Interleukin 2 modulates thymic-derived regulatory T cell epigenetic landscape

Foxp3⁺CD4⁺ regulatory T (T_reg) cells are essential for preventing fatal autoimmunity and safeguard immune homeostasis in vivo. While expression of the transcription factor Foxp3 and IL-2 signals are both required for the development and function of T_reg cells, the commitment to the T_reg cell lineage occurs during thymic selection upon T cell receptor (TCR) triggering, and precedes the expression of Foxp3. Whether signals beside TCR contribute to establish T_reg cell epigenetic and functional identity is still unknown. Here, using a mouse model with reduced IL-2 signaling, we show that IL-2 regulates the positioning of the pioneer factor SATB1 in CD4⁺ thymocytes and controls genome wide chromatin accessibility of thymic-derived T_reg cells. We also show that T_reg cells receiving only low IL-2 signals can suppress endogenous but not WT autoreactive T cell responses in vitro and in vivo. Our findings have broad implications for potential therapeutic strategies to reprogram T_reg cells in vivo.