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

Abstract

TCR signal strength instructs αβ versus γδ lineage decision in immature T cells. Increased signal strength of γδTCR with respect to pre-TCR results in induction of the γδ 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 αβ/γδ lineage bifurcation checkpoint. We show that P2X7 expression was selectively increased in immature γδ+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 γδTCR-expressing thymocytes toward the αβ lineage fate. The impairment of the ERK-Egr-inhibitor of differentiation 3 (Id3) signaling pathway in γδ cells from p2rx7−/− mice resulted in increased representation of the Id3-independent NK1.1-expressing γδ T cell subset in the periphery. Our results indicate that ATP release and P2X7 signaling upon γδTCR 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 γδ T cell compartment.

Noncanonical Mode of ERK Action Controls Alternative αβ and γδ T Cell Lineage Fates

“…The duration of ERK signals has also been linked to the extent of heterodimerization of upstream signaling molecules, MEK1 and MEK2 (Catalanotti et al, 2009). Finally, pharmacologic inhibition of P2X7 (ATP-gated nonselective cationic receptor) has been reported to impair ERK activation, blunt Egr1 induction, and divert γδ T cell progenitors to the αβ T lineage fate (Frascoli et al, 2012). How these regulators of ERK signaling might modulate ERK signals in the context of αβ versus γδ lineage commitment process remains unclear.…”

The ectonucleotidases CD39 and CD73: Novel checkpoint inhibitor targets

“…Yet, studies in CD73‐deficient mice suggest that CD73 is dispensable for γδ T‐cell development, but may play a role in their regulatory functions . In contrast, TCR‐dependent ATP release and autocrine stimulation of P2X7R on immature thymocytes was shown to promote γδ T‐cell development …”

P2X7 receptor activation induces reactive oxygen species formation in erythroid cells

“…Studies of P2X7-deficient mice suggest that the P2X7 is not involved in regulating cell numbers under normal, physiological conditions [50,51], except in bone homeostasis [52] and the peripheral T cell compartment [53]. Nevertheless P2X7-induced apoptosis remains a well-described event [2,3].…”