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.