The BCL2A1 gene as a pre–T cell receptor–induced regulator of thymocyte survival

Abstract

The pre–T cell receptor (TCR) is expressed early during T cell development and imposes a tight selection for differentiating T cell progenitors. Pre-TCR–expressing cells are selected to survive and differentiate further, whereas pre-TCR− cells are “negatively” selected to die. The mechanisms of pre-TCR–mediated survival are poorly understood. Here, we describe the induction of the antiapoptotic gene BCL2A1 (A1) as a potential mechanism regulating inhibition of pre–T cell death. We characterize in detail the signaling pathway involved in A1 induction and show that A1 expression can induce pre–T cell survival by inhibiting activation of caspase-3. Moreover, we show that in vitro “knockdown” of A1 expression can compromise survival even in the presence of a functional pre-TCR. Finally, we suggest that pre-TCR–induced A1 overexpression can contribute to T cell leukemia in both mice and humans.

Increased numbers of thymic and peripheral CD4+ CD25+Foxp3+ cells in the absence of CD5 signaling

“…This result correlates with the increased susceptibility of CD4 1 Foxp3 À CD5 À/À thymocytes to apoptosis. In this context, Akt was shown to play a role in thymocyte survival [63,64], through the induction of Bcl-2 family members, such as Bcl-XL [65] and A1 [66].…”

“…This result correlates with the increased susceptibility of CD4 1 Foxp3 À CD5 À/À thymocytes to apoptosis. In this context, Akt was shown to play a role in thymocyte survival [63,64], through the induction of Bcl-2 family members, such as Bcl-XL [65] and A1 [66].In contrast to naïve thymocytes, the absence of CD5 did not affect Akt phosphorylation in Treg, in response to TCR crosslinking. Interestingly, Bensinger et al [67] recently showed that peripheral Treg, stimulated in the presence of IL-2, show increased survival in the absence of Akt phosphorylation, suggesting that Akt activation is dispensable for Treg survival.…”

Characterisation of mice lacking all functional isoforms of the pro-survival BCL-2 family member A1 reveals minor defects in the haematopoietic compartment

“…A1 expression is markedly upregulated in immature T cells during the process of pre-TCR selection, 38,39 suggesting that A1 may promote cell survival during this critical developmental stage. Accordingly, the A1 knockdown mouse model had an increase in DN2 and DN3 thymocytes and a corresponding reduction in the DN4 and DP populations.…”

Role of the pro-survival molecule Bfl-1 in melanoma

“…As such, although overexpression of Bfl-1 alone was not tumorigenic in mice 391 , Bfl-1 overexpression led to increased E1A-induced transformation 392 , and enhanced mycinduced leukemogenesis 393 . It has also been suggested that Bfl-1 contributes to the transformation of pre-T-cells when T-cell receptor signalling is deregulated 394 and that, along with CEBP, Bfl-1 is essential for anaplastic lymphoma kinase (ALK)-driven transformation to anaplastic large cell lymphoma 387 .…”