Regulation of lymphocyte progenitor survival by the proapoptotic activities of Bim and Bid (original) (raw)

2008, Proceedings of the National Academy of Sciences of the United States of America

On their entry into the thymus, developing lymphocyte progenitors depend on signaling from the pre-T cell receptor (pre-TCR), which orchestrates differentiation, cell proliferation, and survival. The exact mechanism of pre-TCR-mediated suppression of T cell death remains unclear and controversial. Here, we identify Bim and Bid, 2 members of the BH3-only group of the BCL2 family, as important regulators of pre-T cell death. Both factors are highly expressed in proapoptotic thymocytes and their expression is suppressed on signaling through the pre-TCR. Their expression is directly regulated by the transcription factors FoxO3a and p53. Bid expression and p53 activity are related to the ongoing rearrangement of the TCR loci and induced DNA damage responses. Bim expression and FoxO3a nuclear translocation are directly controlled by the pre-TCR by means of its downstream kinase Akt/PKB. Interestingly, deletion of either gene on a pre-TCR ؊/؊ background rescues survival, but fails to induce further progenitor differentiation uncoupling the 2 processes. BCL2 family ͉ cell death ͉ pre-TCR signaling ͉ T cell development Results Bim and Bid Are Overexpressed in Proapoptotic, Pre-TCR Deficient T Cell Progenitors. We have initially compared BCL2-family gene expression in pre-TCR nonexpressing, proapoptotic thymocytes, and cells that receive pre-TCR signals, suppress apoptosis, and differentiate. Thus, we have purified ''small'' (based on FSC axis), pre-TCR-nonexpressing ''DN3'' (CD25 ϩ 44-c-kit Ϫ) and compared them with ''large,'' pre-TCR-expressing ''DN4''