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

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.