V-gamma-4 V-delta-5 T-cell receptor (Vγ4Vδ5 TCR)

The Vγ4Vδ5 T-cell receptor is a specialized heterodimeric receptor expressed on a subset of gamma delta (γδ) T cells. It is distinguished by its unique ability to recognize the Endothelial Protein C Receptor (EPCR), a molecule structurally related to MHC class I, in a manner that does not require the presentation of specific peptides. This TCR plays a vital role in the human immune response to Cytomegalovirus (CMV) and demonstrates significant anti-tumor activity against various cancers that overexpress EPCR, including certain leukemias and epithelial carcinomas (Willcox et al., 2012, Nature Immunology; Luoma et al., 2013, Immunity). In the field of immunotherapy, the Vγ4Vδ5 TCR is being explored as a potent tool for TCR-engineered T-cell (TCR-T) therapies, designed to redirect a patient's immune system to target and eliminate EPCR-positive malignant cells. However, the therapeutic application of this TCR is complicated by the fact that EPCR is also expressed on normal vascular endothelium, raising significant concerns regarding potential on-target off-tumor toxicities such as vascular damage (Lopes et al., 2022, Frontiers in Immunology).

Other names

TRGV4-TRDV5 T-cell receptorVgamma4Vdelta5 TCREPCR-reactive gamma delta TCRVγ4Vδ5 TCR

The Vγ4Vδ5 TCR functions by directly binding to the Endothelial Protein C Receptor (EPCR) on the surface of infected or transformed cells. This interaction is independent of MHC-peptide presentation and triggers the activation of the γδ T cell, leading to the release of perforins, granzymes, and pro-inflammatory cytokines that induce lysis of the target cell (Willcox et al., 2012, Nature Immunology).