Innate receptors with high specificity for HLA class I-peptide complexes

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Killer cell immunoglobulin-like receptors (KIRs) and their HLA class I ligands are genetically linked to various human diseases.
• The precise mechanisms and the roles of inhibitory versus activating KIR in NK cell responses remain incompletely understood.
• KIR-HLA interactions are known to be peptide-dependent, suggesting the immunopeptidome plays a crucial role.

Purpose of the Study:

• To systematically determine the peptide specificity of five KIRs binding to four HLA-C ligands.
• To elucidate the contribution of specific KIR-HLA-peptide interactions to NK cell function.
• To understand how peptide presentation by HLA-I influences NK cell recognition in disease contexts.

Main Methods:

• Performed over 3500 systematic screens of specific KIR-HLA-peptide interactions.
• Assessed binding affinities and specificities of inhibitory KIR2DL1, KIR2DL2, KIR2DL3, and activating KIR2DS1, KIR2DS4.
• Analyzed peptide sequence dependence for KIR recognition of HLA-C complexes.

Main Results:

• Inhibitory KIR2DL1 showed broad, peptide-agnostic binding to ~60% of tested HLA-peptide complexes.
• Other KIRs, including KIR2DL2, KIR2DL3, KIR2DS1, and KIR2DS4, exhibited more restricted binding, recognizing 10% down to 1% of complexes.
• Activating KIR2DS1 demonstrated high binding affinity and significant peptide sequence specificity for HLA-C, contrary to previous descriptions.

Conclusions:

• NK cell receptors demonstrate MHC-restricted peptide recognition, challenging previous assumptions.
• The immunopeptidome presented by HLA-I significantly shapes NK cell responses.
• These findings provide insights into KIR-HLA associations with diseases and infection outcomes.