Reprogramming of Th1 cells into regulatory T cells through rewiring of the metabolic status

Abstract

T helper type 1 (T_h1) cells form one of the most stable CD4 T-cell subsets, and direct conversion of fully differentiated T_h1 to regulatory T (T_reg) cells has been poorly investigated. Here, we established a culture method for inducing Foxp3 from T_h1 cells of mice and humans. This is achieved simply by resting T_h1 cells without T-cell receptor ligation before stimulation in the presence of transforming growth factor-beta (TGF-β). We named the resulting T_h1-derived Foxp3⁺ cells T_h1_reg cells. Mouse T_h1_reg cells showed an inducible T_reg-like phenotype and suppressive ability both in vitro and in vivo. T_h1_reg cells could also be induced from in vivo-developed mouse T_h1 cells. Unexpectedly, the resting process enabled Foxp3 expression not through epigenetic changes at the locus, but through metabolic change resulting from reduced mammalian target of rapamycin complex 1 (mTORC1) activity. mTORC1 suppressed TGF-β-induced phosphorylation of Smad2/3 in T_h1 cells, which was restored in rested cells. Our study warrants future research aiming at development of immunotherapy with T_h1_reg cells.