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

Malcolm J W Sim1, Paul Brennan1, Katherine L Wahl1

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Summary
This summary is machine-generated.

Killer cell immunoglobulin-like receptors (KIRs) interact with HLA class I peptides. This study reveals specificities of KIR-HLA interactions, impacting NK cell responses in disease.

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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.