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NFATc1 plays a critical role in double-negative thymocyte survival and differentiation. However, the signals that regulate  Nfatc1  expression are incompletely characterized. Here we show a developmental stage-specific differential expression pattern of  Nfatc1  driven by the distal (P1) or proximal (P2) promoters in thymocytes. Whereas, preTCR-negative thymocytes exhibit only P2 promoter-derived  Nfatc1β  expression, preTCR-positive thymocytes express both  Nfatc1β  and P1 promoter-derived  Nfatc1α  transcripts. Inducing NFATc1α activity from P1 promoter in preTCR-negative thymocytes, in addition to the NFATc1β from P2 promoter impairs thymocyte development resulting in severe T-cell lymphopenia. In addition, we show that NFATc1 activity suppresses the B-lineage potential of immature thymocytes, and consolidates their differentiation to T cells. Further, in the pTCR-positive DN3 cells, a threshold level of NFATc1 activity is vital in facilitating T-cell differentiation and to prevent Notch3-induced T-acute lymphoblastic leukaemia. Altogether, our results show NFATc1 activity is crucial in determining the T-cell fate of thymocytes.

A threshold level of NFATc1 activity facilitates thymocyte differentiation and opposes notch-driven leukaemia development