The TCR ligand-inducible expression of CD73 marks γδ lineage commitment and a metastable intermediate in effector specification

Numerous studies indicate that.. T cell receptor (gamma delta TCR) expression alone does not reliably mark commitment of early thymic progenitors to the gamma delta fate. This raises the possibility that the gamma delta TCR is unable to intrinsically specify fate and instead requires additional environmental factors, including TCR-ligand engagement. We use single cell progenitor assays to reveal that ligand acts instructionally to direct adoption of the gamma delta fate. Moreover, we identify CD73 as a TCR ligand-induced cell surface protein that distinguishes gamma delta TCR-expressing CD4(-)CD8 -progenitors that have committed to the gamma delta fate from those that have not yet done so. Indeed, unlike CD73(-)gamma delta TCR+ progenitors, which largely adopt the alpha beta fate upon separation from the intrathymic selecting environment, those that express CD73 remain CD4(-)CD8(-) and committed to the gamma delta fate. CD73 is expressed by > 90% of peripheral gamma delta cells, suggesting this is a common occurrence during development. Moreover, CD73 induction appears to mark a metastable intermediate stage before acquisition of effector function, suggesting that gamma delta lineage and effector fate are specified sequentially. These findings have important implications for the role of ligand in gamma delta lineage commitment and its relationship to the specification of effector fate.