Stress-induced ligands recognized by γδ TCR (SILs)

Stress-induced ligands recognized by γδ T-cell receptors (TCRs) are a diverse group of cell surface proteins upregulated in response to cellular stress, such as malignant transformation, viral infection, or oxidative damage. These ligands, which include MHC class I polypeptide-related sequence A/B (MICA/B) and UL16-binding proteins (ULBPs), serve as danger signals that allow γδ T cells to identify and eliminate compromised cells independently of classical MHC restriction. While some ligands like MICA/B are recognized directly by the γδ TCR (particularly the Vδ1 subset) or the co-receptor NKG2D, others like butyrophilins (e.g., BTN3A1) facilitate the recognition of intracellular phosphoantigens by Vγ9Vδ2 T cells. Other identified ligands include Annexin A2, EPCR, and EphA2, which are recognized by specific γδ T-cell clones in a stress-dependent manner. In cancer, these ligands are often downregulated or shed from the cell surface to evade immune detection, making them high-priority targets for immunotherapy. Therapeutic strategies include monoclonal antibodies that stabilize surface expression by preventing shedding, bispecific T-cell engagers that link these ligands to γδ T cells, and agonists that mimic or enhance ligand-mediated activation to boost anti-tumor immunity.

Other names

NKG2D ligandsStress-associated antigensStress-induced moleculesMHC class I-like moleculesNon-classical MHC moleculesLymphoid stress-surveillance ligands