A herpesvirus encoded Qa-1 mimic inhibits natural killer cell cytotoxicity through CD94/NKG2A receptor engagement

Xiaoli Wang; Sytse J. Piersma; Christopher A. Nelson; Ya Nan Dai; Ted Christensen; Eric Lazear; Liping Yang; Marjolein Sluijter; Thorbald van Hall; Ted H. Hansen; Wayne M. Yokoyama; Daved H. Fremont

doi:10.7554/eLife.38667

A herpesvirus encoded Qa-1 mimic inhibits natural killer cell cytotoxicity through CD94/NKG2A receptor engagement

Xiaoli Wang, Sytse J. Piersma, Christopher A. Nelson, Ya Nan Dai, Ted Christensen, Eric Lazear, Liping Yang, Marjolein Sluijter, Thorbald van Hall, Ted H. Hansen, Wayne M. Yokoyama, Daved H. Fremont

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Abstract

A recurrent theme in viral immune evasion is the sabotage of MHC-I antigen presentation, which brings virus the concomitant issue of ‘missing-self’ recognition by NK cells that use inhibitory receptors to detect surface MHC-I proteins. Here, we report that rodent herpesvirus Peru (RHVP) encodes a Qa-1 like protein (pQa-1) via RNA splicing to counteract NK activation. While pQa-1 surface expression is stabilized by the same canonical peptides presented by murine Qa-1, pQa-1 is GPI-anchored and resistant to the activity of RHVP pK3, a ubiquitin ligase that targets MHC-I for degradation. pQa-1 tetramer staining indicates that it recognizes CD94/NKG2A receptors. Consistently, pQa-1 selectively inhibits NKG2A ⁺ NK cells and expression of pQa-1 can protect tumor cells from NK control in vivo. Collectively, these findings reveal an innovative NK evasion strategy wherein RHVP encodes a modified Qa-1 mimic refractory to MHC-I sabotage and capable of specifically engaging inhibitory receptors to circumvent NK activation. DOI: https://doi.org/10.7554/eLife.38667.001.

Original language	English
Article number	e38667
Journal	eLife
Volume	7
DOIs	https://doi.org/10.7554/eLife.38667
State	Published - Dec 1 2018

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@article{24fa6d90f9e74d119cb4338c68679376,

title = "A herpesvirus encoded Qa-1 mimic inhibits natural killer cell cytotoxicity through CD94/NKG2A receptor engagement",

abstract = " A recurrent theme in viral immune evasion is the sabotage of MHC-I antigen presentation, which brings virus the concomitant issue of {\textquoteleft}missing-self{\textquoteright} recognition by NK cells that use inhibitory receptors to detect surface MHC-I proteins. Here, we report that rodent herpesvirus Peru (RHVP) encodes a Qa-1 like protein (pQa-1) via RNA splicing to counteract NK activation. While pQa-1 surface expression is stabilized by the same canonical peptides presented by murine Qa-1, pQa-1 is GPI-anchored and resistant to the activity of RHVP pK3, a ubiquitin ligase that targets MHC-I for degradation. pQa-1 tetramer staining indicates that it recognizes CD94/NKG2A receptors. Consistently, pQa-1 selectively inhibits NKG2A + NK cells and expression of pQa-1 can protect tumor cells from NK control in vivo. Collectively, these findings reveal an innovative NK evasion strategy wherein RHVP encodes a modified Qa-1 mimic refractory to MHC-I sabotage and capable of specifically engaging inhibitory receptors to circumvent NK activation. DOI: https://doi.org/10.7554/eLife.38667.001.",

author = "Xiaoli Wang and Piersma, {Sytse J.} and Nelson, {Christopher A.} and Dai, {Ya Nan} and Ted Christensen and Eric Lazear and Liping Yang and Marjolein Sluijter and {van Hall}, Thorbald and Hansen, {Ted H.} and Yokoyama, {Wayne M.} and Fremont, {Daved H.}",

note = "Funding Information: We thank Nilabh Shastri (UC Berkeley) for the BWZ.36 cell line, Marco Colonna (Washington Univer-sity) for providing NKG2A-/- mice, and Alexander Barrow for helpful discussion. This work is supported by NIH grant R01-AI109687. National Institute of Allergy R01-AI109687 Daved H Fremont and Infectious DiseasesThe funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Publisher Copyright: {\textcopyright} Wang et al.",

year = "2018",

month = dec,

day = "1",

doi = "10.7554/eLife.38667",

language = "English",

volume = "7",

journal = "eLife",

issn = "2050-084X",

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TY - JOUR

T1 - A herpesvirus encoded Qa-1 mimic inhibits natural killer cell cytotoxicity through CD94/NKG2A receptor engagement

