A Viral Immunoevasin Controls Innate Immunity by Targeting the Prototypical Natural Killer Cell Receptor Family

Oscar A. Aguilar; Richard Berry; Mir Munir A. Rahim; Johanna J. Reichel; Branka Popović; Miho Tanaka; Zhihui Fu; Gautham R. Balaji; Timothy N.H. Lau; Megan M. Tu; Christina L. Kirkham; Ahmad Bakur Mahmoud; Aruz Mesci; Astrid Krmpotić; David S.J. Allan; Andrew P. Makrigiannis; Stipan Jonjić; Jamie Rossjohn; James R. Carlyle

doi:10.1016/j.cell.2017.03.002

A Viral Immunoevasin Controls Innate Immunity by Targeting the Prototypical Natural Killer Cell Receptor Family

Oscar A. Aguilar, Richard Berry, Mir Munir A. Rahim, Johanna J. Reichel, Branka Popović, Miho Tanaka, Zhihui Fu, Gautham R. Balaji, Timothy N.H. Lau, Megan M. Tu, Christina L. Kirkham, Ahmad Bakur Mahmoud, Aruz Mesci, Astrid Krmpotić, David S.J. Allan, Andrew P. Makrigiannis, Stipan Jonjić, Jamie Rossjohn, James R. Carlyle

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67 Citations (Scopus)

Abstract

Natural killer (NK) cells play a key role in innate immunity by detecting alterations in self and non-self ligands via paired NK cell receptors (NKRs). Despite identification of numerous NKR-ligand interactions, physiological ligands for the prototypical NK1.1 orphan receptor remain elusive. Here, we identify a viral ligand for the inhibitory and activating NKR-P1 (NK1.1) receptors. This murine cytomegalovirus (MCMV)-encoded protein, m12, restrains NK cell effector function by directly engaging the inhibitory NKR-P1B receptor. However, m12 also interacts with the activating NKR-P1A/C receptors to counterbalance m12 decoy function. Structural analyses reveal that m12 sequesters a large NKR-P1 surface area via a “polar claw” mechanism. Polymorphisms in, and ablation of, the viral m12 protein and host NKR-P1B/C alleles impact NK cell responses in vivo. Thus, we identify the long-sought foreign ligand for this key immunoregulatory NKR family and reveal how it controls the evolutionary balance of immune recognition during host-pathogen interplay.

Original language	English
Pages (from-to)	58-71.e14
Journal	Cell
Volume	169
Issue number	1
DOIs	https://doi.org/10.1016/j.cell.2017.03.002
Publication status	Published - Mar 23 2017
Externally published	Yes

Bibliographical note

Funding Information:
We would like to thank Drs. S. Vidal, M.G. Brown, K. Iizuka, W. Yokoyama, and T. Mallevaey for reagents and Y. Amemiya, G. Awong, and G. Knowles for services. We also acknowledge the Monash Macromolecular Crystallization Facility and the staff at the Australian Synchrotron. O.A.A. was supported by a Natural Sciences and Engineering Research Council of Canada (NSERC) Post-Graduate Scholarship-Doctoral Award; A.M. by a Canadian Institutes of Health Research (CIHR) Vanier Scholarship; C.L.K. by an Ontario Graduate Scholarship Award. R.B. is a recipient of a National Health and Medical Research Council of Australia (NHMRC) Career Development Award (APP1109901). J.R. is a recipient of an Australian Research Council Laureate Fellowship (FL160100049). A.K. is supported by the Croatian Science Foundation (Grant #7132). S.J. is supported by an Advanced Grant from the European Research Council (ERC #322693). This work was supported by CIHR Operating Grants (#86630 to A.P.M. and J.R.C.; #106491 to J.R.C.), an Early Researcher Award from the Ontario Ministry of Research and Innovation (#RE07-04-071 to J.R.C.), a CIHR New Investigator Award (to J.R.C.), and an Investigator in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund (#1007761 to J.R.C.).

Publisher Copyright:
© 2017 Elsevier Inc.

