Stress-associated ligands recognized by gamma-delta T-cell receptor (γδ TCR ligands) (γδ TCR ligands)

Stress-associated ligands recognized by gamma-delta (γδ) T-cell receptors (TCRs) are a heterogeneous group of molecules upregulated on the surface of cells undergoing physiological stress, such as malignant transformation, oxidative stress, or intracellular infection (Bauer et al., 1999). Unlike conventional alpha-beta (αβ) T cells, which require peptide presentation on MHC molecules, γδ T cells recognize these ligands directly, facilitating a rapid, MHC-independent immune response (Hayday, 2000). Prominent examples include the MHC class I-related chains A and B (MICA/B) and members of the butyrophilin family, specifically BTN3A1 and BTN2A1, which are crucial for the activation of the Vγ9Vδ2 T-cell subset in humans (Rigau et al., 2020). In the context of oncology, these ligands act as molecular signatures of altered self, allowing γδ T cells to identify and eliminate tumor cells while sparing healthy tissue. Therapeutic development in this area focuses on leveraging these interactions through bispecific γδ T-cell engagers or monoclonal antibodies designed to recruit γδ T cells to the tumor microenvironment (Lava Therapeutics, 2023). However, challenges such as the shedding of MICA/B from the cell surface, which creates soluble decoys that inhibit T-cell function, remain significant hurdles in clinical application (Groh et al., 2002).

Other names

MHC class I polypeptide-related sequence AMHC class I polypeptide-related sequence BMICAMICBButyrophilin 3A1BTN3A1Butyrophilin 2A1BTN2A1UL16-binding proteinsULBPEndothelial protein C receptorEPCRAnnexin A2PhosphoantigensStress-induced ligands

Activation of gamma-delta T cells through the stabilization or cross-linking of stress-induced ligands with the T-cell receptor, or the accumulation of metabolic intermediates that bind to these ligands to trigger an immune response (Bauer et al., 1999; Rigau et al., 2020).