AU - Wang, Xiaoli

AU - Piersma, Sytse J.

AU - Nelson, Christopher A.

AU - Dai, Ya Nan

AU - Christensen, Ted

AU - Lazear, Eric

AU - Yang, Liping

AU - Sluijter, Marjolein

AU - van Hall, Thorbald

AU - Hansen, Ted H.

AU - Yokoyama, Wayne M.

AU - Fremont, Daved H.

N1 - Funding Information: We thank Nilabh Shastri (UC Berkeley) for the BWZ.36 cell line, Marco Colonna (Washington Univer-sity) for providing NKG2A-/- mice, and Alexander Barrow for helpful discussion. This work is supported by NIH grant R01-AI109687. National Institute of Allergy R01-AI109687 Daved H Fremont and Infectious DiseasesThe funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Publisher Copyright: © Wang et al.

PY - 2018/12/1

Y1 - 2018/12/1

N2 - A recurrent theme in viral immune evasion is the sabotage of MHC-I antigen presentation, which brings virus the concomitant issue of ‘missing-self’ recognition by NK cells that use inhibitory receptors to detect surface MHC-I proteins. Here, we report that rodent herpesvirus Peru (RHVP) encodes a Qa-1 like protein (pQa-1) via RNA splicing to counteract NK activation. While pQa-1 surface expression is stabilized by the same canonical peptides presented by murine Qa-1, pQa-1 is GPI-anchored and resistant to the activity of RHVP pK3, a ubiquitin ligase that targets MHC-I for degradation. pQa-1 tetramer staining indicates that it recognizes CD94/NKG2A receptors. Consistently, pQa-1 selectively inhibits NKG2A + NK cells and expression of pQa-1 can protect tumor cells from NK control in vivo. Collectively, these findings reveal an innovative NK evasion strategy wherein RHVP encodes a modified Qa-1 mimic refractory to MHC-I sabotage and capable of specifically engaging inhibitory receptors to circumvent NK activation. DOI: https://doi.org/10.7554/eLife.38667.001.

AB - A recurrent theme in viral immune evasion is the sabotage of MHC-I antigen presentation, which brings virus the concomitant issue of ‘missing-self’ recognition by NK cells that use inhibitory receptors to detect surface MHC-I proteins. Here, we report that rodent herpesvirus Peru (RHVP) encodes a Qa-1 like protein (pQa-1) via RNA splicing to counteract NK activation. While pQa-1 surface expression is stabilized by the same canonical peptides presented by murine Qa-1, pQa-1 is GPI-anchored and resistant to the activity of RHVP pK3, a ubiquitin ligase that targets MHC-I for degradation. pQa-1 tetramer staining indicates that it recognizes CD94/NKG2A receptors. Consistently, pQa-1 selectively inhibits NKG2A + NK cells and expression of pQa-1 can protect tumor cells from NK control in vivo. Collectively, these findings reveal an innovative NK evasion strategy wherein RHVP encodes a modified Qa-1 mimic refractory to MHC-I sabotage and capable of specifically engaging inhibitory receptors to circumvent NK activation. DOI: https://doi.org/10.7554/eLife.38667.001.

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U2 - 10.7554/eLife.38667

DO - 10.7554/eLife.38667

M3 - Article

C2 - 30575523

AN - SCOPUS:85059496867

SN - 2050-084X

VL - 7

JO - eLife

JF - eLife

M1 - e38667

ER -

A herpesvirus encoded Qa-1 mimic inhibits natural killer cell cytotoxicity through CD94/NKG2A receptor engagement

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