Phosphoantigen-Driven Dissociation of Butyrophilin Oligomers Activates γδ T Cells
Zhou, Q.; Xin, W.; Huang, B.; Gao, W.; Zhang, W.; Hu, Y.; Liu, Y.; Liang, E.; Shi, Y.; Su, Q.
Show abstract
{gamma}{delta} T cells represent a promising avenue for cancer immunotherapy. The V{gamma}9V{delta}2 T cell receptor (TCR), expressed by the predominant subset of {gamma}{delta} T cells, responds to phosphoantigen (pAg)-engaged butyrophilins (BTNs) on various cancer cells. However, the molecular mechanism underlying pAg-mediated activation of V{gamma}9V{delta}2 TCRs remains a subject of debate. Here, we employed an integrative approach to elucidate the mechanism of pAg reactivity in V{gamma}9V{delta}2 T cells. Our results demonstrate that BTNs form higher-order oligomers in the absence of pAg. Upon pAg binding, these oligomers dissociate into tetramers, enabling V{gamma}9V{delta}2 TCR engagement. This pAg-induced dissociation of higher-order BTN complexes is critical for pAg-mediated activation of {gamma}{delta} T cells. Our findings reveal a mechanism of BTN dissociation-driven pAg sensing, providing valuable insight for future immunotherapeutic strategies.
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