NFAT Factors Are Dispensable for the Development but Are Critical for the Maintenance of Foxp3(+) Regulatory T Cells

The transcription factors of the nuclear factor of activated T cell (NFAT) family play a crucial role in multiple aspects of T cell function. It has recently been reported that NFATs play an important role in the suppressive function of CD4(+)CD25(+)Foxp3(+) regulatory T (T(reg)) cells. In this study, we have investigated the role of NFATs in the thymic development of T(reg) cells in mice. We show that NFAT factors are dispensable for the development of Foxp3(+) T(reg) cells in the thymus but are critical for the maintenance of both the phenotype and survival of T(reg) cells in the thymus as well as in peripheral lymphoid organs. Specifically, the homeostasis of CD4(+)CD25(+)Foxp3(+) but not the CD4(+)CD25(−)Foxp3(+) fraction is severely perturbed when NFAT signaling is blocked, leading to a strongly reduced T(reg) population. We underscored this intriguing effect of NFAT on CD4(+)CD25(+)Foxp3(+) T(reg) cells to the disruption of survival signals provided by interleukin 2 (IL-2). Accordingly, blocking T(reg) cell death by abolishing the activity of pro-apoptotic Bcl-2 family member Bim, compensated for the survival defects induced due to a lack of NFAT-IL-2-IL-2R signaling. Inhibition of NFAT activity led to a strong reduction in the number of Foxp3(+) T(reg) cells; however, it did not influence the level of Foxp3 expression on an individual cell basis. In addition, we show a differential effect of IL-2 and IL-7 signaling on Foxp3(+) T(reg) versus CD4(+)CD25(−) T cell development, again underlining the dispensability of NFAT signaling in the development, but not in the maintenance of Foxp3(+) T(reg) cells.