Self-activation of Vγ9Vδ2 T cells by exogenous phosphoantigens involves TCR and butyrophilins

The high cytotoxic activity of V gamma 9V delta 2 T lymphocytes against tumor cells makes them useful candidates in anticancer therapies. However, the molecular mechanism of their activation by phosphoantigens (PAgs) is not completely known. Many studies have depicted the mechanism of V gamma 9V delta 2 T-cell activation by PAg-sensed accessory cells, such as immune presenting cells or tumor cells. In this study, we demonstrated that pure resting V gamma 9V delta 2 T lymphocytes can self-activate through exogenous PAgs, involving their TCR and the butyrophilins BTN3A1 and BTN2A1. This is the first time that these three molecules, concurrently expressed at the plasma membrane of V gamma 9V delta 2 T cells, have been shown to be involved together on the same and unique T cell during PAg activation. Moreover, the use of probucol to stimulate the inhibition of this self-activation prompted us to propose that ABCA-1 could be implicated in the transfer of exogenous PAgs inside V gamma 9V delta 2 T cells before activating them through membrane clusters formed by gamma 9TCR, BTN3A1 and BTN2A1. The self-activation of V gamma 9V delta 2 T cells, which leads to self-killing, can therefore participate in the failure of gamma delta T cell-based therapies with exogenous PAgs and should be taken into account.

Automated summary

This study demonstrates that V gamma 9V delta 2 T cells can self-activate through exogenous PAgs independently, involving the molecules TCR, BTN3A1, and BTN2A1. Additionally, the involvement of ABCA-1 in the transfer of exogenous PAgs inside V gamma 9V delta 2 T cells was proposed, indicating a potential new mechanism for activation of these cytotoxic T cells against tumor cells.