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Phosphoantigens glue butyrophilin 3A1 and 2A1 to activate Vγ9Vδ2 T cells
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 BTN3A1(1–4). Here we show how—in both humans and alpaca—mu...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10533412/ https://www.ncbi.nlm.nih.gov/pubmed/37674084 http://dx.doi.org/10.1038/s41586-023-06525-3 |
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author | Yuan, Linjie Ma, Xianqiang Yang, Yunyun Qu, Yingying Li, Xin Zhu, Xiaoyu Ma, Weiwei Duan, Jianxin Xue, Jing Yang, Haoyu Huang, Jian-Wen Yi, Simin Zhang, Mengting Cai, Ningning Zhang, Lin Ding, Qingyang Lai, Kecheng Liu, Chang Zhang, Lilan Liu, Xinyi Yao, Yirong Zhou, Shuqi Li, Xian Shen, Panpan Chang, Qing Malwal, Satish R. He, Yuan Li, Wenqi Chen, Chunlai Chen, Chun-Chi Oldfield, Eric Guo, Rey-Ting Zhang, Yonghui |
author_facet | Yuan, Linjie Ma, Xianqiang Yang, Yunyun Qu, Yingying Li, Xin Zhu, Xiaoyu Ma, Weiwei Duan, Jianxin Xue, Jing Yang, Haoyu Huang, Jian-Wen Yi, Simin Zhang, Mengting Cai, Ningning Zhang, Lin Ding, Qingyang Lai, Kecheng Liu, Chang Zhang, Lilan Liu, Xinyi Yao, Yirong Zhou, Shuqi Li, Xian Shen, Panpan Chang, Qing Malwal, Satish R. He, Yuan Li, Wenqi Chen, Chunlai Chen, Chun-Chi Oldfield, Eric Guo, Rey-Ting Zhang, Yonghui |
author_sort | Yuan, Linjie |
collection | PubMed |
description | 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 BTN3A1(1–4). 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, (19)F-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. |
format | Online Article Text |
id | pubmed-10533412 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-105334122023-09-29 Phosphoantigens glue butyrophilin 3A1 and 2A1 to activate Vγ9Vδ2 T cells Yuan, Linjie Ma, Xianqiang Yang, Yunyun Qu, Yingying Li, Xin Zhu, Xiaoyu Ma, Weiwei Duan, Jianxin Xue, Jing Yang, Haoyu Huang, Jian-Wen Yi, Simin Zhang, Mengting Cai, Ningning Zhang, Lin Ding, Qingyang Lai, Kecheng Liu, Chang Zhang, Lilan Liu, Xinyi Yao, Yirong Zhou, Shuqi Li, Xian Shen, Panpan Chang, Qing Malwal, Satish R. He, Yuan Li, Wenqi Chen, Chunlai Chen, Chun-Chi Oldfield, Eric Guo, Rey-Ting Zhang, Yonghui Nature Article 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 BTN3A1(1–4). 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, (19)F-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. Nature Publishing Group UK 2023-09-06 2023 /pmc/articles/PMC10533412/ /pubmed/37674084 http://dx.doi.org/10.1038/s41586-023-06525-3 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Yuan, Linjie Ma, Xianqiang Yang, Yunyun Qu, Yingying Li, Xin Zhu, Xiaoyu Ma, Weiwei Duan, Jianxin Xue, Jing Yang, Haoyu Huang, Jian-Wen Yi, Simin Zhang, Mengting Cai, Ningning Zhang, Lin Ding, Qingyang Lai, Kecheng Liu, Chang Zhang, Lilan Liu, Xinyi Yao, Yirong Zhou, Shuqi Li, Xian Shen, Panpan Chang, Qing Malwal, Satish R. He, Yuan Li, Wenqi Chen, Chunlai Chen, Chun-Chi Oldfield, Eric Guo, Rey-Ting Zhang, Yonghui Phosphoantigens glue butyrophilin 3A1 and 2A1 to activate Vγ9Vδ2 T cells |
title | Phosphoantigens glue butyrophilin 3A1 and 2A1 to activate Vγ9Vδ2 T cells |
title_full | Phosphoantigens glue butyrophilin 3A1 and 2A1 to activate Vγ9Vδ2 T cells |
title_fullStr | Phosphoantigens glue butyrophilin 3A1 and 2A1 to activate Vγ9Vδ2 T cells |
title_full_unstemmed | Phosphoantigens glue butyrophilin 3A1 and 2A1 to activate Vγ9Vδ2 T cells |
title_short | Phosphoantigens glue butyrophilin 3A1 and 2A1 to activate Vγ9Vδ2 T cells |
title_sort | phosphoantigens glue butyrophilin 3a1 and 2a1 to activate vγ9vδ2 t cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10533412/ https://www.ncbi.nlm.nih.gov/pubmed/37674084 http://dx.doi.org/10.1038/s41586-023-06525-3 |
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