The transcription factor Tcf1 ensures the development and cytotoxic function of NK cells by limiting the expression of Granzymes [Affymetrix]

The transcription factor Tcf1 plays an essential role for the development of NK cells, however, its precise role for NK cell development, maturation and function is poorly understood. Here we show that distinct domains of Tcf1 direct bone marrow progenitors towards the NK cell lineage and mediate lineage commitment and NK cell expansion, and that Tcf1 downregulation is required for terminal NK cell maturation. Impaired NK cell development in the absence of Tcf1 is explained by increased cell death due to excessive expression of Granzyme family proteins, which results in NK cell self-destruction. In addition, excessive Granzyme B expression leads to target cell induced NK cell death and consequently reduced target cell killing by NK cells lacking Tcf1. Mechanistically, Tcf1 prevents excessive Granzyme B expression by binding to a newly identified enhancer element upstream of the Granzyme B locus. These data identify an unexpected requirement to limit the expression of cytotoxic effector molecules for lymphocyte development. Total RNA was isolated from flow-sorted bone marrow mNK cells (CD3- CD19- CD122+ NK1.1+ DX5+) from Tcf7+/+ (WT) and Tcf7-/- (KO) mice, and cDNA was synthesized, amplified and triplicate samples were hybridized to Affymetrix GeneChip Mouse Gene 1.0 ST array.