Mast cell lineage diversion of T lineage precursors by the essential T cell transcription factor GATA-3

Abstract

GATA-3 is essential for T cell development from the earliest stages. However, highly abundant GATA-3 can drive T-lineage precursors to a non-T fate, depending on Notch signaling and developmental stage. GATA-3 overexpression blocked pro-T cell survival when Notch-Delta signals were present, but enhanced viability in their absence. In double-negative (DN1) and DN2 but not DN3 fetal thymocytes, GATA-3 overexpression rapidly induced mast cell lineage respecification with high frequency by direct transcriptional reprogramming. Normal DN2 thymocytes also displayed mast cell potential, when interleukin 3 and stem cell factor were added in the absence of Notch signaling. Our results suggest a close relationship between the pro-T and mast cell programs and a new role for Notch in T-lineage fidelity.

Intrathymic proliferation wave essential for Vα14 + natural killer T cell development depends on c-Myc

“…Both Plzf, a critical factor for iNKT cell function, and Th-POK, a master regulator of CD4 T cell development, are detectable in c-Myc-deficient ST0 and ST1 cells, whereas Gata3 appears slightly elevated. Even small changes in the levels of transcription factors may deregulate networks in control of developmental processes (34). It remains to be determined whether the small transcriptional alterations we observed reflect a significant disturbance in the transcriptional network controlling iNKT cell development.…”

Adipose Tissue as a Dedicated Reservoir of Functional Mast Cell Progenitors

“…PU.1, GATA-2, GATA-3, and the microphthalmia-associated transcription factor are essential for mast cell development [22][23][24][25]. We showed that adiposederived CFCs express these four transcription factors as peritoneal cell-derived mast cell controls (Fig.…”

Downregulation of the transcription factor KLF4 is required for the lineage commitment of T cells

“…CD4 − CD8 − double negative (DN) thymic progenitors consist of DN1 (CD44 + CD25 − ), DN2 (CD44 + CD25 + ), DN3 (CD44 − CD25 + ), and DN4 (CD44 − CD25 − ) populations [6][7]. DN1 and DN2 cells retain both T cell and non-T cell lineage developmental potential [8], whereas final T cell lineage commitment occurs after an irreversible transition from DN2 to DN3 when most T cell-specific genes are upregulated to a peak level [3,5]. Thus, the differentiation of uncommitted thymic progenitors into T cells is a process that can be used to explore the potential relationship between reprogramming factors and differentiation.…”