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

Klein-Hessling, S.; Rudolf, R.; Muhammad, K.; Knobeloch, K. P.; Maqbool, M. A.; Cauchy, P.; Andrau, J. C.; Avots, A.; Talora, C.; Ellenrieder, V.; Screpanti, I.; Serfling, E.; Patra, A. K.

Nat Commun

2016 / vol 7 / pages 11841


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 Nfatc1beta expression, preTCR-positive thymocytes express both Nfatc1beta and P1 promoter-derived Nfatc1alpha transcripts. Inducing NFATc1alpha activity from P1 promoter in preTCR-negative thymocytes, in addition to the NFATc1beta 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.

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2041-1723 (Electronic) 2041-1723 (Linking)

PMCID: PMC4915031

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