A distinct topology of BTN3A IgV and B30.2 domains controlled by juxtamembrane regions favors optimal human γδ T cell phosphoantigen sensing
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A distinct topology of BTN3A IgV and B30.2 domains controlled by juxtamembrane regions favors optimal human γδ T cell phosphoantigen sensing. / Karunakaran, Mohindar M; Subramanian, Hariharan; Jin, Yiming; Mohammed, Fiyaz; Kimmel, Brigitte; Juraske, Claudia; Starick, Lisa; Nöhren, Anna; Länder, Nora; Willcox, Carrie R; Singh, Rohit; Schamel, Wolfgang W; Nikolaev, Viacheslav O; Kunzmann, Volker; Wiemer, Andrew J; Willcox, Benjamin E; Herrmann, Thomas.
In: NAT COMMUN, Vol. 14, No. 1, 22.11.2023, p. 7617.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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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 -