Abstract
Natural Killer (NK) cell activation requires integration of inhibitory and activating signaling. Inhibitory signals are determined by members of the killer cell immunoglobulin-like receptor (KIR) family, which have major histocompatibility complex (MHC) class I ligands. Loss of this inhibitory signal leads to NK cell activation. Thus, down-regulation of MHC I during viral infection or cancer induces NK cell activation. However, NK cell activation in the presence of MHC-I has been demonstrated for HLA-C*0102 through changes in its peptide content: “peptide antagonism.” Here we identify an antagonist peptide for HLA-C*0304 suggesting that peptide antagonism is a generalizable phenomenon and, using a combination of mathematical modeling, confocal imaging, and immune-assays, we quantitatively determine mechanisms that underlie peptide antagonism in inhibitory KIR2DL2/3 signaling. These data provide a mechanism for NK cell activation based on a reduction of inhibitory signaling in the presence of preserved levels of MHC class I.
Highlights
Natural Killer (NK) cells play an important role in protection against viruses and tumor growth
We previously identified the phenomenon of peptide antagonism for HLA-C∗0102 using peptide variants of VAPWNSLSL
Consistent with GAVPDLDAL being an antagonist, at a 50:50 ratio of inhibitory (GAVPDLRAL) to antagonist peptide (GAVPDLDAL) the level of tight clustering at the immune synapse was reduced to that of the antagonist peptide alone, which is relevant as tight clustering of killer cell immunoglobulin-like receptor (KIR) molecules is associated with a productive inhibitory signal [30, 31]
Summary
Natural Killer (NK) cells play an important role in protection against viruses and tumor growth. Their response requires integration of inhibitory and activating signals. The classical model by which NK cells lose tonic inhibitory signaling is well-described by the “missing-self hypothesis” [1, 2] such that down-regulation of MHC I during viral infection or tumorigenesis can induce NK cell activation [3,4,5]. In addition to MHC class I down-regulation, viral infection and tumorigenesis can induce changes in the peptide content of MHC class I. Peptides that engage KIR have specific motifs at the NK Cells and Peptide Antagonism
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