Ly49C-dependent control of MCMV Infection by NK cells is cis-regulated by MHC Class I molecules.

Natural Killer (NK) cells are crucial in early resistance to murine cytomegalovirus (MCMV) infection. In B6 mice, the activating Ly49H receptor recognizes the viral m157 glycoprotein on infected cells. We previously identified a mutant strain (MCMVG1F) whose variant m157 also binds the inhibitory Ly...

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Main Authors: Catherine A Forbes, Anthony A Scalzo, Mariapia A Degli-Esposti, Jerome D Coudert
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2014-05-01
Series:PLoS Pathogens
Online Access:http://europepmc.org/articles/PMC4038614?pdf=render
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spelling doaj-69dc38085c0d4b8f89e38d601aa737d42020-11-25T00:12:13ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742014-05-01105e100416110.1371/journal.ppat.1004161Ly49C-dependent control of MCMV Infection by NK cells is cis-regulated by MHC Class I molecules.Catherine A ForbesAnthony A ScalzoMariapia A Degli-EspostiJerome D CoudertNatural Killer (NK) cells are crucial in early resistance to murine cytomegalovirus (MCMV) infection. In B6 mice, the activating Ly49H receptor recognizes the viral m157 glycoprotein on infected cells. We previously identified a mutant strain (MCMVG1F) whose variant m157 also binds the inhibitory Ly49C receptor. Here we show that simultaneous binding of m157 to the two receptors hampers Ly49H-dependent NK cell activation as Ly49C-mediated inhibition destabilizes NK cell conjugation with their targets and prevents the cytoskeleton reorganization that precedes killing. In B6 mice, as most Ly49H+ NK cells do not co-express Ly49C, the overall NK cell response remains able to control MCMVm157G1F infection. However, in B6 Ly49C transgenic mice where all NK cells express the inhibitory receptor, MCMV infection results in altered NK cell activation associated with increased viral replication. Ly49C-mediated inhibition also regulates Ly49H-independent NK cell activation. Most interestingly, MHC class I regulates Ly49C function through cis-interactions that mask the receptor and restricts m157 binding. B6 Ly49C Tg, β2m ko mice, whose Ly49C receptors are unmasked due to MHC class I deficient expression, are highly susceptible to MCMVm157G1F and are unable to control a low-dose infection. Our study provides novel insights into the mechanisms that regulate NK cell activation during viral infection.http://europepmc.org/articles/PMC4038614?pdf=render
collection DOAJ
language English
format Article
sources DOAJ
author Catherine A Forbes
Anthony A Scalzo
Mariapia A Degli-Esposti
Jerome D Coudert
spellingShingle Catherine A Forbes
Anthony A Scalzo
Mariapia A Degli-Esposti
Jerome D Coudert
Ly49C-dependent control of MCMV Infection by NK cells is cis-regulated by MHC Class I molecules.
PLoS Pathogens
author_facet Catherine A Forbes
Anthony A Scalzo
Mariapia A Degli-Esposti
Jerome D Coudert
author_sort Catherine A Forbes
title Ly49C-dependent control of MCMV Infection by NK cells is cis-regulated by MHC Class I molecules.
title_short Ly49C-dependent control of MCMV Infection by NK cells is cis-regulated by MHC Class I molecules.
title_full Ly49C-dependent control of MCMV Infection by NK cells is cis-regulated by MHC Class I molecules.
title_fullStr Ly49C-dependent control of MCMV Infection by NK cells is cis-regulated by MHC Class I molecules.
title_full_unstemmed Ly49C-dependent control of MCMV Infection by NK cells is cis-regulated by MHC Class I molecules.
title_sort ly49c-dependent control of mcmv infection by nk cells is cis-regulated by mhc class i molecules.
publisher Public Library of Science (PLoS)
series PLoS Pathogens
issn 1553-7366
1553-7374
publishDate 2014-05-01
description Natural Killer (NK) cells are crucial in early resistance to murine cytomegalovirus (MCMV) infection. In B6 mice, the activating Ly49H receptor recognizes the viral m157 glycoprotein on infected cells. We previously identified a mutant strain (MCMVG1F) whose variant m157 also binds the inhibitory Ly49C receptor. Here we show that simultaneous binding of m157 to the two receptors hampers Ly49H-dependent NK cell activation as Ly49C-mediated inhibition destabilizes NK cell conjugation with their targets and prevents the cytoskeleton reorganization that precedes killing. In B6 mice, as most Ly49H+ NK cells do not co-express Ly49C, the overall NK cell response remains able to control MCMVm157G1F infection. However, in B6 Ly49C transgenic mice where all NK cells express the inhibitory receptor, MCMV infection results in altered NK cell activation associated with increased viral replication. Ly49C-mediated inhibition also regulates Ly49H-independent NK cell activation. Most interestingly, MHC class I regulates Ly49C function through cis-interactions that mask the receptor and restricts m157 binding. B6 Ly49C Tg, β2m ko mice, whose Ly49C receptors are unmasked due to MHC class I deficient expression, are highly susceptible to MCMVm157G1F and are unable to control a low-dose infection. Our study provides novel insights into the mechanisms that regulate NK cell activation during viral infection.
url http://europepmc.org/articles/PMC4038614?pdf=render
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