Purinergic P2X7 receptor drives T cell lineage choice and shapes peripheral γδ cells.
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 Ca(2+) 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.
Institute for Research in Biomedicine, CH-6500 Bellinzona, Switzerland.
Michela
M
Frascoli
Jessica
J
Marcandalli
Ursula
U
Schenk
Fabio
F
Grassi
D000255:Adenosine Triphosphate / Q000378:metabolism / Q000502:physiology; D000818:Animals; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D058486:Receptors, Purinergic P2X7 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*
D016692:Receptors, Antigen, T-Cell, gamma-delta; D058486:Receptors, Purinergic P2X7; D000255:Adenosine Triphosphate