Interleukin-7 abrogates the immunosuppressive function of human double-negative T cells by activating Akt/mTOR signaling. IL-7 impairs DN T-cell function

Recently, a novel subset of TCRαβ+ CD4- CD8- double-negative (DN) T cells has been described to suppress immune responses in both mice and humans. Moreover, in murine models infusion and/or activation of DN T cells specifically suppressed alloreactive T cells and prevented development of Graft-versus-Host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (HSCT). We have demonstrated that human DN T cells like their murine counterparts are highly potent suppressor cells of both, CD4+ and CD8+ T-cell responses. After HSCT and other lymphopenic conditions, Interleukin (IL)-7 plays an important role in the reconstitution, survival, and homeostasis of the T-cell compartment. Since IL-7 was shown to interfere with T-cell functionality, we asked whether IL-7 affects the functionality of human DN T cells. Intriguingly, IL-7 diminished the suppressive activity of DN T cells towards allogeneic CD4+ effector T cells. Of interest our studies revealed that IL-7 activates the Akt/mTOR pathway in human DN T cells. Importantly, selective inhibition of the protein kinases Akt or mTOR was able to reverse the IL-7 effect thereby restoring the functionality of DN T cells, whereas inhibition of other central T-cell signaling pathways did not. Further analyses suggest that the IL-7/Akt/mTOR signaling cascade downregulates anergy-associated genes and upregulates activation- and proliferation-associated factors which may be crucial for DN T cell functionality. These findings indicate that IL-7 and Akt/mTOR signaling are critical factors for the suppressive capacity of DN T cells. Targeting of these pathways by pharmacological agents may restore and/or enhance DN T-cell functionality in GvHD.