Interleukin-7 Represses the Immunoregulatory Function of Human TCRαβ+ CD4- CD8- Double-Negative (DN) T Cells By Activating Akt/mTOR Signaling

Regulatory T (Treg) cells have been shown to be involved in downregulating immune responses in autoimmunity, transplant rejection, and graft-versus-host disease (GvHD). Recently, a novel subset of TCRαβ+ CD4- CD8- (double negative, DN) T cells has been described to possess a very potent suppressive activity on allogeneic T-cell responses in both mice and humans. Of interest, clinical studies in patients after allogeneic stem cell transplantation (SCT) revealed an inverse correlation between the frequency of circulating DN T cells and the severity of GvHD. Interleukin (IL)-7 is required for survival and homeostasis of mature T-cells and has been shown to modulate the functional activity of Treg cells. Here we asked whether IL-7 affects the suppressive activity of human DN T cells. We found that human DN T cells isolated from peripheral blood lymphocytes do express the IL-7 receptor and are able to transduce IL-7 downstream signaling. Intriguingly, IL-7 significantly diminished the suppressive activity of DN T cells towards allogeneic CD4+ and CD8+ T cells. Thereby, IL-7 did not render the responder T cells insensitive to suppression. Instead, blocking of key signaling molecules revealed that IL-7 has a direct impact on the suppressive activity of DN T cells. Further analyses demonstrated that IL-7 activates Akt/mTOR signaling in DN T cells. Importantly, selective inhibition of the Akt or mTOR protein kinase was able to reverse the IL-7 effect thereby restoring the suppressive function of DN T cells, whereas inhibition of other central T-cell signaling pathways did not. Thus, DN T-cell mediated suppression is impaired by IL-7 due to crucial activation of the Akt/mTOR signaling cascade. 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.