IFN-γ Triggered STAT1-PKB/AKT Signalling Pathway Influences the Function of Alloantigen Reactive Regulatory T Cells

CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) play a key role in the induction and maintenance of peripheral tolerance. Rapid and transient production of IFN-γ by Tregs from mice tolerized to alloantigen in vivo has been shown to be critical for their regulatory function. This IFN-γ has the potential to affect the function of cells present in the same local microenvironment as the Tregs, including the Tregs themselves. Here we investigated the mechanism by which IFN-γ produced by Tregs triggered signaling pathways in alloantigen reactive Tregs themselves thereby influencing their function in vivo. We show that IFN-γ production and STAT1 activation was increased, while STAT1-dependent PKB/AKT activation was downregulated in alloantigen reactive Tregs. Further, the activation of STAT1 was blocked in IFN-γ receptor deficient as well as IFN-γ–deficient Tregs, suggesting that IFN-γ produced by the alloantigen reactive Tregs might act in an autocrine manner to induce STAT1 activation. Importantly, STAT1-deficient Tregs failed to control allograft rejection in vivo. Overall, these findings suggest that the IFN-γ–induced STAT1-PKB/AKT signaling pathway plays a key role in upregulating the ability of alloantigen reactive Tregs to control graft rejection in vivo.