Unsynchronized butyrophilin molecules dictate cancer cell evasion of Vγ9Vδ2 T-cell killing
- Author(s)
- Wu, Z; Lamao, Q; Gu, M; Jin, X; Liu, Y; Tian, F; Yu, Y; Yuan, P; Gao, S; Fulford, TS; Uldrich, AP; Wong, CC; Wei, W;
- Details
- Publication Year 2024-04,Volume 21,Issue #4,Page 362-373
- Journal Title
- Cellular & Molecular Immunology
- Publication Type
- Research article
- Abstract
- Vγ9Vδ2 T cells are specialized effector cells that have gained prominence as immunotherapy agents due to their ability to target and kill cells with altered pyrophosphate metabolites. In our effort to understand how cancer cells evade the cell-killing activity of Vγ9Vδ2 T cells, we performed a comprehensive genome-scale CRISPR screening of cancer cells. We found that four molecules belonging to the butyrophilin (BTN) family, specifically BTN2A1, BTN3A1, BTN3A2, and BTN3A3, are critically important and play unique, nonoverlapping roles in facilitating the destruction of cancer cells by primary Vγ9Vδ2 T cells. The coordinated function of these BTN molecules was driven by synchronized gene expression, which was regulated by IFN-γ signaling and the RFX complex. Additionally, an enzyme called QPCTL was shown to play a key role in modifying the N-terminal glutamine of these BTN proteins and was found to be a crucial factor in Vγ9Vδ2 T cell killing of cancer cells. Through our research, we offer a detailed overview of the functional genomic mechanisms that underlie how cancer cells escape Vγ9Vδ2 T cells. Moreover, our findings shed light on the importance of the harmonized expression and function of gene family members in modulating T-cell activity.
- Publisher
- Springer Nature
- Keywords
- *T-Lymphocytes; Receptors, Antigen, T-Cell, gamma-delta/metabolism; Butyrophilins/genetics/metabolism; Lymphocyte Activation/genetics; Cell Death; *Neoplasms; Butyrophilin; Cancer-specific immune evasion; Glutaminyl-peptide cyclotransferase-like; Immunotherapy; Pyrophosphate metabolite; Vγ9Vδ2 T-cell
- Department(s)
- Laboratory Research
- Publisher's Version
- https://doi.org/10.1038/s41423-024-01135-z
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2024-07-25 05:51:37
Last Modified: 2024-07-25 05:51:55