Interaction of a dengue virus NS1-derived peptide with the inhibitory receptor KIR3DL1 on natural killer cells.

E Townsley,H A F Stephens,A Srikiatkhachorn,I-K Yoon,A L Rothman,S Kalayanarooj,A Mathew,C Cosgrove,M Co,D A Price,M Carrington,G O'Connor,M Woda,S J Thomas,E Gostick,S Green,G Alter,D W Mcvicar,A Nisalak

doi:10.1111/cei.12722

Abstract

SummaryKiller immunoglobulin‐like receptors (KIRs) interact with human leucocyte antigen (HLA) class I ligands and play a key role in the regulation and activation of NK cells. The functional importance of KIR–HLA interactions has been demonstrated for a number of chronic viral infections, but to date only a few studies have been performed in the context of acute self‐limited viral infections. During our investigation of CD8+ T cell responses to a conserved HLA‐B57‐restricted epitope derived from dengue virus (DENV) non‐structural protein‐1 (NS1), we observed substantial binding of the tetrameric complex to non‐T/non‐B lymphocytes in peripheral blood mononuclear cells (PBMC) from a long‐standing clinical cohort in Thailand. We confirmed binding of the NS1 tetramer to CD56dim NK cells, which are known to express KIRs. Using depletion studies and KIR‐transfected cell lines, we demonstrated further that the NS1 tetramer bound the inhibitory receptor KIR3DL1. Phenotypical analysis of PBMC from HLA‐B57+ subjects with acute DENV infection revealed marked activation of NS1 tetramer‐binding natural killer (NK) cells around the time of defervescence in subjects with severe dengue disease. Collectively, our findings indicate that subsets of NK cells are activated relatively late in the course of acute DENV illness and reveal a possible role for specific KIR–HLA interactions in the modulation of disease outcomes.

Highlights

Killer immunoglobulin-like receptors (KIRs) are expressed predominantly on natural killer (NK) cells and interact with specific human leukocyte antigen (HLA) class I ligands to transduce inhibitory or activating signals 1
We demonstrate binding of the NK cell-expressed inhibitory receptor KIR3DL1 to an HLA-B57-restricted dengue virus (DENV) non-structural protein-1 (NS1)-derived peptide that serves as a CD8+ T cell epitope
NS126-34 tetramer (NS1 TET)+ and total NK cells were activated to express CD38 during the critical phase of DENV illness only in HLA-B57+ patients with DHF, suggesting that NK cell subsets may contribute to the immunopathogenesis of dengue disease

Summary

Introduction

Killer immunoglobulin-like receptors (KIRs) are expressed predominantly on natural killer (NK) cells and interact with specific human leukocyte antigen (HLA) class I ligands to transduce inhibitory or activating signals 1. A role for KIR3DL1 in the control of chronic viral infections has been proposed on the basis of associations with disease outcome in HIV-infected individuals [3,4,5,6,7,8]. These studies suggest that both MHC class I and KIR genotypes may contribute to protection in the context of HLA-B57. The role of KIR-HLA interactions in acute self-limited viral infections remains largely unexplored

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Conclusion