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

Abstract

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 Nfatc1 beta expression, preTCR-positive thymocytes express both Nfatc1 beta and P1 promoter-derived Nfatc1 alpha transcripts. Inducing NFATc1 alpha activity from P1 promoter in preTCR-negative thymocytes, in addition to the NFATc1 beta 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.