Autocrine IFN‐gamma directly regulates Foxp3 expression in naive CD4+CD25− T cells

Regulatory T cells (Treg) can control the balance between tolerance and immunity. However, the relationship between IFN‐γ and Treg is not yet clearly clarified. Two major populations of Treg, namely natural and induced Treg, arise in the thymus and the periphery, respectively. Here we show that IFN‐γ has no relation with the development and inhibitory function of naturally occurring regulatory T cells (nTeg). On the other side, naïve CD4 T cells can develop into regulatory T cells by acquiring the transcription factor Foxp3. Combined signals from the TCR, CD28, IL‐2R, and TGF‐βR promote Foxp3 expression in primed naïve CD25 − CD4 + T cells. In this case, surprisingly, autocrine IFN‐γ regulates TGF‐β‐driven Foxp3 expression in induced regulatory T cells (iTreg) and suppresses the conversion of naïve CD4 T cells into Foxp + CD4 + T cells. These data identify autocrine IFN‐γ as a self‐regulator of Foxp3 expression and suggest that IFN‐γ can play a pivotal role in regulating the balance between effector and regulatory T cell numbers in immune responses. Therefore, autocrine IFN‐γ can regulate the induction of Treg in the periphery, not in the thymus.