Down-regulation of Tet2 prevents TSDR demethylation in IL2 deficient regulatory T cells

Stable expression of Foxp3 in regulatory T (Treg) cells is dependent on both intrinsic factors like epigenetic changes (demethylation) of Treg cell specific demethylation region (TSDR) and environmental cues like inflammations. Interleukin-2 (IL2) was reported to be one of the cytokines that give signals to Foxp3 stability but the underlying mechanism is still elusive. Here we show that IL2 and epigenetic changes in foxp3 locus are closely connected through tet methylcytosine dioxygenase 2 (Tet2) and, together help Treg cells to express Foxp3 stably. TSDR in foxp3 locus was not demethylated and Foxp3 expression was labile in IL2 deficient Treg cells, which was not restored by recombinant IL2, but correlated with the down-regulation of Tet2. Tet2 was up-regulated by TCR signaling and IL2 had a minimal effect. Rather, IL2 seemed to maintain the high level of Tet2 indirectly. Furthermore, over-expression of Tet2 restored TSDR demethylation in IL2 deficient Treg precursors. Collectively, our results suggest that up-regulation of Tet2 is required for Foxp3 stability and IL2 is required to maintain the high level of Tet2 during the thymic Treg development.