Immunogenetics of infection: MHC class I molecules and NK cell receptors interplay in the recognition of MCMV-infected cell and infection outcome

Human cytomegalovirus (HCMV) is a herpesvirus found commonly in the world population, causing a severe and potentially fatal disease in neonates and immunocompromised patients. Clinical and experimental data indicate that a subset of innate lymphocytes, natural killer (NK) cells, plays a crucial role in resistance to infection. As infection with mouse CMV (MCMV) shares many pathophysiological aspects with the human disease, the mouse represents an excellent model to study CMV infection. The outcome of MCMV infection depends on the host genetic background and thus varies among the multiple inbred mouse strains. Importantly, mouse NK cells, through the expression of germ line encoded receptors, have the ability to recognize CMV infection, resulting in NK cell activation and the destruction of the infected cells. In each strain NK cells express amongst others, different sets of activating and inhibitory Ly49 receptors, in the presence of strain-specific MHC class I molecules, some of which are natural ligands to Ly49 receptors. Nevertheless, the exact mode of NK cell recognition of infected cell and the impact on the outcome of infection are complex and not fully understood. In order to characterize the molecular mechanisms underlying innate resistance to MCMV, we have initiated a systematic study to identify the possible ligands of Ly49 receptors and the nature of their interaction. We assessed the ability of distinct activating and inhibitory Ly49 receptors to recognize MCMV infection, in the context of diverse MHC class I haplotypes in vitro and in vivo. We show that the cognate interaction between several activating Ly49 receptors and MHC class I molecules depends on the presence of the viral regulator of antigen presentation, gp34/m04. Furthermore, we illustrate that, analogous to activating Ly49 receptors, inhibitory Ly49 receptors can be triggered by MCMV infection. This complex interaction, conditional on the type of MHC class I molecules, results in a spectrum of innate immune control of MCMV spread. Altogether, our results identify the fundamental mechanisms of NK cell receptor function in the recognition and eradication of viral infection. These will provide new grounds to understand and manipulate human NK cells in response to viral infections. %%%%Le cytomegalovirus humain (HCMV) est un herpesvirus omnipresent dans la population mondiale, qui provoque des symptomes graves et potentiellement mortels chez les nouveau-nes et les patients immunodeprimes. Les donnees cliniques et experimentales indiquent qu'un sous-ensemble de lymphocytes innes, dites tueuses naturelles (NK), joue un role crucial dans la resistance a l'infection. Comme l'infection par le CMV murin (MCMV) partage de nombreux aspects physiopathologiques de la maladie humaine, la souris constitue un excellent modele pour etudier l'infection par le CMV. La susceptibilite au MCMV varie grandement selon les lignees de souris congeniques et ce, en fonction de leur patrimoine genetique. Plus precisement, chaque lignee de souris exprime une variete de…