• To identify the specific ligand for the activating KIR2DS2.
• To elucidate the structural basis of KIR2DS2-ligand interaction.
• To understand the influence of peptide sequence on KIR-HLA binding.

Main Methods:

• X-ray crystallography to determine the structure of the KIR2DS2-HLA-A*11:01 complex.
• KIR2DS2 tetramer staining to assess binding to live cells expressing HLA-A*11:01.
• Heteronuclear single quantum coherence Nuclear Magnetic Resonance (NMR) spectroscopy to map binding interfaces.

Main Results:

• HLA-A*11:01 was identified as the cognate ligand for the activating KIR2DS2.
• The crystal structure revealed distinct binding characteristics compared to inhibitory KIR-HLA interactions, highlighting the roles of Tyr45 and Asp72 in specificity.
• Binding to live cells was confirmed, and peptide residue changes at p8 were shown to modulate KIR-HLA association.
• NMR data validated the structural findings and identified critical residues at the KIR-HLA interface.

Conclusions:

• This study provides the first structural evidence for the recognition of HLA-A*11:01 by the activating KIR2DS2.
• The findings expand the known spectrum of KIR-HLA interactions and offer insights into immune synapse formation.
• Understanding these interactions is vital for fields like transplantation immunology and cancer immunotherapy.