Functional definition of a transcription factor hierarchy regulating T cell lineage commitment
Laura García-Pérez, Farbod Famili, Martijn Cordes, Martijn H. Brugman, Marja van Eggermond, Haoyu Wu, Jihed Chouaref, David San León, Machteld M. Tiemessen, Karin Pike‐Overzet, Lucia Daxinger, Frank J. T. Staal
Abstract
. Tcf1 deficiency results in partial arrests in T cell development, high apoptosis, and increased development of B and myeloid cells. Phenotypically, seemingly fully T cell-committed thymocytes with Tcf1 deficiency have promiscuous gene expression and an altered epigenetic profile and can dedifferentiate into more immature thymocytes and non-T cells. Restoring Bcl11b expression in Tcf1-deficient cells rescues T cell development but does not strongly suppress the development of non-T cells; in contrast, expressing Gata3 suppresses their development but does not rescue T cell development. Thus, T cell development is controlled by a minimal transcription factor network involving Notch signaling, Tcf1, and the subsequent division of labor between Bcl11b and Gata3, thereby ensuring a properly regulated T cell gene expression program.