NFATc1 induction by an intronic enhancer restricts NKT y delta cell formation

In thymus, the ablation of T cell receptor (TCR)-activated transcription factor NFATc1 or its inducible isoforms during the double-negative (DN) stages of thymocyte development leads to a marked increase in gamma delta thymocytes whereas the development of alpha beta thymocytes remains mostly unaffected. These gamma delta thymo-cytes are characterized by the upregulation of the promyelocytic leukemia zinc-finger factor (PLZF), the "master regulator"of natural killer T (NKT) cell development, and the acquisition of an NKT gamma delta cell phenotype with higher cell survival rates. The suppressive function of NFATc1 in NKT gamma delta cell formation crit-ically depends on the remote enhancer E2, which is essential for the inducible expression of NFATc1 directed by its distal promoter P1. Thus, the enhancer de-ciphers a strong gamma delta TCR signal into the expression of inducible NFATc1 isoforms resulting in high levels of NFATc1 protein that are essential to control the numbers of NKT gamma delta cells.