Ly49C-Dependent Control of MCMV Infection by NK Cells Is Cis-Regulated by MHC Class I Molecules

PLoS Pathogens

Catherine A. Forbes¹  Mariapia A. Degli-Esposti¹  Anthony A. Scalzo¹  Jerome D. Coudert² 

[1] Centre for Experimental Immunology, Lions Eye Institute, Nedlands, Western Australia, Australia;Centre for Ophthalmology and Vision Science, M517, University of Western Australia, Crawley, Western Australia, Australia

关键词: NK cells;    Cell binding;    Major histocompatibility complex;    Flow cytometry;    MHC class I genes;    Viral replication;    Cell staining;    Binding analysis;   

DOI  :  10.1371/journal.ppat.1004161

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY