The transcription factor TCF1 is a critical target of ID2 that limits natural killer cell maturation

Abstract

Abstract ID2 is an inhibitor of the E protein transcription factors that is expressed in all innate lymphoid cells. In natural killer (NK) cells, ID2 prevents immature cells from acquiring a naïve T cell – like gene program that restricts NK cell maturation and function. Here we show that Tcf7 (encoding the transcription factor TCF1) is the critical E protein target gene in immature NK cells that maintains NK cell progenitors. TCF1 binds to a subset of key “naïve T cell” genes that are normally expressed at low, but detectable, levels in immature NK cells and whose expression is deregulated in the absence of ID2. Importantly, combined deficiency of TCF1 and ID2 restores expression of these naïve T cell genes to near wild-type levels. Moreover, in the absence of TCF1, ID2-deficient NK cells mature and acquire functional capacity but fail to expand to wild-type numbers. Our data indicate that ID2 is essential for NK cell maturation because it controls TCF1, whose heightened expression arrests NK cell maturation and activates a naïve – like gene program.