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

Area of Science:

• Cell biology
• Immunology
• Cancer research

Background:

• Epithelial cells possess a cell competition mechanism for immune surveillance.
• The precise molecular mechanisms by which epithelial cells recognize and extrude precancerous cells remain largely unknown.

Purpose of the Study:

• To elucidate the molecular pathway and receptor-ligand interactions involved in epithelial cell competition against transformed cells.

Main Methods:

• Investigated the role of leukocyte immunoglobulin-like receptor B3 (LILRB3) in cell competition.
• Utilized assays to detect interactions between LILRB3 and major histocompatibility complex class I (MHC class I).
• Analyzed signaling pathways including SHP2-ROCK2 and mechanical force generation in extruded cells.

Main Results:

• Identified LILRB3 on non-transformed epithelial cells as a receptor for highly expressed MHC class I on transformed cells.
• Demonstrated that MHC class I-LILRB3 interaction activates the SHP2-ROCK2 pathway, generating mechanical force for extrusion.
• Showcased that transformed cell removal is independent of natural killer (NK) cells or CD8+ cytotoxic T cells.

Conclusions:

• Discovered a novel mechanism where an immunological ligand-receptor system in non-immune epithelial cells generates mechanical force to extrude precancerous cells.
• This pathway represents a new mode of immune surveillance within epithelial layers, distinct from adaptive or innate immune cell activity.