Gene-targeting studies have been invaluable for dissecting the role of specific genes in lymphocyte development. B and T cells, as well as natural killer (NK) cells and some dendritic cells, develop in the thymus from multipotent lymphoid progenitors (MLPs). The signalling pathways that influence the development of MLPs and their progeny are not well understood. Mice that do not express the receptor for interleukin 7 (IL-7) (IL-7Rα) or the transcription factor E47 (encoded by the E2A gene) have very similar defects in B- and T-cell development, which indicates that these proteins might function in the same signalling pathways. However, Kee and colleagues now report in EMBO Journal that IL-7-mediated signalling and E47 function independently to promote the development of MLPs.

IL-7R signalling is required for expression of the antiapoptotic protein BCL2, and the defects in T- and B-cell development and survival in Il-7rα−/− mice are rescued when these mice are crossed with Bcl2 transgenic mice. By contrast, the authors show that expression of the Bcl2 transgene in the E47−/− mice does not rescue the lymphopoietic defects in these animals. In addition, CD25+CD4−CD8− E47−/− thymocytes are highly sensitive to apoptosis in vitro and more cells express the proapoptotic protein caspase-3. These results indicate that E2A proteins promote lymphocyte survival through a BCL2-independent pathway.

Considering that BCL2 is one of the main targets of the IL-7 survival pathway, does this mean that E2A proteins function independently of IL-7 signalling? To address this, Kee and colleagues generated Il-7rα−/− × E47−/− double knockout mice. All subsets of thymocytes were severely reduced in the double knockout mice and thymocyte development was blocked before T-cell commitment. Thymic NK cells were also reduced. Therefore, despite similarities between the IL-7Rα and E47 single knockouts, the more severe phenotype seen in the double knockouts indicates that IL-7Rα and E47 act in distinct pathways to promote the survival of MLPs.