Abstract
A functional and effective cell-based immunosurveillance system requires two necessary components: a repertoire of receptors derived from immunoglobulin-like molecules for diverse molecular recognition and a signalling pathway-based activation mechanism for sorting signals and enabling effective activation. Besides the MHC restricted recognition pattern adopt by the adaptive immune cells, such as T cells, and the “missing-self” mechanism discovered in innate immune, such as NK cells, we proposed another novel artificial bionic immune cell system based on a synthetic receptor repertoire and genetic circuits. For this system, a pre-established population of genetically engineered lymphocyte repertoires was developed in which a particular antigen can exclusively activate its specific counter cell, enabling that specific cell to survive and multiply under a specific artificial environment and to destroy particular antigens. Two synthetic patterns were postulated based on CAR receptors and synNotch receptors, in which the antibody library took the place of the antigen-recognition region. The inhibited expression of the inducible caspase-9 suicide gene was coupled with the activation of the synthetic receptor, allowing the lymphocyte repertoire to co-evolve with the dynamic expression of antigens. Synthetic cell repertoire shows significant anti-tumour effect both in vitro and in vivo. Tumour specific killer cells were enriched within one month in vivo even for large repertoire with abundant diversity. In theory, if the diversity of the lymphocyte repertoire is sufficient, then this artificial system can be used for the treatment of any human disease.