Purinergic P2X7 Receptor Drives T Cell Lineage Choice and Shapes Peripheral γδ Cells

TCR signal strength instructs alpha beta versus gamma delta lineage decision in immature T cells. Increased signal strength of gamma delta TCR with respect to pre-TCR results in induction of the gamma delta differentiation program. Extracellular ATP evokes physiological responses through purinergic P2 receptors expressed in the plasma membrane of virtually all cell types. In peripheral T cells, ATP released upon TCR stimulation enhances MAPK activation through P2X receptors. We investigated whether extracellular ATP and P2X receptors signaling tuned TCR signaling at the alpha beta/gamma delta lineage bifurcation checkpoint. We show that P2X7 expression was selectively increased in immature gamma delta(+)CD25(+) cells. These cells were much more competent to release ATP than pre-TCR-expressing cells following TCR stimulation and Ca2+ influx. Genetic ablation as well as pharmacological antagonism of P2X7 resulted in impaired ERK phosphorylation, reduction of early growth response (Egr) transcripts induction, and diversion of gamma delta TCR-expressing thymocytes toward the alpha beta lineage fate. The impairment of the ERK-Egr-inhibitor of differentiation 3 (Id3) signaling pathway in gamma delta cells from p2rx7(-/-) mice resulted in increased representation of the Id3-independent NK1.1-expressing gamma delta T cell subset in the periphery. Our results indicate that ATP release and P2X7 signaling upon gamma delta TCR expression in immature thymocytes constitutes an important costimulus in T cell lineage choice through the ERK-Egr-Id3 signaling pathway and contributes to shaping the peripheral gamma delta T cell compartment. The Journal of Immunology, 2012, 189: 174-180.