Phosphoantigens glue butyrophilin 3A1 and 2A1 to activate Vγ9Vδ2 T cells

Linjie Yuan, Xianqiang Ma, Yunyun Yang, Yingying Qu, Xin Li, Xiaoyu Zhu, Weiwei Ma, Jianxin Duan, Jing Xue, Haoyu Yang, Jian-Wen Huang, Simin Yi, Mengting Zhang, Ningning Cai, Lin Zhang, Qingyang Ding, Kecheng Lai, Chang Liu, Lilan Zhang, Xinyi Liu, Yirong Yao, Shuqi Zhou, Xian Li, Panpan Shen, Qing Chang, Satish R. Malwal, Yuan He, Wenqi Li, Chunlai Chen, Chun-Chi Chen, Eric Oldfield, Rey-Ting Guo () and Yonghui Zhang ()
Additional contact information
Linjie Yuan: Tsinghua University
Xianqiang Ma: Tsinghua University
Yunyun Yang: Tsinghua University
Yingying Qu: Tsinghua University
Xin Li: Tsinghua University
Xiaoyu Zhu: University of Science and Technology of China
Weiwei Ma: Tsinghua University
Jianxin Duan: Schrödinger
Jing Xue: Tsinghua University
Haoyu Yang: Tsinghua University
Jian-Wen Huang: Hubei University
Simin Yi: Hubei University
Mengting Zhang: Hubei University
Ningning Cai: Tsinghua University
Lin Zhang: Tsinghua University
Qingyang Ding: Tsinghua University
Kecheng Lai: Hubei University
Chang Liu: Hubei University
Lilan Zhang: Hubei University
Xinyi Liu: Tsinghua University
Yirong Yao: Tsinghua University
Shuqi Zhou: Tsinghua University
Xian Li: Hubei University
Panpan Shen: Hubei University
Qing Chang: Tsinghua University
Satish R. Malwal: University of Illinois at Urbana-Champaign
Yuan He: Boehringer Ingelheim (China)
Wenqi Li: Tsinghua University
Chunlai Chen: Tsinghua University
Chun-Chi Chen: Hubei University
Eric Oldfield: University of Illinois at Urbana-Champaign
Rey-Ting Guo: Hubei University
Yonghui Zhang: Tsinghua University

Nature, 2023, vol. 621, issue 7980, 840-848

Abstract: Abstract In both cancer and infections, diseased cells are presented to human Vγ9Vδ2 T cells through an ‘inside out’ signalling process whereby structurally diverse phosphoantigen (pAg) molecules are sensed by the intracellular domain of butyrophilin BTN3A11–4. Here we show how—in both humans and alpaca—multiple pAgs function as ‘molecular glues’ to promote heteromeric association between the intracellular domains of BTN3A1 and the structurally similar butyrophilin BTN2A1. X-ray crystallography studies visualized that engagement of BTN3A1 with pAgs forms a composite interface for direct binding to BTN2A1, with various pAg molecules each positioned at the centre of the interface and gluing the butyrophilins with distinct affinities. Our structural insights guided mutagenesis experiments that led to disruption of the intracellular BTN3A1–BTN2A1 association, abolishing pAg-mediated Vγ9Vδ2 T cell activation. Analyses using structure-based molecular-dynamics simulations, 19F-NMR investigations, chimeric receptor engineering and direct measurement of intercellular binding force revealed how pAg-mediated BTN2A1 association drives BTN3A1 intracellular fluctuations outwards in a thermodynamically favourable manner, thereby enabling BTN3A1 to push off from the BTN2A1 ectodomain to initiate T cell receptor–mediated γδ T cell activation. Practically, we harnessed the molecular-glue model for immunotherapeutics design, demonstrating chemical principles for developing both small-molecule activators and inhibitors of human γδ T cell function.

Date: 2023
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DOI: 10.1038/s41586-023-06525-3

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