T cell or B cell — what's a lymphoid progenitor to do? The molecular basis of this fundamental cell-fate decision is not known, although there are indications that Notch signalling might be involved. Reporting in Immunity, Koch and co-workers provide further support for the role of Notch1 in the T- versus B-cell-fate decision, and show that lunatic fringe, a Notch regulator, can influence this choice — but in an unexpected and novel way.

Notch proteins are evolutionarily conserved receptors that are known to direct cell-fate decisions in a variety of developmental settings. In the absence of Notch1, B-cell development is promoted at the expense T-cell development, and B cells are found in the thymus. Conversely, in the presence of a constitutively active Notch1, B-cell development is blocked, and T cells develop in the bone marrow. These studies imply that Notch1 expression normally blocks B-cell commitment. But Notch proteins do not act alone. The fringe family are Golgi-resident proteins that are thought to modulate Notch signalling in a cell-autonomous manner by modifying the Notch receptors.

One fringe protein, lunatic fringe, is expressed at high levels in the thymic medulla but not in the thymic cortex, in which immature thymocytes are found. The authors constructed transgenic mice expressing lunatic fringe under the control of the Lck proximal-promoter, which have high levels of lunatic fringe in the thymic cortex. These mice have a striking reduction in the number of CD4−CD8−CD25+ pro-T cells in the thymus, where there is instead an expanded population of immature B cells.

How does lunatic fringe disrupt the balance of T- and B-lineage cells? To address this question, transgenic and wild-type bone-marrow cells were transferred together into irradiated Rag2−/− mice, which lack lymphocytes and their precursors. Transgenic bone marrow gave rise to thymic B cells, as expected, but, surprisingly, so did the non-transgenic cells. This shows lunatic fringe can also act cell-non-autonomously. The authors also show that ectopic expression of lunatic fringe inhibits Notch1 activation in lymphoid progenitors

In these bone marrow chimaeras it is impossible to tell whether lunatic fringe promotes B-cell development merely by promoting their expansion, or by directly influencing the T- or B-cell-fate decision. To test this, lymphoid progenitors from normal mice were injected directly into the thymi of transgenic or non-transgenic mice, and their development was followed. In transgenic thymi, up to 90% of the non-transgenic lymphoid progenitors developed into B-lineage cells and became mature B cells through the normal developmental programme.

The authors suggest that the choice of T- versus B-cell fate can be influenced by the degree of Notch1 activity in neighbouring progenitors, and ectopic lunatic fringe biases towards the B-cell fate in the thymus. Whether lunatic fringe has a physiological role in lineage commitment remains to be seen.