BTNL2 promotes colitis‐associated tumorigenesis in mice by regulating IL‐22 production

Abstract Interleukin 22 (IL‐22) has an important role in colorectal tumorigenesis and many colorectal diseases such as inflammatory bowel disease and certain infections. However, the regulation of IL‐22 production in the intestinal system is still unclear. Here, we present evidence that butyrophilin‐like protein 2 (BTNL2) is required for colorectal IL‐22 production, and BTNL2 knockout mice show decreased colonic tumorigenesis and more severe colitis phenotypes than control mice due to defective production of IL‐22. Mechanistically, BTNL2 acts on group 3 innate lymphoid cells (ILC3s), CD4 + T cells, and γδ T cells to promote the production of IL‐22. Importantly, we find that a monoclonal antibody against BTNL2 attenuates colorectal tumorigenesis in mice and that the mBTNL2‐Fc recombinant protein has a therapeutic effect in a dextran sulfate sodium (DSS)‐induced colitis model. This study not only identifies a regulatory mechanism of IL‐22 production in the colorectal system but also provides a potential therapeutic target for the treatment of human colorectal cancer and inflammatory bowel diseases.