T-cell receptor alpha constant (TRAC) (TRAC)

The T-cell receptor alpha constant (TRAC) locus is the genomic region encoding the constant domain of the T-cell receptor (TCR) alpha chain, which is essential for the formation and signaling of the TCR complex in T lymphocytes (UniProt P01848; NCBI Gene ID: 28755). In the context of advanced cell therapies, the TRAC locus serves as a critical target for genome editing tools such as CRISPR/Cas9, TALENs, and Zinc Finger Nucleases. By disrupting this locus, researchers can eliminate the expression of the endogenous TCR, a vital step in the production of allogeneic (off-the-shelf) CAR-T cells to prevent life-threatening Graft-versus-Host Disease (GvHD) (Qasim et al., 2017, Science Translational Medicine). Furthermore, the TRAC locus is a preferred site for the targeted insertion of Chimeric Antigen Receptors (CARs). Placing a CAR transgene under the control of the endogenous TRAC promoter ensures physiological regulation of CAR expression, which significantly reduces tonic signaling and T-cell exhaustion while enhancing the durability and potency of the therapeutic cells compared to traditional viral vector-mediated random integration (Eyquem et al., 2017, Nature). This genomic target is central to the development of next-generation universal immune cell therapies for both hematological and solid malignancies (MacLeod et al., 2020, Molecular Therapy).

Other names

T cell receptor alpha constantTCRAT-cell receptor alpha locusTRAC locusT-cell receptor alpha constant genomic DNA

Targeted gene disruption (knock-out) via site-specific endonucleases to eliminate endogenous TCR expression and/or site-specific gene insertion (knock-in) via homology-directed repair for regulated transgene expression.