Abstract
Natural killer cells are controlled by peptide selective inhibitory receptors for MHC class I, including the killer cell immunoglobulin‐like receptors (KIRs). Despite having similar ligands, KIR2DL2 and KIR2DL3 confer different levels of protection to infectious disease. To investigate how changes in peptide repertoire may differentially affect NK cell reactivity, NK cells from KIR2DL2 and KIR2DL3 homozygous donors were tested for activity against different combinations of strong inhibitory (VAPWNSFAL), weak inhibitory (VAPWNSRAL), and antagonist peptide (VAPWNSDAL). KIR2DL3‐positive NK cells were more sensitive to changes in the peptide content of MHC class I than KIR2DL2‐positive NK cells. These differences were observed for the weakly inhibitory peptide VAPWNSRAL in single peptide and double peptide experiments (p < 0.01 and p < 0.03, respectively). More significant differences were observed in experiments using all three peptides (p < 0.0001). Mathematical modeling of the experimental data demonstrated that VAPWNSRAL was dominant over VAPWNSFAL in distinguishing KIR2DL3‐ from KIR2DL2‐positive donors. Donors with different KIR genotypes have different responses to changes in the peptide bound by MHC class I. Differences in the response to the peptide content of MHC class I may be one mechanism underlying the protective effects of different KIR genes against infectious disease.
Highlights
ResultsNK cells are innate lymphocytes involved in the immune response to viruses and cancer, either through direct interaction with target cells or through interactions with macrophages, dendritic cells, and T cells [1, 2]
While the activating receptors are derived from a number of different gene families and have diverse ligands, the dominant inhibitory receptors expressed on NK cells are either from the killer cell immunoglobulin-like receptor (KIR) family or the C-type lectin-like receptor CD94:NKG2A and have MHC class I ligands [4, 5]
We have used a model system to investigate how NK cells may respond to changes in peptide repertoire
Summary
NK cells are innate lymphocytes involved in the immune response to viruses and cancer, either through direct interaction with target cells or through interactions with macrophages, dendritic cells, and T cells [1, 2]. VAP-FA and VAP-RA inhibited CD158b-positive NK cells from both sets of donors at all peptide concentrations (Fig. 2A–C) This is consistent with our previous data showing that in a single peptide model, inhibition is determined by levels of MHC class I expression, and this starts to decline significantly only at levels of less than 2 μM peptide. The [RA] term is dominant over the [FA] term and the [RA][DA] term dominant over [FA][DA] These data imply that KIR2DL3-positive NK cells respond more readily to changes in peptide repertoire than KIR2DL2-positive NK cells, and the difference in inhibition between donors is determined by the concentrations of the weak agonist peptide and the weak agonist/antagonist peptide combination
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