KIR2DS2 recognizes conserved peptides derived from viral helicases in the context of HLA-C.

Killer cell immunoglobulin-like receptors (KIRs) are rapidly evolving species-specific natural killer (NK) cell receptors associated with protection against multiple different human viral infections. We report that the activating receptor KIR2DS2 directly recognizes viral peptides derived from conserved regions of flaviviral superfamily 2 RNA helicases in the context of major histocompatibility complex class I. We started by documenting that peptide LNPSVAATL from the hepatitis C virus (HCV) helicase binds HLA-C*0102, leading to NK cell activation through engagement of KIR2DS2. Although this region is highly conserved across HCV isolates, the sequence is not present in other flaviviral helicases. Embarking on a search for a conserved target of KIR2DS2, we show that HLA-C*0102 presents a different highly conserved peptide from the helicase motif 1b region of related flaviviruses, including dengue, Zika, yellow fever, and Japanese encephalitis viruses, to KIR2DS2. In contrast to LNPSVAATL from HCV, these flaviviral peptides all contain an "MCHAT" motif, which is present in 61 of 63 flaviviruses. Despite the difference in the peptide sequences, we show that KIR2DS2 recognizes endogenously presented helicase peptides and that KIR2DS2 is sufficient to inhibit HCV and dengue virus replication in the context of HLA-C*0102. Targeting short, but highly conserved, viral peptides provide nonrearranging innate immune receptors with an efficient mechanism to recognize multiple, highly variable, pathogenic RNA viruses.

Effects of Peptide on NK cell-mediated MHC I recognition.

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.