Butyrophilin subfamily 3 member A1 (BTN3A1) and Butyrophilin subfamily 2 member A1 (BTN2A1) complex (BTN3A1/BTN2A1 complex)

The Butyrophilin subfamily 3 member A1 (BTN3A1) and Butyrophilin subfamily 2 member A1 (BTN2A1) complex is a heteromeric molecular assembly that serves as the primary mediator for the activation of Vγ9Vδ2 T cells in humans (Rigau et al., 2020, Nature). This complex functions as a sensor for intracellular phosphoantigens (pAgs), such as isopentenyl pyrophosphate (IPP), which are metabolic intermediates that accumulate in tumor cells or cells infected by certain pathogens (Karunakaran et al., 2020, Nature). Upon binding of pAgs to the intracellular B30.2 domain of BTN3A1, the complex undergoes a critical conformational change that is transmitted to the extracellular domains, a process known as inside-out signaling (Yuan et al., 2021, PNAS). BTN2A1 acts as a mandatory co-factor that directly binds to the Vγ9 chain of the T-cell receptor (TCR), while BTN3A1 facilitates the overall structural presentation required for T-cell recognition (Lapiedra et al., 2023, Nature Communications). In oncology, this complex is targeted by agonistic antibodies like ICT01, which are designed to stabilize the active conformation and trigger a potent anti-tumor immune response (ImCheck Therapeutics, 2024). Because Vγ9Vδ2 T cells recognize these butyrophilins in an MHC-independent manner, the BTN3A1/BTN2A1 complex represents a versatile target for broad-spectrum cancer immunotherapy across various solid and hematologic malignancies (UniProt Q96A58).

Other names

BTN3A1-BTN2A1 heteromerCD277/BTN2A1 complexButyrophilin 3A1/2A1 complexpAg-induced BTN3A1/BTN2A1 complex

Agonistic stabilization of the phosphoantigen-induced conformational state to trigger Vγ9Vδ2 T-cell receptor activation.