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) |
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Pages (from-to) | 1043-1053.e5 |
Journal | Immunity |
Volume | 50 |
Issue number | 4 |
DOIs | |
State | Published - Apr 16 2019 |
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