A Viral Immunoevasin Controls Innate Immunity by Targeting the Prototypical Natural Killer Cell Receptor Family.
Natural killer (NK) cells play a key role in innate immunity by detecting alterations in self and non-self ligands via paired NK cell receptors (NKRs). Despite identification of numerous NKR-ligand interactions, physiological ligands for the prototypical NK1.1 orphan receptor remain elusive. Here, we identify a viral ligand for the inhibitory and activating NKR-P1 (NK1.1) receptors. This murine cytomegalovirus (MCMV)-encoded protein, m12, restrains NK cell effector function by directly engaging the inhibitory NKR-P1B receptor. However, m12 also interacts with the activating NKR-P1A/C receptors to counterbalance m12 decoy function. Structural analyses reveal that m12 sequesters a large NKR-P1 surface area via a "polar claw" mechanism. Polymorphisms in, and ablation of, the viral m12 protein and host NKR-P1B/C alleles impact NK cell responses in vivo. Thus, we identify the long-sought foreign ligand for this key immunoregulatory NKR family and reveal how it controls the evolutionary balance of immune recognition during host-pathogen interplay.
Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada; Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada.
Oscar A
OA
Aguilar
Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; ARC Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, VIC 3800, Australia.
Richard
R
Berry
Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
Mir Munir A
MMA
Rahim
Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia.
Johanna J
JJ
Reichel
Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia.
Branka
B
Popović
Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada; Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada.
Miho
M
Tanaka
Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.
Zhihui
Z
Fu
Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; ARC Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, VIC 3800, Australia.
Gautham R
GR
Balaji
Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada; Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada.
Timothy N H
TNH
Lau
Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
Megan M
MM
Tu
Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada; Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada.
Christina L
CL
Kirkham
Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada; College of Applied Medical Sciences, Taibah University, 30001 Madinah Munawwarah, Kingdom of Saudi Arabia.
Ahmad Bakur
AB
Mahmoud
Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada; Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada.
Aruz
A
Mesci
Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia.
Astrid
A
Krmpotić
Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada; Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada.
David S J
DSJ
Allan
Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada. Electronic address: andrew.makrigiannis@dal.ca.
Andrew P
AP
Makrigiannis
Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia. Electronic address: stipan.jonjic@medri.uniri.hr.
Stipan
S
Jonjić
Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; ARC Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, VIC 3800, Australia; Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK. Electronic address: jamie.rossjohn@monash.edu.
Jamie
J
Rossjohn
Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada; Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada. Electronic address: james.carlyle@utoronto.ca.
James R
JR
Carlyle
D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D002460:Cell Line; D057809:HEK293 Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D057131:Immune Evasion; D007113:Immunity, Innate; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D018146:Muromegalovirus / Q000276:immunology*; D041681:NIH 3T3 Cells; D055651:NK Cell Lectin-Like Receptor Subfamily B / Q000378:metabolism; D051381:Rats; D055607:Receptors, Natural Killer Cell / Q000276:immunology*; D014764:Viral Proteins / Q000378:metabolism*
D000950:Antigens, Ly; C527212:Klrb1b protein, mouse; C527211:Klrb1c protein, mouse; D055651:NK Cell Lectin-Like Receptor Subfamily B; D055607:Receptors, Natural Killer Cell; D014764:Viral Proteins
NK1.1 ligand; Natural killer cell; host-pathogen interactions; murine cytomegalovirus; viral immune evasion