Ly49P recognition of cytomegalovirus-infected cells expressing H2-Dk and CMV-encoded m04 correlates with the NK cell antiviral response

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confidence: 99%

Effect of Ly49 Haplotype Variance on NK Cell Function and Education

Patel

Bélanger

Tai

et al. 2010

“…with 5 3 10 3 PFU/mouse MCMV. Tissue culture-grown Dm157 MCMV, m157 revertant (m157-Rev) MCMV, and MCMV-GFP viruses were described previously (9,20). Dm157 MCMV was injected i.p.…”

Section: Virus Stocks and Mouse Infectionsmentioning

confidence: 99%

“…This direct recognition results in NK cell activation, proliferation, secretion of inflammatory cytokines, direct killing of MCMV-infected cells, and efficient viral control in target organs (5)(6)(7). Additionally, Ly49P, Ly49L, and Ly49D2 receptors recognize MCMV infection based on the presence of the viral m04/gp34 protein associated with particular H-2 molecules (8)(9)(10). The deletion of the m04 gene from the viral genome or an inappropriate H-2 context result in decreased IFN-g secretion with high viral propagation in target organs during MCMV infection of MA/My or BALB.By mice, respectively (9,10).…”

mentioning

confidence: 99%

“…Additionally, Ly49P, Ly49L, and Ly49D2 receptors recognize MCMV infection based on the presence of the viral m04/gp34 protein associated with particular H-2 molecules (8)(9)(10). The deletion of the m04 gene from the viral genome or an inappropriate H-2 context result in decreased IFN-g secretion with high viral propagation in target organs during MCMV infection of MA/My or BALB.By mice, respectively (9,10). Such frequent recognition of MCMV-encoded ligands by NK cell-activating receptors raises the issue of their emergence and persistence in viral genomes.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Viral MHC Class I–like Molecule Allows Evasion of NK Cell Effector Responses In Vivo

Pyzik

Dumaine

Charbonneau

et al. 2014

Self Cite

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. Dominant inhibition by Ly49C bound to self–H-2b encoded MHC-I molecules masks this effect, which only becomes apparent in distinct H-2 haplotypes, such as H-2f. The recognition of m157-expressing cells by Ly49C resulted in both decreased NK cell killing in vitro and reduced rejection in vivo. Further, control of infection with m157-deletant (Δm157) MCMV was improved in mice carrying H-2 molecules unrecognized by Ly49C but allowing expansion of NK cell effectors expressing activating Ly49L receptors. Hence, our study is the first, to our knowledge, to demonstrate that MHC-I mimicry strategies used by MCMV to avoid NK cell control are biologically relevant during in vivo viral infection. Of value for human studies is that only a few genetic assortments conditional on the repertoires of viral MHC-I–like proteins/host NK receptors/MHC haplotypes should allow efficient protection against CMV infection.

“…Two likely examples of this evolutionary struggle have been documented: interaction of the cI-like MCMV-encoded protein m157 with the inhibitory Ly49C and Ly49I molecules and the activatory Ly49H molecule (61)(62)(63), and the interaction of the activating Ly49P molecules with an endogenous cI molecule modified in some unknown manner by MCMV infection (64). Pathogen-driven diversification of individual Ly49 molecules would be facilitated by the redundancy provided by multigenism, allowing Ly49s that had acquired inactivating mutations to regain functionality via counteracting mutations.…”

mentioning

confidence: 99%

Mutagenesis of Ly49B Reveals Key Structural Elements Required for Promiscuous Binding to MHC Class I Molecules and New Insights into the Molecular Evolution of Ly49s

Mickiewicz

Gays

Lewis

et al. 2014

Ly49B is a potentially important immunoregulator expressed on mouse myeloid cells, and it is thus an unusual member of the wider Ly49 family whose members are ordinarily found on NK cells. Ly49B displays substantial sequence divergence from other Ly49s and in particular shares virtually no amino acid sequence identity with the residues that have been reported to bind to MHC class I (cI) ligands in other Ly49s. Despite this, we show in this study that the BALB/c, but not the C57, isoform of Ly49B displays promiscuous cI binding. Binding was not significantly affected by inactivation of any of the four predicted N-linked glycosylation sites of Ly49B, nor was it affected by removal of the unique 20-aa C-terminal extension found in Ly49B. However, transfer of these C-terminal 20 aa to Ly49A inhibited cI binding, as did the addition of a hemagglutinin tag to the C terminus of Ly49B, demonstrating unexpectedly that the C-terminal region of Ly49s can play a significant role in ligand binding. Systematic exchange of BALB/c and C57 residues revealed that Trp166, Asn167, and Cys251 are of major importance for cI binding in Ly49B. These residues are highly conserved in the Ly49 family. Remarkably, however, Ly49BBALB variants that have C57 residues at positions 166 or 167, and are unable to bind cI multimers, regain substantial cI binding when amino acid changes are made at distal positions, providing an explanation of how highly divergent Ly49s that retain the ability to bind cI molecules might have evolved.