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Sci Immunol. 2017 Sep 15;2(15). pii: eaal5296. doi: 10.1126/sciimmunol.aal5296.

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

Author information

1
Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Tremona Road, Southampton S016 6YD, UK.
2
Section of Hepatology, Division of Medicine, Imperial College London, South Wharf Road, London W2 1PG, UK.
3
Medical Research Council-University of Glasgow Centre for Virus Research, Garscube Campus, 464 Bearsden Road, Glasgow G61 1QH, UK.
4
Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy.
5
Department of Statistics, Population and Primary Care Medicine, Faculty of Medicine, University of Southampton, Southampton General Hospital, Tremona Road, Southampton S016 6YD, UK.
6
Department of Medicine, University College Cork, Cork, Ireland.
7
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, PO Box 9600, 2300RC Leiden, Netherlands.
8
School of Cellular and Molecular Medicine, Biomedical Sciences Building, University of Bristol, Bristol BS8 1TD, UK.
9
Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Tremona Road, Southampton S016 6YD, UK. s.i.khakoo@southampton.ac.uk.

Abstract

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.

PMID:
28916719
DOI:
10.1126/sciimmunol.aal5296

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