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

Shiyu Ayukawa; Nagisa Kamoshita; Jun Nakayama; Ryohei Teramoto; Novalia Pishesha; Kenji Ohba; Nanami Sato; Kei Kozawa; Hikari Abe; Kentaro Semba; Nobuhito Goda; Yasuyuki Fujita; Takeshi Maruyama

doi:10.1038/s41590-021-01045-6

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.

Authors

Shiyu Ayukawa¹, Nagisa Kamoshita^#², Jun Nakayama^#¹, Ryohei Teramoto¹, Novalia Pishesha³, Kenji Ohba⁴, Nanami Sato⁵, Kei Kozawa⁵, Hikari Abe¹, Kentaro Semba¹, Nobuhito Goda¹, Yasuyuki Fujita^{5

6}, Takeshi Maruyama⁷

Affiliations

¹ Department of Life Science and Medical Bioscience, School of Advanced Science and Engineering, Waseda University, Tokyo, Japan.
² Waseda Institute for Advanced Study, Waseda University, Tokyo, Japan.
³ Faculty of Arts and Sciences, Harvard University, Cambridge, MA, USA.
⁴ Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan.
⁵ Division of Molecular Oncology, Institute for Genetic Medicine, Hokkaido University Graduate School of Chemical Sciences and Engineering, Hokkaido, Japan.
⁶ Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
⁷ Waseda Institute for Advanced Study, Waseda University, Tokyo, Japan. tmaru@aoni.waseda.jp.

^# Contributed equally.

PMID: 34686865
DOI: 10.1038/s41590-021-01045-6

Abstract

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

Substances

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