TGF-β1 maintains Foxp3 expression and inhibits glycolysis in natural regulatory T cells via PP2A-mediated suppression of mTOR signaling

Natural regulatory T cells (nTregs) play a dominant role in maintaining immunological homeostasis and they are known to undergo metabolic reprogramming during immune responses. Transforming growth factor-β1 (TGF-β1), an anti-inflammatory cytokine, can promote the induction of regulatory T cells. Here, we investigated the effects of TGF-β1 on the stability and metabolism of nTregs stimulated in vitro. CD4+CD25+ nTregs were isolated from mouse spleens and stimulated with anti-CD3 and anti-CD28 antibodies plus IL-2 in the presence or absence of TGF-β1. Exposure to TGF-β1 induced the activation of STAT5 and sustained the expression of the nTregs transcription factor Foxp3. In addition, TGF-β1 inhibited glycolysis, as shown by reduced lactate production and diminished expression of Glut1, Hk2, Enolase1, and Hif-1α. nTregs treated with TGF-β1 exhibited downregulated mTORC1 signaling but enhanced activation of the serine-threonine phosphatase PP2A. Moreover, treat with the PP2A inhibitor okadaic acid disrupted the maintenance of Foxp3 expression by TGF-β1. Thus, TGF-β1 serves to maintain Foxp3 expression in cultured nTregs, possibly via PP2A activation and suppression of mTORC1-regulated glycolysis.