ASJC Scopus Subject Areas

General Biochemistry,Genetics and Molecular Biology

PubMed: MeSH publication types

Journal Article
Research Support, Non-U.S. Gov't

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10.1016/j.cell.2017.03.002

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Aguilar, O. A., Berry, R., Rahim, M. M. A., Reichel, J. J., Popović, B., Tanaka, M., Fu, Z., Balaji, G. R., Lau, T. N. H., Tu, M. M., Kirkham, C. L., Mahmoud, A. B., Mesci, A., Krmpotić, A., Allan, D. S. J., Makrigiannis, A. P., Jonjić, S., Rossjohn, J., & Carlyle, J. R. (2017). A Viral Immunoevasin Controls Innate Immunity by Targeting the Prototypical Natural Killer Cell Receptor Family. Cell, 169(1), 58-71.e14. https://doi.org/10.1016/j.cell.2017.03.002

Aguilar, OA, Berry, R, Rahim, MMA, Reichel, JJ, Popović, B, Tanaka, M, Fu, Z, Balaji, GR, Lau, TNH, Tu, MM, Kirkham, CL, Mahmoud, AB, Mesci, A, Krmpotić, A, Allan, DSJ, Makrigiannis, AP, Jonjić, S, Rossjohn, J & Carlyle, JR 2017, 'A Viral Immunoevasin Controls Innate Immunity by Targeting the Prototypical Natural Killer Cell Receptor Family', Cell, vol. 169, no. 1, pp. 58-71.e14. https://doi.org/10.1016/j.cell.2017.03.002

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title = "A Viral Immunoevasin Controls Innate Immunity by Targeting the Prototypical Natural Killer Cell Receptor Family",

abstract = "Natural killer (NK) cells play a key role in innate immunity by detecting alterations in self and non-self ligands via paired NK cell receptors (NKRs). Despite identification of numerous NKR-ligand interactions, physiological ligands for the prototypical NK1.1 orphan receptor remain elusive. Here, we identify a viral ligand for the inhibitory and activating NKR-P1 (NK1.1) receptors. This murine cytomegalovirus (MCMV)-encoded protein, m12, restrains NK cell effector function by directly engaging the inhibitory NKR-P1B receptor. However, m12 also interacts with the activating NKR-P1A/C receptors to counterbalance m12 decoy function. Structural analyses reveal that m12 sequesters a large NKR-P1 surface area via a “polar claw” mechanism. Polymorphisms in, and ablation of, the viral m12 protein and host NKR-P1B/C alleles impact NK cell responses in vivo. Thus, we identify the long-sought foreign ligand for this key immunoregulatory NKR family and reveal how it controls the evolutionary balance of immune recognition during host-pathogen interplay.",

author = "Aguilar, {Oscar A.} and Richard Berry and Rahim, {Mir Munir A.} and Reichel, {Johanna J.} and Branka Popovi{\'c} and Miho Tanaka and Zhihui Fu and Balaji, {Gautham R.} and Lau, {Timothy N.H.} and Tu, {Megan M.} and Kirkham, {Christina L.} and Mahmoud, {Ahmad Bakur} and Aruz Mesci and Astrid Krmpoti{\'c} and Allan, {David S.J.} and Makrigiannis, {Andrew P.} and Stipan Jonji{\'c} and Jamie Rossjohn and Carlyle, {James R.}",

note = "Funding Information: We would like to thank Drs. S. Vidal, M.G. Brown, K. Iizuka, W. Yokoyama, and T. Mallevaey for reagents and Y. Amemiya, G. Awong, and G. Knowles for services. We also acknowledge the Monash Macromolecular Crystallization Facility and the staff at the Australian Synchrotron. O.A.A. was supported by a Natural Sciences and Engineering Research Council of Canada (NSERC) Post-Graduate Scholarship-Doctoral Award; A.M. by a Canadian Institutes of Health Research (CIHR) Vanier Scholarship; C.L.K. by an Ontario Graduate Scholarship Award. R.B. is a recipient of a National Health and Medical Research Council of Australia (NHMRC) Career Development Award (APP1109901). J.R. is a recipient of an Australian Research Council Laureate Fellowship (FL160100049). A.K. is supported by the Croatian Science Foundation (Grant #7132). S.J. is supported by an Advanced Grant from the European Research Council (ERC #322693). This work was supported by CIHR Operating Grants (#86630 to A.P.M. and J.R.C.; #106491 to J.R.C.), an Early Researcher Award from the Ontario Ministry of Research and Innovation (#RE07-04-071 to J.R.C.), a CIHR New Investigator Award (to J.R.C.), and an Investigator in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund (#1007761 to J.R.C.). Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",

year = "2017",

month = mar,

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doi = "10.1016/j.cell.2017.03.002",

language = "English",

volume = "169",

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T1 - A Viral Immunoevasin Controls Innate Immunity by Targeting the Prototypical Natural Killer Cell Receptor Family

AU - Aguilar, Oscar A.

