A Viral Immunoevasin Controls Innate Immunity by Targeting the Prototypical Natural Killer Cell Receptor Family

Cell. 2017 Mar 23;169(1):58-71.e14. doi: 10.1016/j.cell.2017.03.002.


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.

Keywords: NK1.1 ligand; Natural killer cell; host-pathogen interactions; murine cytomegalovirus; viral immune evasion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Ly / metabolism
  • Cell Line
  • HEK293 Cells
  • Host-Pathogen Interactions
  • Humans
  • Immune Evasion
  • Immunity, Innate
  • Killer Cells, Natural / immunology*
  • Mice
  • Muromegalovirus / immunology*
  • NIH 3T3 Cells
  • NK Cell Lectin-Like Receptor Subfamily B / metabolism
  • Rats
  • Receptors, Natural Killer Cell / immunology*
  • Viral Proteins / metabolism*


  • Antigens, Ly
  • Klrb1b protein, mouse
  • Klrb1c protein, mouse
  • NK Cell Lectin-Like Receptor Subfamily B
  • Receptors, Natural Killer Cell
  • Viral Proteins