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

TY - JOUR

T1 - A distinct topology of BTN3A IgV and B30.2 domains controlled by juxtamembrane regions favors optimal human γδ T cell phosphoantigen sensing

AU - Karunakaran, Mohindar M

AU - Subramanian, Hariharan

AU - Jin, Yiming

AU - Mohammed, Fiyaz

AU - Kimmel, Brigitte

AU - Juraske, Claudia

AU - Starick, Lisa

AU - Nöhren, Anna

AU - Länder, Nora

AU - Willcox, Carrie R

AU - Singh, Rohit

AU - Schamel, Wolfgang W

AU - Nikolaev, Viacheslav O

AU - Kunzmann, Volker

AU - Wiemer, Andrew J

AU - Willcox, Benjamin E

AU - Herrmann, Thomas

N1 - © 2023. The Author(s).

PY - 2023/11/22

Y1 - 2023/11/22

N2 - 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.

AB - 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.

KW - Humans

KW - Receptors, Antigen, T-Cell, gamma-delta/metabolism

KW - B30.2-SPRY Domain

KW - Lymphocyte Activation

KW - Intraepithelial Lymphocytes

KW - Protein Domains

KW - Butyrophilins/genetics

KW - Antigens, CD/metabolism

U2 - 10.1038/s41467-023-41938-8

DO - 10.1038/s41467-023-41938-8

M3 - SCORING: Journal article

C2 - 37993425

VL - 14

SP - 7617

JO - NAT COMMUN

JF - NAT COMMUN

SN - 2041-1723

IS - 1

ER -