Structural characterization of two full length γδTCR/CD3 complexes

Hoque, M.; Grigg, J. B.; Ramlall, T.; Jones, J.; McGoldrick, L. L.; Olson, W. C.; Lin, J. C.; Smith, E.; Franklin, M. C.; Zhang, T.; Saotome, K.

doi:10.1101/2024.07.19.604350

bioRxiv · 10.1101/2024.07.19.604350

Structural characterization of two full length γδTCR/CD3 complexes

Hoque, M.·Grigg, J. B.·Ramlall, T.·Jones, J.·McGoldrick, L. L.·Olson, W. C.·Lin, J. C.·Smith, E.·Franklin, M. C.·Zhang, T.·Saotome, K.

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Abstract

The T-cell receptor (TCR)/CD3 complex plays an essential role in the immune response and is a key player in cancer immunotherapies. There are two classes of TCR/CD3 complexes, defined by their TCR chain usage ({beta} or {gamma}{delta}). Recently reported structures have revealed the organization of the {beta} TCR/CD3 complex, but similar studies regarding the {gamma}{delta} TCR/CD3 complex have lagged behind. Here, we report cryoelectron microscopy (cryoEM) structural analysis of two full-length {gamma}{delta} TCRs, G115 (V{gamma}9V{delta}2) and 9C2 (V{gamma}5V{delta}1), in complex with CD3 subunits. Our results show that the overall subunit organization of the {gamma}{delta} TCR-CD3 complexes is similar to {beta} TCRs. However, both {gamma}{delta} TCRs display highly mobile extracellular domains (ECDs), unlike {beta} TCRs, which have TCR ECDs that are rigidly coupled to its transmembrane (TM) domains. We corroborate this finding in cells by demonstrating that a {gamma}{delta} T-cell specific antibody can bind a site that would be inaccessible in the more rigid {beta} TCR/CD3 complex. Furthermore, we observed that a V{gamma}5V{delta}1 complex forms a TCR {gamma}5-chain mediated dimeric species whereby two TCR/CD3 complexes are assembled. Collectively, these data shed light on {gamma}{delta} TCR/CD3 complex formation and may aid the design of {gamma}{delta} TCR-based therapies.

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Hoque, M., Grigg, J. B., Ramlall, T., Jones, J., McGoldrick, L. L., Olson, W. C., Lin, J. C., Smith, E., Franklin, M. C., Zhang, T., Saotome, K.. 2024-07-19. Structural characterization of two full length γδTCR/CD3 complexes. https://doi.org/10.1101/2024.07.19.604350

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