Transfer of mRNA Encoding Invariant NKT Cell Receptors Imparts Glycolipid Specific Responses to T Cells and γδT Cells

Cell-based therapies using genetically engineered lymphocytes expressing antigen-specific T cell receptors (TCRs) hold promise for the treatment of several types of cancers. Almost all studies using this modality have focused on transfer of TCR from CD8 cytotoxic T lymphocytes (CTLs). The transfer of TCR from innate lymphocytes to other lymphocytes has not been studied. In the current study, innate and adaptive lymphocytes were transfected with the human NKT cell-derived TCR alpha and beta chain mRNA (the V alpha 24 and V beta 11 TCR chains). When primary T cells transfected with NKT cell-derived TCR were subsequently stimulated with the NKT ligand, alpha-galactosylceramide (alpha-GalCer), they secreted IFN-gamma in a ligand-specific manner. Furthermore when gamma delta T cells were transfected with NKT cell-derived TCR mRNA, they demonstrated enhanced proliferation, IFN-gamma production and antitumor effects after alpha-GalCer stimulation as compared to parental gamma delta T cells. Importantly, NKT cell TCR-transfected gamma delta T cells responded to both NKT cell and gamma delta T cell ligands, rendering them bi-potential innate lymphocytes. Because NKT cell receptors are unique and universal invariant receptors in humans, the TCR chains do not yield mispaired receptors with endogenous TCR alpha and beta chains after the transfection. The transfection of NKT cell TCR has the potential to be a new approach to tumor immunotherapy in patients with various types of cancer.