Effects of Peptide on NK cell-mediated MHC I recognition

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.

Keywords: CD94; KIR; MHC class I; NKG2A; antagonism; natural killer cells; peptides; synergy.

Figure 1

Peptide antagonism is associated with loss of tight clustering of KIR. (A) The antagonist peptide induces clustering of KIR and SHP-1 recruitment to the immune synapse. However, the clustering is diffuse and there is no inhibitory signal generated. (B) An inhibitory peptide induces tight clustering of KIR, SHP-1 recruitment, and inhibitory signaling. (C) The antagonist peptide abrogates tight clustering and thence inhibitory signaling.

Figure 2

Model for peptide synergy. (A) A synergistic peptide induces recruitment of CD94 homodimers, but not CD94:NKG2A to the immune synapse. Therefore, there is no inhibitory signal generated. (B) At low levels of inhibitory peptide CD94:NKG2A is recruited to the immune synapse and there is inhibitory signaling. (C) The synergistic peptide augments the inhibitory signaling due to low levels of inhibitory peptide by stabilizing the immune synapse.

Figure 3

NKG2A+ NK cells are more sensitive to changes in the cell-surface levels of MHC class I at low, as compared to high, surface levels of MHC class I. 721.174 cells were loaded with increasing concentrations of peptide and used as targets in CD107a assays. The levels of degranulation of NKG2A+ (A) or KIR2D:2/3+ (B) NK cells were plotted against levels of cognate MHC class I:peptide. In (A) HLA-E was loaded with increasing concentrations of the HLA-G leader peptide and in (B) HLA-Cw*0102 was loaded with increasing concentrations of the VAP-FA peptide. At between 10 and 20% of maximal HLA-E levels, there is an increase of ~20% in the fraction of degranulating NKG2A+ NK cells (δ_lo) but between 60 and 70% of maximal HLA-E levels, this change is less than 5% (δ_hi). For KIR+ NK cells, δ_lo and δ_hi are similar at ~10%. Data were derived from Cheent et al. (47).