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Adenoviral Transduction of Naive CD4 T Cells to Study Treg Differentiation
Published on: August 13, 2013
VNUT-mediated ATP release suppresses T helper 1 (TH1) cell differentiation via the P2X7R-JNK-FOXO3a-Eomes signaling
Bolong Wu1,2, Linlin Sheng1,2, Ziyi Feng1,2
1State Key Laboratory of Membrane Biology, School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Tsinghua University, 100084 Beijing, China.
Abstract:
Extracellular ATP (eATP), a well-recognized danger signal and immune activator, is implicated in the activation, differentiation, and function of T cells, directly or indirectly. Yet, how T cells release ATP themselves and its effects remain poorly investigated. Here, we found vesicular nucleotide transporter (VNUT), critical for vesicular ATP storage/release, is highly expressed in TH1 cells and selectively restricts their differentiation and effector functions. Mechanistically, VNUT facilitates lysosomal ATP import and its extracellular release upon T cell receptor engagement. This eATP then activates the purinergic receptor P2X7R and downstream SRC kinase, triggering a signaling cascade involving heightened Ca2+ influx and hyperphosphorylation of JNK and FOXO3a, which ultimately impairs Eomes-directed IFN-γ production in TH1 cells. Genetic/pharmacological of VNUT inhibition significantly potentiates TH1 effector functions against Listeria infection and transplanted tumors. These findings identify VNUT as a critical checkpoint in limiting TH1 immunity, coupling vesicular ATP transport to transcriptional control via the P2X7R-JNK-FOXO3a-Eomes axis, offering a target for treating infection and cancer.
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