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.