A distinct topology of BTN3A IgV and B30.2 domains controlled by juxtamembrane regions favors optimal human γδ T cell phosphoantigen sensing

Mohindar M. Karunakaran (), Hariharan Subramanian, Yiming Jin, Fiyaz Mohammed, Brigitte Kimmel, Claudia Juraske, Lisa Starick, Anna Nöhren, Nora Länder, Carrie R. Willcox, Rohit Singh, Wolfgang W. Schamel, Viacheslav O. Nikolaev, Volker Kunzmann, Andrew J. Wiemer, Benjamin E. Willcox and Thomas Herrmann ()
Additional contact information
Mohindar M. Karunakaran: University of Würzburg
Hariharan Subramanian: University Medical Center Hamburg-Eppendorf
Yiming Jin: University of Connecticut
Fiyaz Mohammed: University of Birmingham, Edgbaston
Brigitte Kimmel: University Hospital Wuerzburg, Department of Internal Medicine II and Comprehensive Cancer Center (CCC) Mainfranken Wuerzburg
Claudia Juraske: University of Freiburg
Lisa Starick: University of Würzburg
Anna Nöhren: University of Würzburg
Nora Länder: University of Würzburg
Carrie R. Willcox: University of Birmingham, Edgbaston
Rohit Singh: University of Connecticut
Wolfgang W. Schamel: University of Freiburg
Viacheslav O. Nikolaev: University Medical Center Hamburg-Eppendorf
Volker Kunzmann: University Hospital Wuerzburg, Department of Internal Medicine II and Comprehensive Cancer Center (CCC) Mainfranken Wuerzburg
Andrew J. Wiemer: University of Connecticut
Benjamin E. Willcox: University of Birmingham, Edgbaston
Thomas Herrmann: University of Würzburg

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Butyrophilin (BTN)–3A and BTN2A1 molecules control the activation of human Vγ9Vδ2 T cells during T cell receptor (TCR)-mediated sensing of phosphoantigens (PAg) derived from microbes and tumors. However, the molecular rules governing PAg sensing remain largely unknown. Here, we establish three mechanistic principles of PAg-mediated γδ T cell activation. First, in humans, following PAg binding to the intracellular BTN3A1-B30.2 domain, Vγ9Vδ2 TCR triggering involves the extracellular V-domain of BTN3A2/BTN3A3. Moreover, the localization of both protein domains on different chains of the BTN3A homo-or heteromers is essential for efficient PAg-mediated activation. Second, the formation of BTN3A homo-or heteromers, which differ in intracellular trafficking and conformation, is controlled by molecular interactions between the juxtamembrane regions of the BTN3A chains. Finally, the ability of PAg not simply to bind BTN3A-B30.2, but to promote its subsequent interaction with the BTN2A1-B30.2 domain, is essential for T-cell activation. Defining these determinants of cooperation and the division of labor in BTN proteins improves our understanding of PAg sensing and elucidates a mode of action that may apply to other BTN family members.

Date: 2023
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DOI: 10.1038/s41467-023-41938-8

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