Phosphoantigen-driven dissociation of butyrophilin oligomers activates γδ T cells.

Authors

Weizhi Xin, Bangdong Huang, Weijie Gao, Wenjia Zhang, Yundi Hu, Yuehua Liu, Enyuan Liang, Jin Chen, Yigong Shi, Qiang Su, Qiang Zhou

Published in

Cell discovery. Volume 12. Issue 1. Aug 11, 2026. Epub Aug 11, 2026.

Abstract

γδ T cells represent a promising avenue for cancer immunotherapy. The Vγ9Vδ2 T-cell receptor (TCR), which is expressed by the predominant subset of γδ T cells, responds to phosphoantigen (pAg)-engaged butyrophilins (BTNs) on various cancer cells. However, the molecular mechanism underlying the pAg-mediated activation of Vγ9Vδ2 TCRs remains a subject of debate. Here, we employed an integrative approach to elucidate the mechanism of pAg reactivity in Vγ9Vδ2 T cells. Our results demonstrate that BTNs form higher-order oligomers in the absence of pAg. Upon pAg binding, these higher-order oligomers dissociate into separate tetramers, enabling Vγ9Vδ2 TCR engagement. This pAg-induced dissociation of higher-order BTN oligomers is critical for pAg-mediated activation of γδ T cells. Our findings reveal a mechanism of BTN higher-order oligomer dissociation-driven pAg sensing, providing valuable insight for future immunotherapeutic strategies.

PMID:
42575881
Bibliographic data and abstract were imported from PubMed on 11 Aug 2026.

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