Precursor thymocyte proliferation and differentiation are controlled by signals unrelated to the pre-TCR

In-frame rearrangement of the TCR-P locus and expression of the pre-TCR are compulsory for the production of CD4(+)8(+) thymocytes from CD4(-)8(-) pre cursors. Signals delivered via the pre-TCR are thought to induce the differ entiation process as well as the extensive proliferation that accompanies t his transition. However, it is equally possible that pre-TCR expression is required for the success of this transition, but does not play a direct rol e in the inductive process. In the present manuscript we examine this possi bility using a variety of normal and genetically modified mouse models. Our evidence shows that differentiation and mitogenesis can both occur indepen dently of pre-TCR expression. However, these processes are absolutely depen dent on the presence of normal thymic architecture and cellular composition . These findings are consistent with a checkpoint role for the pre-TCR in r egulating the divergence of survival and cell death fates at the CD4(-)8(-) to CD4(+)8(+) transition. Further, our data suggest that precursor thymocy te differentiation is induced by other, probably ubiquitous, mechanisms tha t require the presence of normal thymic cellularity, composition, and archi tecture.