Thymocytes must pass a series of checkpoints on the road to becoming mature T cells. On page 603, Mandal et al. show that cells use Bcl2A1, a member of the Bcl2 family of survival proteins, to pass one critical checkpoint. The cell cannot make substitutes for this protein in a pinch, revealing that Bcl2A1 may be uniquely specialized for promoting survival without suppressing proliferation.
To become mature T cells, thymocytes must express a functional T cell receptor (TCR). A requisite early step in fulfilling this goal is the expression of the pre-TCR—the β chain of the mature TCR coupled with a pre–α chain—which sends essential survival and proliferation signals to the developing cell. Activation of NF-κB was shown recently to be required at this checkpoint, known as β-selection, but beyond that the components of this survival signal have remained elusive.
In an attempt to define these components, Mandal and colleagues searched for NF-κB–responsive proteins that may have a hand in β-selection. Their search led them to Bcl2A1, a protein involved in protecting B cells from apoptosis.
When the authors looked for Bcl2A1 in developing thymocytes, they found that it was the sole member of the Bcl2 family whose expression was coordinated with β-selection. Introduction of Bcl2A1 into thymocyte progenitors lacking a pre-TCR, which cannot undergo β-selection, allowed the cells to survive and differentiate in vivo.
What remains mysterious is why the cell doesn't turn on one of the other Bcl2 proteins, which are known to have redundant functions, to make up for the loss of Bcl2A1 in deficient cells. The authors think this may be because Bcl2 and Bcl-xL, although good at promoting survival, inhibit proliferation—an indispensable feature of pre-TCR signaling.