AU - Berry, Richard

AU - Rahim, Mir Munir A.

AU - Reichel, Johanna J.

AU - Popović, Branka

AU - Tanaka, Miho

AU - Fu, Zhihui

AU - Balaji, Gautham R.

AU - Lau, Timothy N.H.

AU - Tu, Megan M.

AU - Kirkham, Christina L.

AU - Mahmoud, Ahmad Bakur

AU - Mesci, Aruz

AU - Krmpotić, Astrid

AU - Allan, David S.J.

AU - Makrigiannis, Andrew P.

AU - Jonjić, Stipan

AU - Rossjohn, Jamie

AU - Carlyle, James R.

N1 - Funding Information: We would like to thank Drs. S. Vidal, M.G. Brown, K. Iizuka, W. Yokoyama, and T. Mallevaey for reagents and Y. Amemiya, G. Awong, and G. Knowles for services. We also acknowledge the Monash Macromolecular Crystallization Facility and the staff at the Australian Synchrotron. O.A.A. was supported by a Natural Sciences and Engineering Research Council of Canada (NSERC) Post-Graduate Scholarship-Doctoral Award; A.M. by a Canadian Institutes of Health Research (CIHR) Vanier Scholarship; C.L.K. by an Ontario Graduate Scholarship Award. R.B. is a recipient of a National Health and Medical Research Council of Australia (NHMRC) Career Development Award (APP1109901). J.R. is a recipient of an Australian Research Council Laureate Fellowship (FL160100049). A.K. is supported by the Croatian Science Foundation (Grant #7132). S.J. is supported by an Advanced Grant from the European Research Council (ERC #322693). This work was supported by CIHR Operating Grants (#86630 to A.P.M. and J.R.C.; #106491 to J.R.C.), an Early Researcher Award from the Ontario Ministry of Research and Innovation (#RE07-04-071 to J.R.C.), a CIHR New Investigator Award (to J.R.C.), and an Investigator in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund (#1007761 to J.R.C.). Publisher Copyright: © 2017 Elsevier Inc.

PY - 2017/3/23

Y1 - 2017/3/23

N2 - Natural killer (NK) cells play a key role in innate immunity by detecting alterations in self and non-self ligands via paired NK cell receptors (NKRs). Despite identification of numerous NKR-ligand interactions, physiological ligands for the prototypical NK1.1 orphan receptor remain elusive. Here, we identify a viral ligand for the inhibitory and activating NKR-P1 (NK1.1) receptors. This murine cytomegalovirus (MCMV)-encoded protein, m12, restrains NK cell effector function by directly engaging the inhibitory NKR-P1B receptor. However, m12 also interacts with the activating NKR-P1A/C receptors to counterbalance m12 decoy function. Structural analyses reveal that m12 sequesters a large NKR-P1 surface area via a “polar claw” mechanism. Polymorphisms in, and ablation of, the viral m12 protein and host NKR-P1B/C alleles impact NK cell responses in vivo. Thus, we identify the long-sought foreign ligand for this key immunoregulatory NKR family and reveal how it controls the evolutionary balance of immune recognition during host-pathogen interplay.

AB - Natural killer (NK) cells play a key role in innate immunity by detecting alterations in self and non-self ligands via paired NK cell receptors (NKRs). Despite identification of numerous NKR-ligand interactions, physiological ligands for the prototypical NK1.1 orphan receptor remain elusive. Here, we identify a viral ligand for the inhibitory and activating NKR-P1 (NK1.1) receptors. This murine cytomegalovirus (MCMV)-encoded protein, m12, restrains NK cell effector function by directly engaging the inhibitory NKR-P1B receptor. However, m12 also interacts with the activating NKR-P1A/C receptors to counterbalance m12 decoy function. Structural analyses reveal that m12 sequesters a large NKR-P1 surface area via a “polar claw” mechanism. Polymorphisms in, and ablation of, the viral m12 protein and host NKR-P1B/C alleles impact NK cell responses in vivo. Thus, we identify the long-sought foreign ligand for this key immunoregulatory NKR family and reveal how it controls the evolutionary balance of immune recognition during host-pathogen interplay.

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DO - 10.1016/j.cell.2017.03.002

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A Viral Immunoevasin Controls Innate Immunity by Targeting the Prototypical Natural Killer Cell Receptor Family

Abstract

Bibliographical note

ASJC Scopus Subject Areas

PubMed: MeSH publication types

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