Evidence That γδ versus αβ T Cell Fate Determination Is Initiated Independently of T Cell Receptor Signaling

Abstract

Two types of T cells, αβ and γδ, develop in vertebrates. How these two T cell lineages arise from a common thymic T progenitor is poorly understood. Differentiation of αβ lineage T cells requires the surrogate α chain (pTα), which associates with the T cell receptor (TCR) β chain to form the pre-TCR. γδ lineage development does not appear to involve an obligatory surrogate chain, but instead requires productive rearrangement and expression of both TCR γ and δ genes. It has been proposed that the quality of signals transmitted by the pre-TCR and γδ TCR are distinct and that these “instructive” signals determine the lineage fate of an uncommitted progenitor cell. Here we show that the thymic T progenitor cells (CD25⁺CD44⁺c-kit⁺CD3⁻CD4⁻CD8⁻ thymocytes, 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 γδ versus αβ lineage (CD4⁺CD8⁺ cells) in the thymus. Upon intrathymic injection, IL-7R^neg-lo pro-T cells generated a 13-fold higher ratio of αβ lineage to γδ 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-γδ T cells. Evidence indicates that this biased developmental potential is not a result of enhanced TCR-γ gene rearrangement/expression in IL-7R⁺ pro-T cells. These results indicate that the pro-T cells are heterogeneous in developmental potential before TCR gene rearrangement and suggest that in some precursor cells the initial lineage commitment is independent of TCR-mediated signals.