Butyrophilin subfamily 3 member A1 (BTN3A1) (BTN3A1)

Butyrophilin subfamily 3 member A1 (BTN3A1), also known as CD277, is a transmembrane protein that plays a critical role in the activation of Vγ9Vδ2 T cells, the most abundant γδ T cell subset in human peripheral blood (UniProt: O00481). It functions as part of a molecular sensor for intracellular phosphoantigens (pAg), such as isopentenyl pyrophosphate (IPP), which accumulate in cancer cells due to a dysregulated mevalonate pathway (PubMed: 32730233). Upon pAg binding to its intracellular B30.2 domain, BTN3A1 undergoes a conformational change that, in complex with Butyrophilin 2A1 (BTN2A1), is recognized by the γδ T cell receptor (TCR) (Science: 32327603). This mechanism allows γδ T cells to distinguish between healthy and malignant cells based on metabolic stress rather than specific peptide-MHC complexes. In the context of engineered therapies, αβ T cells are often transduced with high-affinity γδ TCRs (TEGs) to target the BTN3A1/BTN2A1 complex on a wide range of hematological and solid tumors (JCI: 132489). Therapeutic strategies include agonist antibodies like ICT01, which mimic the pAg-induced conformational change to activate endogenous γδ T cells, and cell therapies like TEG001 (ImCheck Therapeutics; Gadeta).

Other names

CD277BTF1BT3.1Butyrophilin 3A1Butyrophilin subfamily 3 member A1BTN3A1/BTN2A1 complex

Agonism of BTN3A1 to induce a conformational change that activates γδ T cells; direct recognition of the BTN3A1/BTN2A1 complex by engineered γδ T cell receptors (TEGs).