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. Dominant inhibition by Ly49C bound to self-H-2(b) encoded MHC-I molecules masks this effect, which only becomes apparent in distinct H-2 haplotypes, such as H-2(f). 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.
Department of Human Genetics, McGill University, Montreal, Quebec H3G 0B1, Canada; Complex Traits Group, McGill University, Montreal, Quebec H3G 0B1, Canada;
Michal
M
Pyzik
Anne
A
Dumaine
Department of Human Genetics, McGill University, Montreal, Quebec H3G 0B1, Canada; Complex Traits Group, McGill University, Montreal, Quebec H3G 0B1, Canada;
Anne A
AA
Dumaine
Department of Human Genetics, McGill University, Montreal, Quebec H3G 0B1, Canada; Complex Traits Group, McGill University, Montreal, Quebec H3G 0B1, Canada;
Benoît
B
Charbonneau
Department of Human Genetics, McGill University, Montreal, Quebec H3G 0B1, Canada; Complex Traits Group, McGill University, Montreal, Quebec H3G 0B1, Canada;
Nassima
N
Fodil-Cornu
Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka 51000, Croatia; and.
Stipan
S
Jonjic
Department of Human Genetics, McGill University, Montreal, Quebec H3G 0B1, Canada; Complex Traits Group, McGill University, Montreal, Quebec H3G 0B1, Canada; Department of Medicine, McGill University, Montreal, Quebec H3G 0B1, Canada silvia.vidal@mcgill.ca.
Silvia M
SM
Vidal
D000818:Animals; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D004198:Disease Susceptibility / Q000276:immunology; D005260:Female; D020022:Genetic Predisposition to Disease; D006183:H-2 Antigens / Q000235:genetics / Q000276:immunology; D006566:Herpesviridae Infections / Q000235:genetics / Q000276:immunology* / Q000821:virology*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000821:virology*; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D018146:Muromegalovirus / Q000235:genetics* / Q000276:immunology / Q000472:pathogenicity; D055650:NK Cell Lectin-Like Receptor Subfamily A / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics* / Q000276:immunology
D006183:H-2 Antigens; D055650:NK Cell Lectin-Like Receptor Subfamily A; D014764:Viral Proteins