Immune suppressive activity and lack of T helper differentiation are differentially regulated in natural regulatory T cells.

The mechanism for controlling Th cytokine expression in natural regulatory T (nTreg) cells is unclear. Here, it was found that under polarizing conditions Foxp3 did not affect Th1 cell, partially inhibited Th17 cell, but greatly inhibited Th2 cell differentiation of conventional CD4 T cells. Under the polarizing conditions, nTreg cells failed to differentiate into Th2 and Th17 cells, but differentiated into IFN-gamma-producing cells. Such Foxp3-transduced CD4 T cells and nTreg cells expressed T-bet, GATA-3, or retinoic acid-related orphan receptor (ROR)gammat, and retroviral GATA-3 and RORgammat could not induce Th2 and Th17 differentiation from nTreg cells. However, regardless of their cytokine profiles, the Foxp3-transduced CD4 T cells and nTreg cells remained immune suppressive. These results suggested that it is possible to convert pathogenic Th cells to Treg-like cells for therapeutic application. In conclusion, our studies show that Foxp3 is sufficient for immune suppression, whereas the inhibition of cytokine expression requires additional mechanisms.