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bioRxiv · 10.1101/2025.09.26.677252

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.
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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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Zhou, Q., Xin, W., Huang, B., Gao, W., Zhang, W., Hu, Y., Liu, Y., Liang, E., Shi, Y., Su, Q.. 2025-09-28. Phosphoantigen-Driven Dissociation of Butyrophilin Oligomers Activates γδ T Cells. https://doi.org/10.1101/2025.09.26.677252

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