Epithelial cells remove precancerous cells by cell competition via MHC class I-LILRB3 interaction

Nat Immunol. 2021 Nov;22(11):1391-1402. doi: 10.1038/s41590-021-01045-6. Epub 2021 Oct 22.


Epithelial cells have an ability termed 'cell competition', which is an immune surveillance-like function that extrudes precancerous cells from the epithelial layer, leading to apoptosis and clearance. However, it remains unclear how epithelial cells recognize and extrude transformed cells. Here, we discovered that a PirB family protein, leukocyte immunoglobulin-like receptor B3 (LILRB3), which is expressed on non-transformed epithelial cells, recognizes major histocompatibility complex class I (MHC class I) that is highly expressed on transformed cells. MHC class I interaction with LILRB3 expressed on normal epithelial cells triggers an SHP2-ROCK2 pathway that generates a mechanical force to extrude transformed cells. Removal of transformed cells occurs independently of natural killer (NK) cell or CD8+ cytotoxic T cell-mediated activity. This is a new mechanism in that the immunological ligand-receptor system generates a mechanical force in non-immune epithelial cells to extrude precancerous cells in the same epithelial layer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / metabolism*
  • Apoptosis*
  • Cell Competition*
  • Core Binding Factor Alpha 1 Subunit / metabolism
  • Dogs
  • Epithelial Cells / immunology
  • Epithelial Cells / metabolism*
  • Epithelial Cells / pathology
  • HaCaT Cells
  • Histocompatibility Antigens Class I / metabolism*
  • Humans
  • Lung Neoplasms / genetics
  • Lung Neoplasms / immunology
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology
  • Madin Darby Canine Kidney Cells
  • Mechanotransduction, Cellular
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Precancerous Conditions / genetics
  • Precancerous Conditions / immunology
  • Precancerous Conditions / metabolism*
  • Precancerous Conditions / pathology
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism
  • RAW 264.7 Cells
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism*
  • Stress, Mechanical
  • rho-Associated Kinases / metabolism


  • Antigens, CD
  • Core Binding Factor Alpha 1 Subunit
  • Histocompatibility Antigens Class I
  • LILRB3 protein, human
  • RUNX2 protein, human
  • Receptors, Immunologic
  • ROCK2 protein, human
  • rho-Associated Kinases
  • PTPN11 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11