Regulation of lymphocyte progenitor survival by the proapoptotic activities of Bim and Bid

Abstract

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

MYB IS Required for B-Selection During Thymopoises

“…In pre-TCR-negative thymocytes, p53 induces apoptosis through direct transcriptional induction of Bid [95]. Mice that do not express a pre-TCR and lack Bid contain thymi with an increased number of progenitor cells and DN3 thymocytes that survive longer than pre-TCR-negative thymocytes that express Bid [95]. Interestingly, expression of Bim is also decreased in response to pre-TCR signals [95].…”

“…p53 induces apoptosis in cells with double-strand DNA breaks which occur during V(D)J recombination [108,110]. In pre-TCR-negative thymocytes, p53 induces apoptosis through direct transcriptional induction of Bid [95]. Mice that do not express a pre-TCR and lack Bid contain thymi with an increased number of progenitor cells and DN3 thymocytes that survive longer than pre-TCR-negative thymocytes that express Bid [95].…”

“…Expression of the tumor suppressor protein p53 is reduced in DN4 thymocytes compared to DN3 thymocytes undergoing V(D)J recombination [95] and introduction of a p53 deficiency in SCID mice allowed for the generation of some DP thymocytes [53,[107][108][109][110]. p53 induces apoptosis in cells with double-strand DNA breaks which occur during V(D)J recombination [108,110].…”

“…Evidence suggests that the pre-TCR induces the expression of pro-survival molecules and the down-modulation of pro-apoptotic molecules to ensure survival [53,86,94,95]. One way in which the pre-TCR signals survival is through the activation of NFkB family members [65,85] and increased transcription of the pro-survival protein Bcl2a1 in DN4 thymocytes [86].…”

“…There are two pathways (extrinsic and intrinsic) that result in caspase-3 activation and apoptosis ( Figure 4) and both pathways appear to induce apoptosis in the absence of a pre-TCR signal [86,94,95]. The extrinsic pathway involves ligand induced activation of a cell surface death receptor (members of the Tumor Necrosis Factor Receptor Superfamily [TNFRSF]) which signals formation of the death-inducing signaling complex (DISC), and activation of initiator caspases 8 and 10.…”