Attenuation of γδTCR signaling efficiently diverts thymocytes to the αβ lineage

The role of the T cell antigen receptor complex (TCR) in alpha beta-gamma delta lineage commitment remains controversial, in particular whether different TCR isoforms intrinsically favor adoption of a certain lineage. Here, we demonstrate that impairing the signaling capacity of a gamma delta TCR complex enables it to efficiently direct thymocytes to the up lineage. In the presence of a ligand, a transgenic gamma delta TCR mediates almost exclusive adoption of the gamma delta lineage, while in the absence of ligand, the same gamma delta TCR promotes alpha beta lineage development with efficiency comparable to the pre-TCR. Importantly, attenuating gamma delta TCR signaling through Lck deficiency causes reduced ERK1/2 activation and Egr expression and diverts thymocytes to the up lineage even in the presence of ligand. Conversely, ectopic Egr overexpression favors gamma delta T cell development. Our data support a model whereby gamma delta versus alpha beta lineage commitment is controlled by TCR signal strength, which depends critically on the ERK MAPK-Egr pathway.