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

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Science Immunology  15 Sep 2017:
Vol. 2, Issue 15, eaal5296
DOI: 10.1126/sciimmunol.aal5296

Killing viral helicases

Recognition of evolutionarily conserved pathogen-associated molecules drives innate immune responses. Naiyer et al. report that a killer cell immunoglobulin-like receptor (KIR), KIR2DS2, promotes activation of natural killer (NK) cells by recognizing conserved peptides from flaviviral RNA helicases when presented by a particular human leukocyte antigen (HLA) allele, HLA-C*0102. They have identified two distinct peptide motifs—LNPSVAATL and MCHAT—that are sensed by KIR2DS2. The former is conserved across hepatitis C virus isolates; the latter is conserved in a number of flaviviruses including dengue, Zika, and yellow fever viruses. The study illustrates that a single KIR receptor has evolved to activate NK cells in response to multiple pathogenic viruses.


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.

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