T-cell receptor alpha constant and T-cell receptor beta constant (TRAC and TRBC)

The T-cell receptor alpha constant (TRAC) and T-cell receptor beta constant (TRBC) loci encode the structural, invariant portions of the T-cell receptor (TCR) alpha and beta chains, respectively (UniProt P01848, P01850). These components are vital for the assembly of the TCR-CD3 complex and its subsequent expression on the cell surface, where it facilitates the recognition of antigens presented by the major histocompatibility complex (MHC) (PubMed: 28225754). In modern biotechnology, the TRAC locus is a frequent target for site-specific gene editing, such as with CRISPR-Cas9, to eliminate endogenous TCR expression in allogeneic CAR-T cell therapies, thereby reducing the risk of graft-versus-host disease (GvHD) (Nature: Eyquem et al., 2017). The TRBC locus is unique because it contains two highly homologous genes, TRBC1 and TRBC2, which are expressed in a mutually exclusive manner by individual T cells. This mutual exclusivity allows for the development of therapies that selectively target malignant T-cell clones (which are restricted to one TRBC type) while sparing the healthy T-cell compartment (Nature Medicine: Maciocia et al., 2017). Therapeutic agents interacting with these loci include gene-editing nucleases for TRAC disruption and monoclonal antibodies or CAR-T cells, such as AUTO4, designed to target TRBC1-positive lymphomas (ClinicalTrials.gov: NCT03590574). The precise manipulation of these constant regions is essential for optimizing the safety and efficacy of next-generation adoptive cell transfers.

Other names

TRACTRBC1TRBC2TCR alpha constantTCR beta constantT-cell receptor alpha locusT-cell receptor beta locus

Disruption of the TRAC locus to prevent endogenous TCR expression and GvHD in allogeneic cell therapies; selective targeting of TRBC1 or TRBC2 isoforms to deplete clonal malignant T-cell populations.