Abstract
The inhibitory receptors for MHC class I have a central role in controlling natural killer (NK) cell activity. Soon after their discovery, it was found that these receptors have a degree of peptide selectivity. Such peptide selectivity has been demonstrated for all inhibitory killer cell immunoglobulin-like receptor (KIR) tested to date, certain activating KIR, and also members of the C-type lectin-like family of receptors. This selectivity is much broader than the peptide specificity of T cell receptors, with NK cell receptors recognizing peptide motifs, rather than individual peptides. Inhibitory receptors on NK cells can survey the peptide:MHC complexes expressed on the surface of target cells, therefore subsequent transduction of an inhibitory signal depends on the overall peptide content of these MHC class I complexes. Functionally, KIR-expressing NK cells have been shown to be unexpectedly sensitive to changes in the peptide content of MHC class I, as peptide:MHC class I complexes that weakly engage KIR can antagonize the inhibitory signals generated by engagement of stronger KIR-binding peptide:MHC class I complexes. This property provides KIR-expressing NK cells with the potential to recognize changes in the peptide:MHC class I repertoire, which may occur during viral infections and tumorigenesis. By contrast, in the presence of HLA class I leader peptides, virus-derived peptides can induce a synergistic inhibition of CD94:NKG2A-expressing NK cells through recruitment of CD94 in the absence of NKG2A. On the other hand, CD94:NKG2A-positive NK cells can be exquisitely sensitive to changes in the levels of MHC class I. Peptide antagonism and sensitivity to changes in MHC class I levels are properties that distinguish KIR and CD94:NKG2A. The subtle difference in the properties of NK cells expressing these receptors provides a rationale for having complementary inhibitory receptor systems for MHC class I.
Highlights
Our knowledge of the functional role of natural killer (NK) cells has greatly increased in recent years
P8 is solvent accessible and changes in this residue do lead to alterations in NK cell function, implying secondary effects of MHC class I peptide on KIR2DL1:HLA-C binding
PEPTIDE ANTAGONISM OF killer cell immunoglobulinlike receptor (KIR)-POSITIVE NK CELLS Using a model system, we have investigated the functional consequences of KIR peptide selectivity
Summary
Our knowledge of the functional role of natural killer (NK) cells has greatly increased in recent years. PEPTIDE SELECTIVITY OF INHIBITORY RECEPTORS Key experiments performed in the mid 1990s demonstrated that the KIR are sensitive to the peptide bound by MHC class I. P8 is solvent accessible and changes in this residue do lead to alterations in NK cell function, implying secondary effects of MHC class I peptide on KIR2DL1:HLA-C binding.
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