The Adhesion G Protein-Coupled Receptor GPR56/ADGRG1 Is an Inhibitory Receptor on Human NK Cells

Cell Rep. 2016 May 24;15(8):1757-70. doi: 10.1016/j.celrep.2016.04.053. Epub 2016 May 12.


Natural killer (NK) cells possess potent cytotoxic mechanisms that need to be tightly controlled. Here, we explored the regulation and function of GPR56/ADGRG1, an adhesion G protein-coupled receptor implicated in developmental processes and expressed distinctively in mature NK cells. Expression of GPR56 was triggered by Hobit (a homolog of Blimp-1 in T cells) and declined upon cell activation. Through studying NK cells from polymicrogyria patients with disease-causing mutations in ADGRG1, encoding GPR56, and NK-92 cells ectopically expressing the receptor, we found that GPR56 negatively regulates immediate effector functions, including production of inflammatory cytokines and cytolytic proteins, degranulation, and target cell killing. GPR56 pursues this activity by associating with the tetraspanin CD81. We conclude that GPR56 inhibits natural cytotoxicity of human NK cells.

Keywords: NK cells; adhesion GPCRs; cytotoxicity; immune regulation; transcription factor.

MeSH terms

  • Cell Differentiation / drug effects
  • Cell Division / drug effects
  • Cell Line
  • Cells, Cultured
  • Cytokines / pharmacology
  • Cytotoxicity, Immunologic / drug effects
  • Down-Regulation / drug effects
  • Humans
  • Immunological Synapses / drug effects
  • Inflammation Mediators / metabolism
  • Killer Cells, Natural / cytology
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / metabolism*
  • Malformations of Cortical Development / pathology
  • Receptors, G-Protein-Coupled / deficiency
  • Receptors, G-Protein-Coupled / metabolism*
  • Tetraspanin 28 / metabolism
  • Transcription Factors / metabolism


  • ADGRG1 protein, human
  • Cytokines
  • Inflammation Mediators
  • Receptors, G-Protein-Coupled
  • Tetraspanin 28
  • Transcription Factors

Supplementary concepts

  • Polymicrogyria, Bilateral Frontoparietal