Phosphoantigens are Molecular Glues that Promote Butyrophilin 3A1/2A1 Association Leading to Vγ9Vδ2 T Cell Activation

Yuan, L.; Ma, X.; Yang, Y.; Li, X.; Ma, W.; Yang, H.; Huang, J.-W.; Xue, J.; Yi, S.; Zhang, M.; Cai, N.; Ding, Q.; Li, L.; Duan, J.; Malwal, S.; Chen, C.-C.; Oldfield, E.; Guo, R.-T.; Zhang, Y.

doi:10.1101/2022.01.02.474068

bioRxiv · 10.1101/2022.01.02.474068

Phosphoantigens are Molecular Glues that Promote Butyrophilin 3A1/2A1 Association Leading to Vγ9Vδ2 T Cell Activation

Yuan, L.·Ma, X.·Yang, Y.·Li, X.·Ma, W.·Yang, H.·Huang, J.-W.·Xue, J.·Yi, S.·Zhang, M.·Cai, N.·Ding, Q.·Li, L.·Duan, J.·Malwal, S.·Chen, C.-C.·Oldfield, E.·Guo, R.-T.·Zhang, Y.

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Abstract

Tumor cells and pathogen-infected cells are presented to human {gamma}{delta} T cells based on "inside-out" signaling in which metabolites called phosphoantigens (pAgs) inside target cells are recognized by the intracellular domain of a butyrophilin protein (BTN3A1), leading to an extracellular conformational change. Here, we report that pAgs function as molecular "glues" that initiate a heteromeric association between the intracellular domains of BTN3A1 and the structurally similar BTN2A1. Working with both exogenous and endogenous pAgs, we used x-ray crystallography, mutational studies, cellular assays, synthetic probe as well as molecular dynamics investigations to determine how pAgs glue intracellular BTN3A1 and BTN2A1 together for the "inside-out" signaling that triggers {gamma}{delta} T cell activation. This {gamma}{delta} T cell-specific mode of antigen sensing creates opportunities for the development of alternative immunotherapies against cancer and infectious diseases that do not involve {beta} T cells. One Sentence SummaryThe responses of gamma-delta T cells to cancer cells or pathogens are initiated via the intracellular association of heteromeric butyrophilins that are glued together by isoprenoid metabolites.

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Yuan, L., Ma, X., Yang, Y., Li, X., Ma, W., Yang, H., Huang, J.-W., Xue, J., Yi, S., Zhang, M., Cai, N., Ding, Q., Li, L., Duan, J., Malwal, S., Chen, C.-C., Oldfield, E., Guo, R.-T., Zhang, Y.. 2022-01-03. Phosphoantigens are Molecular Glues that Promote Butyrophilin 3A1/2A1 Association Leading to Vγ9Vδ2 T Cell Activation. https://doi.org/10.1101/2022.01.02.474068

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