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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1043-1053.e5 |
| Journal | Immunity |
| Volume | 50 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 16 2019 |
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Keywords
- HMBPP
- T cell antigen recognition
- Vγ9Vδ2 T cells
- allogenic cell therapy
- butyrophilin 3A1
- cell therapy
- immune stimulant
- immunotherapy
- inside-out signaling
- phosphoantigens
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology
- Infectious Diseases
Cite this
A Structural Change in Butyrophilin upon Phosphoantigen Binding Underlies Phosphoantigen-Mediated Vγ9Vδ2 T Cell Activation. / Yang, Yunyun; Li, Liping; Yuan, Linjie; Zhou, Xiaoying; Duan, Jianxin; Xiao, Hongying; Cai, Ningning; Han, Shuai; Ma, Xianqiang; Liu, Weidong; Chen, Chun Chi; Wang, Lingle; Li, Xin; Chen, Jiahuan; Kang, Ning; Chen, Jing; Shen, Zhixun; Malwal, Satish R.; Liu, Wanli; Shi, Yan; Oldfield, Eric; Guo, Rey Ting; Zhang, Yonghui.
In: Immunity, Vol. 50, No. 4, 16.04.2019, p. 1043-1053.e5.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - A Structural Change in Butyrophilin upon Phosphoantigen Binding Underlies Phosphoantigen-Mediated Vγ9Vδ2 T Cell Activation
AU - Yang, Yunyun
AU - Li, Liping
AU - Yuan, Linjie
AU - Zhou, Xiaoying
AU - Duan, Jianxin
AU - Xiao, Hongying
AU - Cai, Ningning
AU - Han, Shuai
AU - Ma, Xianqiang
AU - Liu, Weidong
AU - Chen, Chun Chi
AU - Wang, Lingle
AU - Li, Xin
AU - Chen, Jiahuan
AU - Kang, Ning
AU - Chen, Jing
AU - Shen, Zhixun
AU - Malwal, Satish R.
AU - Liu, Wanli
AU - Shi, Yan
AU - Oldfield, Eric
AU - Guo, Rey Ting
AU - Zhang, Yonghui
PY - 2019/4/16
Y1 - 2019/4/16
N2 - 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.
AB - 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.
KW - HMBPP
KW - T cell antigen recognition
KW - Vγ9Vδ2 T cells
KW - allogenic cell therapy
KW - butyrophilin 3A1
KW - cell therapy
KW - immune stimulant
KW - immunotherapy
KW - inside-out signaling
KW - phosphoantigens
UR - http://www.scopus.com/inward/record.url?scp=85064170356&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85064170356&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2019.02.016
DO - 10.1016/j.immuni.2019.02.016
M3 - Article
C2 - 30902636
AN - SCOPUS:85064170356
VL - 50
SP - 1043-1053.e5
JO - Immunity
JF - Immunity
SN - 1074-7613
IS - 4
ER -