Abstract

Natural killer cells are key players in the immune response to viral infections. Their functions are regulated by cell surface activating and inhibitory receptors. Crucially the inhibitory receptors appear to play a key part in their maturation and in the regulation of their functions in response to target cells. The ligands for these inhibitory receptors are MHC Class I molecules. These include both polymorphic HLA -A, -B and –C molecules, which interact the killer cell immunoglobulin-like receptors (KIR) and also the conserved HLA -E molecule, which is the ligand for the inhibitory receptor NKG2A . Cell surface down-regulation of MHC class I can lead to activation of NK cells expressing these inhibitory receptors.

However, although NKG2A and KIR are from distinct gene families, both receptors are sensitive to the peptide bound by MHC Class I such that some peptides that bind MHC class I are not permissive for KIR or fro NKG2A binding.

We have investigated how these different receptors respond to cognate and non-cognate peptides presented by MHC class I. We find that peptides that bind HLA -C, but are not permissive for KIR binding can act as peptide antagonists. Conversely peptides that bind HLA -E, but are not permissive for NKG2A binding act as synergists.

Thus, unexpectedly, peptide selectivity results in functionally different outcomes for these two classes of inhibitory receptors for MHC class I.