@article{d9afb259dc944202a896b4e71b4f30a9,
title = "A Structural Change in Butyrophilin upon Phosphoantigen Binding Underlies Phosphoantigen-Mediated Vγ9Vδ2 T Cell Activation",
abstract = "Human Vγ9Vδ2 T cells respond to microbial infections and malignancy by sensing diphosphate-containing metabolites called phosphoantigens, which bind to the intracellular domain of butyrophilin 3A1, triggering extracellular interactions with the Vγ9Vδ2 T cell receptor (TCR). Here, we examined the molecular basis of this “inside-out” triggering mechanism. Crystal structures of intracellular butyrophilin 3A proteins alone or in complex with the potent microbial phosphoantigen HMBPP or a synthetic analog revealed key features of phosphoantigens and butyrophilins required for γδ T cell activation. Analyses with chemical probes and molecular dynamic simulations demonstrated that dimerized intracellular proteins cooperate in sensing HMBPP to enhance the efficiency of γδ T cell activation. HMBPP binding to butyrophilin doubled the binding force between a γδ T cell and a target cell during “outside” signaling, as measured by single-cell force microscopy. Our findings provide insight into the “inside-out” triggering of Vγ9Vδ2 T cell activation by phosphoantigen-bound butyrophilin, facilitating immunotherapeutic drug design.",
keywords = "HMBPP, T cell antigen recognition, Vγ9Vδ2 T cells, allogenic cell therapy, butyrophilin 3A1, cell therapy, immune stimulant, immunotherapy, inside-out signaling, phosphoantigens",
author = "Yunyun Yang and Liping Li and Linjie Yuan and Xiaoying Zhou and Jianxin Duan and Hongying Xiao and Ningning Cai and Shuai Han and Xianqiang Ma and Weidong Liu and Chen, {Chun Chi} and Lingle Wang and Xin Li and Jiahuan Chen and Ning Kang and Jing Chen and Zhixun Shen and Malwal, {Satish R.} and Wanli Liu and Yan Shi and Eric Oldfield and Guo, {Rey Ting} and Yonghui Zhang",
note = "We thank Erin J. Adams (University of Chicago, USA) for providing us with the BTN3A1 B30.2 domain plasmid, Xinquan Wang (Tsinghua University) for helping to analyze the BTN3A3 data, and Brian Kent Kobilka (Standford University School of Medicine) and Ye Xiang and Wenqi Li (Tsinghua University) for helpful discussions. We thank Peter Schuck (National Institute of Biomedical Imaging and Bioengineering) for helping to analyze SV-AUC data. This work was funded by grants to Y.Z. from the National Key R&D Program of China ( 2017YFA1014000 and 2017YFA1014001 ), the National Natural Science Foundation of China ( 81573270 ), the Beijing Advanced Innovation Center for Structural Biology , the Tsinghua-Peking Center for Life Sciences , and the 1000 Young Talents Program . It was also funded in part by the United States Public Health Service ( GM065307 ) to E.O. Synchrotron data were collected at the National Synchrotron Radiation Research Center, Taiwan, supported by the National Science Council , and at the Shanghai Synchrotron Radiation Facility.",
year = "2019",
month = apr,
day = "16",
doi = "10.1016/j.immuni.2019.02.016",
language = "English (US)",
volume = "50",
pages = "1043--1053.e5",
journal = "Immunity",
issn = "1074-7613",
publisher = "Cell Press",
number = "4",
}