A Peptide Antagonist Disrupts NK Cell Inhibitory Synapse Formation

Productive engagement of MHC class I by inhibitory NK cell receptors depends on the peptide bound by the MHC class I molecule. Peptide: MHC complexes that bind weakly to killer cell Ig-like receptors (KIRs) can antagonize the inhibition mediated by high-affinity peptide: MHC complexes and cause NK cell activation. We show that low-affinity peptide: MHC complexes stall inhibitory signaling at the step of Src homology protein tyrosine phosphatase 1 recruitment and do not go on to form the KIR microclusters induced by high-affinity peptide: MHC, which are associated with Vav dephosphorylation and downstream signaling. Furthermore, the low-affinity peptide: MHC complexes prevented the formation of KIR microclusters by high-affinity peptide: MHC. Thus, peptide antagonism of NK cells is an active phenomenon of inhibitory synapse disruption. The Journal of Immunology, 2013, 190: 2924-2930.