Molecular immunology lessons from therapeutic T‐cell receptor gene transfer

The T‐cell receptor (TCR) is critical for T‐cell lineage selection, antigen specificity, effector function and survival. Recently, TCR gene transfer has been developed as a reliable method to generate ex vivo large numbers of T cells of a given antigen‐specificity and functional avidity. Such approaches have major applications for the adoptive cellular therapy of viral infectious diseases, virus‐associated malignancies and cancer. TCR gene transfer utilizes retroviral or lentiviral constructs containing the gene sequences of the TCR‐α and TCR‐β chains, which have been cloned from a clonal T‐cell population of the desired antigen specificity. The TCR‐encoding vector is then used to infect (transduce) primary T cells in vitro. To generate a transduced T cell with the desired functional specificity, the introduced TCR‐α and TCR‐β chains must form a heterodimer and associate with the CD3 complex in order to be stably expressed at the T‐cell surface. In order to optimize the function of TCR‐transduced T cells, researchers in the field of TCR gene transfer have exploited many aspects of basic research in T‐cell immunology relating to TCR structure, TCR–CD3 assembly, cell‐surface TCR expression, TCR‐peptide/major histocompatibility complex (MHC) affinity and TCR signalling. However, improving the introduction of exogenous TCRs into naturally occurring T cells has provided further insights into basic T‐cell immunology. The aim of this review was to discuss the molecular immunology lessons learnt through therapeutic TCR transfer.