Abstract: Provided are a method of producing a modified T cell comprising introducing into a precursor T cell a first nucleic acid encoding a Nef protein, wherein the Nef protein upon expression results in down-modulation of the endogenous T cell receptor (TCR) in the modified T cell, wherein the modified T cell furthermore expresses a functional exogenous receptor, such as an engineered TCR (e.g., chimeric TCR), T cell antigen coupler (TAC), TAC-like chimeric receptor, or a chimeric antigen receptor (CAR), the modified cell obtained by the method and the pharmaceutical composition comprising the modified T cell. Also provided is a non-naturally occurring Nef protein comprising one or more mutations.