Cell Reports
Volume 15, Issue 9, 31 May 2016, Pages 1973-1985
Journal home page for Cell Reports

Article
RhoB Mediates Phosphoantigen Recognition by Vγ9Vδ2 T Cell Receptor

https://doi.org/10.1016/j.celrep.2016.04.081Get rights and content
Under a Creative Commons license
open access

Highlights

  • Identification of SNPs near RhoB is associated with poor Vγ9Vδ2 T cell activation

  • RhoB activity and distribution in tumor cells modulate Vγ9Vδ2 T cell activation

  • Relocalization of RhoB induces membrane immobility of BTN3A1

  • Tumor recognition by a Vγ9Vδ2 TCR depends on BTN3A1 conformation

Summary

Human Vγ9Vδ2 T cells respond to tumor cells by sensing elevated levels of phosphorylated intermediates of the dysregulated mevalonate pathway, which is translated into activating signals by the ubiquitously expressed butyrophilin A1 (BTN3A1) through yet unknown mechanisms. Here, we developed an unbiased, genome-wide screening method that identified RhoB as a critical mediator of Vγ9Vδ2 TCR activation in tumor cells. Our results show that Vγ9Vδ2 TCR activation is modulated by the GTPase activity of RhoB and its redistribution to BTN3A1. This is associated with cytoskeletal changes that directly stabilize BTN3A1 in the membrane, and the subsequent dissociation of RhoB from BTN3A1. Furthermore, phosphoantigen accumulation induces a conformational change in BTN3A1, rendering its extracellular domains recognizable by Vγ9Vδ2 TCRs. These complementary events provide further evidence for inside-out signaling as an essential step in the recognition of tumor cells by a Vγ9Vδ2 TCR.

Cited by (0)