Evidence that gamma delta versus alpha beta T cell fate determination is initiated independently of T cell receptor signaling

Two types of T cells, alpha beta and gamma delta, develop in vertebrates. H ow these two T cell lineages arise from a common thymic T progenitor is poo rly understood. Differentiation of alpha beta lineage T cells requires the surrogate ct chain (pT alpha), which associates with the T cell receptor (T CR) beta chain to form the pre-TCR. gamma delta lineage development does no t appear to involve an obligatory surrogate chain, but instead requires pro ductive rearrangement and expression of both TCR gamma and delta genes. It has been proposed that the quality of signals transmitted by the pre-TCR an d gamma delta TCR are distinct and that these "instructive" signals determi ne the lineage fate of an uncommitted progenitor cell. Here we show that th e thymic T progenitor cells (CD25(+) CD44(+)c-kit(+)CD3(-)CD4(-)CD8(-) thym ocytes, termed pro-T cells) from young adult mice that have yet to express TCRs can be subdivided based on interleukin 7 receptor (IL-7R) expression. These subsets exhibit differential potential to develop into ya versus ap l ineage (CD4(+)CD8(+) cells) in the thymus. Upon intrathymic injection, IL-7 R(neg-lo) pro-T cells generated a 13-fold higher ratio of alpha beta lineag e to gamma delta lineage cells than did IL-7R(+) pro-T cells. Much of this difference was due to a fivefold greater potential of IL-7R(+) pro-T cells to develop into TCR-ys T cells. Evidence indicates that this biased develop mental potential is not a result of enhanced TCR-gamma gene rearrangement/e xpression in IL-7R(+) pro-T cells. These results indicate that the pro-T ce lls are heterogeneous in developmental potential before TCR gene rearrangem ent and suggest that in some precursor cells the initial lineage commitment is independent of TCR-mediated signals.