Peptide-specific engagement of the activating NK cell receptor KIR2DS1

Area of Science:

• Immunology
• Cellular and Molecular Immunology

Background:

• The activating NK cell receptor KIR2DS1 is implicated in various diseases, but its ligands and functions are not fully understood.
• Understanding KIR2DS1 interactions with HLA class I molecules is crucial for elucidating its role in health and disease.

Purpose of the Study:

• To investigate the binding specificities of KIR2DS1 and KIR2DL1 to HLA class I molecules.
• To identify specific peptides that mediate KIR2DS1 binding and activation of NK cells.

Main Methods:

• Systematic screening of KIR2DS1 and KIR2DL1 binding to 97 HLA-I proteins.
• Utilizing reporter cell lines and peptide-pulsed cells to identify peptide-HLA interactions.
• Functional assays with primary NK cell clones to assess activation.

Main Results:

• KIR2DS1 binding was restricted to HLA-C group 2, while KIR2DL1 exhibited broader specificity.
• The peptide SRGPVHHLL presented by HLA-C*06:02 was identified as a strong binder for both KIR2DS1 and KIR2DL1.
• This peptide-HLA complex activated primary KIR2DS1+ NK cells.

Conclusions:

• Demonstrated peptide-dependent binding for the activating NK cell receptor KIR2DS1.
• Provided novel insights into the molecular mechanisms underlying KIR2DS1 function and related disorders.