Structural Basis of γδ T-Cell Receptor Crosslinking and Activation by a Spontaneously Dimerized Fab

Abstract

The gamma delta T-cell receptor ({gamma}{delta} TCR) mediates {gamma}{delta} T-cell responses that are crucial for immune defense, tissue surveillance, and homeostasis. While recent studies suggest that {gamma}{delta} TCRs engage ligands multivalently, how multivalent engagement activates the {gamma}{delta} TCR remains elusive. Here, we present the structures of the V{gamma}9V{delta}2 (clone G115) TCR in both the inactive and the agonist-crosslinked active states. In the {gamma}{delta} TCR lipoprotein complex, cholesterol and phospholipids form a "barrier" that isolates CD3{zeta}{zeta} from the other subunits and likely prevents autoactivation. As an agonist, the Fab fragment of the UCHT1 antibody dimerizes upon binding the V{gamma}9V{delta}2 TCR, thereby crosslinking and activating the receptor. Cryo-EM analysis of Fab-crosslinked V{gamma}9V{delta}2 TCR identifies three Fab dimer interfaces, one between the two light chains and the other two between light and heavy chains. These Fab-Fab interfaces, together with the Fab-CD3{epsilon} interface, mediate the assembly of the V{gamma}9V{delta}2 TCR and UCHT1 Fab into 2:2 tetramers. Upon activation, the V{gamma}9V{delta}2 TCR becomes conformationally plastic and loses enriched lipids, including cholesterol and phosphatidylethanolamine. Our findings reveal a dimerization-driven activation mechanism, inform the design of rigid TCR-crosslinking agonists, and suggest multivalency-induced clustering as a general paradigm for {gamma}{delta} TCR activation.

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BibTeX RIS

BibTeX

@misc{li2026structural,
  title = {{Structural Basis of γδ T-Cell Receptor Crosslinking and Activation by a Spontaneously Dimerized Fab}},
  author = {Z. Li and Y. Fan and J. Li and Y. Zhao and L. Chen and Y. Chen and Z. Wang and Y. Zheng and Y. Zhang and J. Wang and H. Wu and D. Wu and L. Wang},
  howpublished = {bioRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.08.757522},
  url = {https://www.biorxiv.org/content/10.64898/2026.10.08.757522v1},
  note = {CC BY-NC-ND},
}

RIS

TY  - UNPB
TI  - Structural Basis of γδ T-Cell Receptor Crosslinking and Activation by a Spontaneously Dimerized Fab
AU  - Z. Li
AU  - Y. Fan
AU  - J. Li
AU  - Y. Zhao
AU  - L. Chen
AU  - Y. Chen
AU  - Z. Wang
AU  - Y. Zheng
AU  - Y. Zhang
AU  - J. Wang
AU  - H. Wu
AU  - D. Wu
AU  - L. Wang
PY  - 2026
DA  - 2026/10/08
PB  - bioRxiv
DO  - 10.64898/2026.10.08.757522
UR  - https://www.biorxiv.org/content/10.64898/2026.10.08.757522v1
AB  - The gamma delta T-cell receptor ({gamma}{delta} TCR) mediates {gamma}{delta} T-cell responses that are crucial for immune defense, tissue surveillance, and homeostasis. While recent studies suggest that {gamma}{delta} TCRs engage ligands multivalently, how multivalent engagement activates the {gamma}{delta} TCR remains elusive. Here, we present the structures of the V{gamma}9V{delta}2 (clone G115) TCR in both the inactive and the agonist-crosslinked active states. In the {gamma}{delta} TCR lipoprotein complex, cholesterol and phospholipids form a "barrier" that isolates CD3{zeta}{zeta} from the other subunits and likely prevents autoactivation. As an agonist, the Fab fragment of the UCHT1 antibody dimerizes upon binding the V{gamma}9V{delta}2 TCR, thereby crosslinking and activating the receptor. Cryo-EM analysis of Fab-crosslinked V{gamma}9V{delta}2 TCR identifies three Fab dimer interfaces, one between the two light chains and the other two between light and heavy chains. These Fab-Fab interfaces, together with the Fab-CD3{epsilon} interface, mediate the assembly of the V{gamma}9V{delta}2 TCR and UCHT1 Fab into 2:2 tetramers. Upon activation, the V{gamma}9V{delta}2 TCR becomes conformationally plastic and loses enriched lipids, including cholesterol and phosphatidylethanolamine. Our findings reveal a dimerization-driven activation mechanism, inform the design of rigid TCR-crosslinking agonists, and suggest multivalency-induced clustering as a general paradigm for {gamma}{delta} TCR activation.
ER  -

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