Bcl11b: a novel regulator of T-lineage commitment (36.50)

Abstract

Abstract Commitment of HSC to a T-lineage fate is driven by a network of transcription factors and environment cues. Transcription factor Bcl11b is expected to be a crucial component of the network. Bcl11b is an essential regulator for T-cell development. However, little is known about how Bcl11b works in the commitment stage of T-cell development. Using an in vitro growth system, we have found that under certain conditions Bcl11b-deficient pre-T cells fail to pass the DN2/DN3 transition, which is the lineage commitment step in T-cell development. Instead, Bcl11b-deficient cells continuously grow at DN1-like and DN2A-like stages for more than twenty days, while wild-type controls can develop normally to DN3 and DN4 cells. Unlike their wild-type counterparts, the long-term Bcl11b-deficient cells still possess developmental plasticity with an IKDC-like population growing out from the cells. Gene expression profile reveals that Bcl11b-deficient cells express T-cell identity genes including Cd3e and Lck, and continue to silence some important genes associated with major developmental alternatives, such as B-cell factors; however, they fail to turn off stem cell genes and some lineage-regulators, such as Scl, Lyl1, Gfi1b, Id2, Il2rb, Zbtb16 and Bcl11a. The results indicate that Bcl11b plays a major role in T-lineage commitment by controlling the correct exit of T-cell precursors from a progenitor cell state. No other factor has been shown to have this distinctive function.