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

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

doi:10.1111/cei.12722

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

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

^*Corresponding author for this work

Dermatology

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Abstract

Killer 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 CD56^dim 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.

Original language	English (US)
Pages (from-to)	419-430
Number of pages	12
Journal	Clinical and Experimental Immunology
Volume	183
Issue number	3
DOIs	https://doi.org/10.1111/cei.12722
State	Published - Mar 1 2016

Funding

We thank the subjects who generously donated peripheral blood samples for use in our studies, the NIAID Tetramer Core Facility for provision of the B57-NS126-34 tetramer, Brenda Hartman for expert assistance with graphics and Dr Suchitra Nimmannitya and staff at theQueen SirikitNational Institute for Child Health, the Department of Virology, Armed Forces Research Institute of Medical Science s and the Department of Transfusion Medicine, Siriraj Hospital, for patient recruitment, sample collection and clinical, virological and HLA typing information. This work was funded by the National Institutes of Health (NIH) via Grants P01 AI34533, U19 AI57319 and R21 AI113479 with core support from NIH P30 DK032520 and federal funds from the Frederick National Laboratory for Cancer Research under Contract No.HHSN261200800001E. Additional support was provided by the Intramural Research Program of the NIH, Frederick National Laboratory, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government. D. A. P. is a Wellcome Trust Senior Investigator.

Keywords

Dengue
HLA
KIR
NK
Pathogenesis

ASJC Scopus subject areas

General Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1111/cei.12722

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Townsley, E., O'Connor, G., Cosgrove, P. G. C., Woda, M., Co, M., Thomas, S. J., Kalayanarooj, S., Yoon, I. K., Nisalak, A., Srikiatkhachorn, A., Green, S., Stephens, H. A. F., Gostick, E., Price, D. A., Carrington, M., Alter, G., Mcvicar, D. W., Rothman, A. L., & Mathew, A. (2016). Interaction of a dengue virus NS1-derived peptide with the inhibitory receptor KIR3DL1 on natural killer cells. Clinical and Experimental Immunology, 183(3), 419-430. https://doi.org/10.1111/cei.12722

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title = "Interaction of a dengue virus NS1-derived peptide with the inhibitory receptor KIR3DL1 on natural killer cells",

abstract = "Killer 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.",

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Townsley, E, O'Connor, G, Cosgrove, PGC, Woda, M, Co, M, Thomas, SJ, Kalayanarooj, S, Yoon, IK, Nisalak, A, Srikiatkhachorn, A, Green, S, Stephens, HAF, Gostick, E, Price, DA, Carrington, M, Alter, G, Mcvicar, DW, Rothman, AL & Mathew, A 2016, 'Interaction of a dengue virus NS1-derived peptide with the inhibitory receptor KIR3DL1 on natural killer cells', Clinical and Experimental Immunology, vol. 183, no. 3, pp. 419-430. https://doi.org/10.1111/cei.12722

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AU - Townsley, E.

AU - O'Connor, G.

AU - Cosgrove, Patrick Gerard Cormac

AU - Woda, M.

AU - Co, M.

AU - Thomas, S. J.

AU - Kalayanarooj, S.

AU - Yoon, I. K.

AU - Nisalak, A.

AU - Srikiatkhachorn, A.

AU - Green, S.

AU - Stephens, H. A.F.

AU - Gostick, E.

AU - Price, D. A.

AU - Carrington, M.

AU - Alter, G.

AU - Mcvicar, D. W.

AU - Rothman, A. L.

AU - Mathew, A.

PY - 2016/3/1

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N2 - Killer 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.

AB - Killer 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.

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KW - HLA

KW - KIR

KW - NK

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

Abstract

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UN SDGs

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