Viral MHC class I-like molecule allows evasion of NK cell effector responses in vivo.

The outcome of mouse CMV (MCMV) infection varies among different inbred mouse strains depending on NK cell effector functions governed through recognition receptor triggering. NK cells from different mouse strains possess diverse repertoires of activating or inhibitory Ly49 receptors, which share some of their polymorphic MHC class I (MHC-I) ligands. By examining the NK cell response to MCMV infection in novel BALB substrains congenic for different MHC (or H-2 in mice) haplotypes, we show that recognition of viral MHC-I-like protein m157 by inhibitory Ly49C receptor allows escape from NK cell control of viral replication.

Genetic dissection of NK cell responses.

The association of Natural Killer (NK) cell deficiencies with disease susceptibility has established a central role for NK cells in host defence. In this context, genetic approaches have been pivotal in elucidating and characterizing the molecular mechanisms underlying NK cell function. To this end, homozygosity mapping and linkage analysis in humans have identified mutations that impact NK cell function and cause life-threatening diseases.

TGF-β is responsible for NK cell immaturity during ontogeny and increased susceptibility to infection during mouse infancy.

A large gap in our understanding of infant immunity is why natural killer (NK) cell responses are deficient, which makes infants more prone to viral infection. Here we demonstrate that transforming growth factor-β (TGF-β) was responsible for NK cell immaturity during infancy. We found more fully mature NK cells in CD11c(dnR) mice, whose NK cells lack TGF-β receptor (TGF-βR) signaling.

The NK cell response to mouse cytomegalovirus infection affects the level and kinetics of the early CD8(+) T-cell response.

Natural killer (NK) cells and CD8(+) T cells play a prominent role in the clearance of mouse cytomegalovirus (MCMV) infection. The role of NK cells in modulating the CD8(+) T-cell response to MCMV infection is still the subject of intensive research. For analyzing the impact of NK cells on mounting of a CD8(+) T-cell response and the contribution of these cells to virus control during the first days postinfection (p.

NK cell receptor/H2-Dk-dependent host resistance to viral infection is quantitatively modulated by H2q inhibitory signals.

The cytomegalovirus resistance locus Cmv3 has been linked to an epistatic interaction between two loci: a Natural Killer (NK) cell receptor gene and the major histocompatibility complex class I (MHC-I) locus. To demonstrate the interaction between Cmv3 and H2(k), we generated double congenic mice between MA/My and BALB.K mice and an F(2) cross between FVB/N (H-2(q)) and BALB.

Self or nonself? That is the question: sensing of cytomegalovirus infection by innate immune receptors.

Cytomegaloviruses (CMV) are ubiquitous, opportunistic DNA viruses that have mastered the art of immune evasion through their ability to mimic host proteins or to inhibit antiviral responses. The study of the host response against CMV infection has illuminated many facets of the complex interaction between host and pathogen. Here, we review evidence derived from the animal models and human studies that supports the central role played by innate immune receptors in the recognition of virus infection and their participation in the many layers of defense.

Use of inbred mouse strains to map recognition receptors of MCMV infected cells in the NK cell gene locus.

Genetically distinct inbred strains of mice that differ in their susceptibility to mouse cytomegalovirus (MCMV) are invaluable for dissecting complex host-pathogen interactions. Their study has allowed the identification of host-resistance loci, including several activating NK cell receptors of major histocompatibility complex (MHC) class I. In this chapter, we provide a practical guide to the genetic mapping and functional characterization of NK cell receptors that control innate immunity against MCMV via specific recognition of infected cells.

Activating receptors promote NK cell expansion for maintenance, IL-10 production, and CD8 T cell regulation during viral infection.

Natural killer (NK) cells have the potential to deliver both direct antimicrobial effects and regulate adaptive immune responses, but NK cell yields have been reported to vary greatly during different viral infections. Activating receptors, including the Ly49H molecule recognizing mouse cytomegalovirus (MCMV), can stimulate NK cell expansion. To define Ly49H's role in supporting NK cell proliferation and maintenance under conditions of uncontrolled viral infection, experiments were performed in Ly49h(-/-), perforin 1 (Prf1)(-/-), and wild-type (wt) B6 mice.

Positive regulation of plasmacytoid dendritic cell function via Ly49Q recognition of class I MHC.

Plasmacytoid dendritic cells (pDCs) are an important source of type I interferon (IFN) during initial immune responses to viral infections. In mice, pDCs are uniquely characterized by high-level expression of Ly49Q, a C-type lectin-like receptor specific for class I major histocompatibility complex (MHC) molecules. Despite having a cytoplasmic immunoreceptor tyrosine-based inhibitory motif, Ly49Q was found to enhance pDC function in vitro, as pDC cytokine production in response to the Toll-like receptor (TLR) 9 agonist CpG-oligonucleotide (ODN) could be blocked using soluble monoclonal antibody (mAb) to Ly49Q or H-2K(b).

Ly49h-deficient C57BL/6 mice: a new mouse cytomegalovirus-susceptible model remains resistant to unrelated pathogens controlled by the NK gene complex.

Cmv1 was the first mouse cytomegalovirus (MCMV) resistance locus identified in C57BL/6 mice. It encodes Ly49H, a NK cell-activating receptor that specifically recognizes the m157 viral protein at the surface of MCMV-infected cells. To dissect the effect of the Ly49h gene in host-pathogen interactions, we generated C57BL/6 mice lacking the Ly49h region.

Type I interferon response to cytomegalovirus infection: the kick-start.

Host responses to cytomegalovirus infection include initial early production of alpha and beta interferons, also called type I interferons, which are elicited directly by viral products via Toll-like receptors. New data indicate that, preceding these events, an earlier critical type I interferon elicited in primary infected stromal cells via the lymphotoxin beta receptor system and mediated by B cells is necessary to kick-start an efficient antiviral response.

Cmv4, a new locus linked to the NK cell gene complex, controls innate resistance to cytomegalovirus in wild-derived mice.

CMV can cause life-threatening disease in immunodeficient hosts. Experimental infection in mice has revealed that the genetically determined natural resistance to murine CMV (MCMV) may be mediated either by direct recognition between the NK receptor Ly49H and the pathogen-encoded glycoprotein m157 or by epistatic interaction between Ly49P and the host MHC H-2D(k). Using stocks of wild-derived inbred mice as a source of genetic diversity, we found that PWK/Pas (PWK) mice were naturally resistant to MCMV.