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

Abstract

This is the author accepted manuscript (AAM). The final published version (version of record) is available online via AAAS at http://immunology.sciencemag.org/content/2/15/eaal5296. Please refer to any applicable terms of use of the publisher. University of Bristol -Explore Bristol Research General rightsThis document is made available in accordance with publisher policies. Please cite only the published version using the reference above. KIR2DS2, an activating natural killer cell receptor recognizes highly conserved peptides derived from the RNA helicases of pathogenic flaviviruses. AbstractKiller cell immunoglobulin-like receptors (KIR) are rapidly evolving species-specific natural killer 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 MHC class I. The peptide LNPSVAATL, from the HCV helicase, binds HLA-C*0102 leading to NK cell activation through engagement of KIR2DS2. Similarly, HLA-C*0102 presents highly conserved peptides from the helicase motif 1b region of related flaviviruses, including dengue, Zika, yellow fever and Japanese encephalitis viruses, to KIR2DS2. These flaviviral peptides all contain an "MCHAT" motif, which is present in 61 out of 63 flaviviruses.LNPSVAATL is also highly conserved across HCV genotypes and mutation of this epitope is poorly tolerated by HCV. KIR2DS2 recognizes endogenously presented helicase peptides and 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 non-rearranging innate immune receptors with an efficient mechanism to recognize multiple, highly variable pathogenic RNA viruses.4

Human leucocyte antigen but not KIR alleles and haplotypes associated with chronic HCV infection in a Chinese Han population

“…Romero et al found the interaction between KIR2DL3/2DL3 and HLA‐C1C1 associated with HCV spontaneous clearance ( p = 0.03, OR = 3.05) (Romero et al, ). Recently, Nalyer et al found KIR2DS2 recognizes conserved peptides derived from viral helicases in the context of HLA‐C, and KIR2DS2 in combination with HLA‐C1 was protective against chronic HCV infection ( p = 0.033, OR = 2.06, 95%CI: 1.06–4.02) in UK people (Naiyer et al, ). In present study, we did not find any associations between KIR2DL1, KIR2DL3, KIR2DS1 and their HLA‐C1 ligands.…”

A novel antibody combination to identify KIR2DS2high natural killer cells in KIR2DL3/L2/S2 heterozygous donors

“…The activating KIR, KIR2DS2, is of particular interest given its protective role in bone marrow and cord blood transplantation for various hematological malignancies and in glioblastoma models in vivo . In addition, KIR2DS2 has recently been shown to directly recognise viral helicase peptides in the context of HLA‐C and to be protective against chronic hepatitis C virus infection . One of the barriers to understanding KIR2DS2 has been that, the high sequence homology between KIR2DS2 and the inhibitory KIR, KIR2DL2 and KIR2DL3, makes it difficult to develop antibodies that specifically detect KIR2DS2.…”

Activating killer‐cell immunoglobulin‐like receptor haplotype influences clinical outcome following HLA‐matched sibling haematopoietic stem cell transplantation

“…The promiscuous nature of KIR2DL2 has been demonstrated through binding to a number of HLA‐C alleles while allelic diversity has also been shown to impact their specificity . While the ligands for activating KIR remain poorly characterised in general, KIR2DS1 has been demonstrated to mediate alloreactivity while KIRDS2 also appears to recognise discrete subsets of HLA class I allotypes . KIR3DS1 has been shown to reduce mortality and despite structural similarity to 3DL1 appears to recognise the non‐classical molecule HLA‐F .…”