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

Catherine A Forbes¹, Anthony A Scalzo¹, Mariapia A Degli-Esposti²

¹Centre for Experimental Immunology, Lions Eye Institute, Nedlands, Western Australia, Australia.

|May 31, 2014

Abstract:

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.

Insights

Natural Killer (NK) cells resist cytomegalovirus (CMV) infection. Inhibitory Ly49C receptors can block NK cell activation, impacting viral control, especially when MHC class I is absent.

Area of Science:

Immunology
Virology
Cellular Biology

Background:

Natural Killer (NK) cells are vital for early defense against murine cytomegalovirus (MCMV).
The activating Ly49H receptor on NK cells recognizes the MCMV m157 glycoprotein.
A mutant MCMV (MCMVG1F) has an m157 variant that binds both activating Ly49H and inhibitory Ly49C receptors.

Purpose of the Study:

To investigate how simultaneous binding of viral m157 to Ly49H and Ly49C receptors affects NK cell activation.
To determine the role of Ly49C expression levels and MHC class I regulation in NK cell responses to MCMV infection.

Main Methods:

Utilized B6 mice and B6 Ly49C transgenic mice.
Introduced MCMVG1F mutant strain into mouse models.
Analyzed NK cell activation, conjugate stability, and cytoskeleton reorganization.
Examined the impact of MHC class I expression on Ly49C function using β2m knockout mice.

Main Results:

Simultaneous m157 binding to Ly49H and Ly49C inhibits NK cell activation by destabilizing conjugates and preventing cytoskeleton reorganization.
In standard B6 mice, NK cell response controls MCMVG1F infection due to low Ly49C co-expression.
In Ly49C transgenic mice, MCMV infection leads to impaired NK cell activation and increased viral replication.
MHC class I normally restricts m157 binding to Ly49C; its absence in B6 Ly49C Tg, β2m ko mice increases susceptibility to MCMVG1F.

Conclusions:

Ly49C-mediated inhibition significantly impacts NK cell responses to MCMV, particularly when MHC class I regulation is lost.
NK cell activation during viral infection is a complex process regulated by the interplay between activating and inhibitory receptors and MHC class I expression.

Read full analysis

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